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Blood Disorders: Common Anemias

Date Prepared: April 2007

S. Rutledge Harding, MD, FRCPC

Anemia is typically defined as a hemoglobin (Hgb) value that is two standard deviations below the mean, according
to sex, age and, sometimes, race. This defines the lower limit of the normal range provided by most clinical
laboratories with their patient reports. Recently, arguments have been advanced to establish optimal rather than
1
statistical lower limits of Hgb, especially in older adults, based on morbidity and mortality data. Optimal Hgb
concentrations were found to be 130 g/L in elderly women and 140 g/L in elderly men.

Goals of Therapy

Alleviate the signs and symptoms of anemia


Determine and address the underlying cause(s) of the anemia
Restore normal or adequate Hgb level
improve quality of life2
3
possibly prolong survival
Avoid allogeneic red cell transfusion

Investigations

Signs and symptoms of anemia occur when the oxygen-carrying capacity of the blood is unable to meet the
1
oxygen requirements of body tissues (Figure 1 - Evaluation of Anemia).
Identify the underlying cause of anemia. Underlying cause(s) may include medications (cytotoxic agents,
antiretrovirals, ribavirin, folate antagonists, etc.), alcohol use, diet (vegans are at particular risk for vitamin B12
deficiency), gastrointestinal complaints (blood loss, malabsorption, gastric or terminal ileal surgery),
menorrhagia history, cancer, impaired kidney/liver/thyroid function and chronic inflammation. Seek signs and
symptoms that point to the etiology of the anemia (e.g., glossitis and koilonychia in iron deficiency, paresthesia
in B12 deficiency).
Diagnostic algorithms are given as guidelines in Figure 2 - Diagnostic Algorithm for Microcytic Anemia, Figure 3
- Diagnostic Algorithm for Normocytic Anemia and Figure 4 - Diagnostic Algorithm for Macrocytic Anemia,
based on the traditional classification of anemia according to red cell size, as reflected in the mean cell volume
(MCV).4
The serum folate level is prone to short-term fluctuations and may be misleading. The red blood cell (RBC)
folate level reflects time-averaged folate availability and is a more reliable indicator of tissue folate adequacy.5
There is significant intra- and inter-individual variation in serum cobalamin levels, so patients with macrocytosis
6
and borderline (as defined by the local laboratory) cobalamin levels need further assessment. Cobalamin levels
drop during pregnancy without other evidence of deficiency.7

Iron-deficiency Anemia

Nonpharmacologic Choices
Pharmacologic Choices
Therapeutic Tips

Nonpharmacologic Choices

Dietary iron, especially from foods rich in heme iron (i.e., liver; lean red meats; seafood such as oyster, clams,
tuna, salmon, sardines and shrimp), can contribute to the treatment of iron deficiency anemia, but works more
slowly than pharmacologic replacement therapy,8 and may not be sufficient in the face of more severe or persistent
causes of iron deficiency.

Vitamin C enhances the absorption of iron but the effect is small. Consumption of foods that are good sources of
vitamin C has a minimal impact on the therapy of iron deficiency anemia.

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Therapeutic Choice

Pharmacologic Choices (Table 1)

Simple oral iron salts are the mainstay of iron supplementation therapy in most circumstances of iron
deficiency anemia.
a variety of salts are available, with differing amounts of elemental iron per tablet; however, the gut is
limited in its ability to absorb iron and such differences have little effect on the outcome of replacement
therapy
the usual target dose is 105-200 mg/day of elemental iron, in divided doses
Parenteral iron is reserved for patients with malabsorption or true intolerance to oral iron therapy, or where
ongoing losses exceed the capacity of the gut to absorb oral iron. Although newer formulations are somewhat
9
safer and better tolerated than older preparations, anaphylaxis remains a risk.
in those who can tolerate and absorb oral iron salts, the use of parenteral iron does not lead to a more
rapid resolution of anemia

Therapeutic Tips

Search for the cause of iron deficiency, including very careful consideration of occult gastrointestinal bleeding
(see Suggested Readings). Menorrhagia must be convincing before it is accepted as the sole cause of iron
10
deficiency. This may be an opportunity for early recognition of a gastrointestinal malignancy—don’t miss it!
A reticulocyte response should be evident within one week of beginning iron therapy, with subsequent
improvement in the Hgb of about 10 g/L every 7–10 days.
If the Hgb fails to respond as anticipated, consider that there may be:
ongoing blood loss
use of other medications that impair iron absorption (Table 1)
a different or concurrent cause of anemia and/or an impaired erythropoietic response
compliance issues
Gastrointestinal side effects are the most common reasons for non-compliance:
use a graduated approach to dosing. Begin with a single tablet taken after a meal. On a weekly basis, as
tolerance permits, add another tablet until the patient is taking one dose with each meal. Thereafter,
gradually shift the timing of the doses to the beginning of meals
small oral doses may be adequate in patients that are susceptible to gastrointestinal upset.
In the elderly, daily doses of elemental iron as low as 15 to 50 mg are effective in the treatment of iron
deficiency anemia9
In pregnant women, 20 mg/day of elemental iron, started at 20 weeks' gestation, is sufficient to prevent
11
iron deficiency
iron contained in enteric-coated tablets is poorly absorbed. These products should be avoided
Some physicians replenish iron stores while others prefer to stop therapy when the Hgb normalizes, so that
further blood loss will not be masked by robust iron stores. As a compromise:
completely replenish iron stores when the cause of iron deficiency has been identified and corrected
do not replenish iron stores when investigation has failed to identify the cause of the iron deficiency.
Recurrence of anemia flags the need and provides the opportunity for further investigation.

Megaloblastic Anemia

Nonpharmacologic Choices
Pharmacologic Choices
Therapeutic Tips

Megaloblastic anemias arise because of impaired DNA synthesis from deficiencies of cobalamin (vitamin B12) or folic
acid (folate). Other causes of impaired DNA and RNA metabolism (i.e., drugs, myelodysplasia) produce similar
hematologic findings.

Cobalamin deficiency may also lead to subacute combined degeneration of the spinal cord. Folate may partially
alleviate and mask the hematologic effects of cobalamin deficiency, but does nothing to slow the progression of the
neurologic lesion.

Systemic symptoms of megaloblastosis may be subtle in older adults and may precede the development of anemia.
12
A high index of suspicion is warranted.

Cobalamin (Vitamin B12) Deficiency


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Meat and dairy products are the only dietary sources of cobalamin. The typical Canadian diet exceeds the daily
requirement, provided that absorption is normal.
Cobalamin stores are usually sufficient to last several years.
Strict vegans are at risk of deficiency unless they take cobalamin supplements. Vegetarians may be at risk of
deficiency during times of high demand, such as pregnancy.
The most common cause of cobalamin deficiency is malabsorption due to pernicious anemia, gastrectomy,
gastritis, ileal resection, Crohn’s disease, blind loops, pancreatic insufficiency and certain drugs (i.e., neomycin,
metformin, proton pump inhibitors). Some patients have trouble absorbing cobalamin from food but are able to
absorb pharmaceutical cobalamin.

Folic Acid Deficiency

Dietary deficiency and alcoholism are the most common causes of folate deficiency.
Although folate is plentiful in a variety of foods (i.e., leafy green vegetables, liver, legumes) it is labile and
easily destroyed by exposure to light and during cooking.
Alcohol inhibits folate absorption and interferes with its enterohepatic cycle.
Folate deficiency can develop within a few months of adopting a folate-deficient diet and even more quickly in
the setting of increased alcohol intake.
Increased folate requirements are seen in pregnancy, hemolytic anemia and therapy with certain drugs (i.e.,
methotrexate, phenytoin, trimethoprim).

Nonpharmacologic Choices

Restoring normal dietary intake of cobalamin and folate may be sufficient to completely reverse megaloblastosis.
However, patients with neurologic deficits due to cobalamin deficiency should be treated pharmacologically to
maximize the likelihood of full neurologic recovery.

Abstinence from alcohol may be necessary.

Pharmacologic Choices (Table 1)

Cobalamin (Vitamin B12)

Cobalamin deficiency is treated with either cyanocobalamin or hydroxocobalamin (hydroxycobalamin).


The daily requirement is 6–9 µg. Doses greater than 100 µg/day exceed the physiologic binding capacity, but
the excess is not toxic and is readily excreted by the kidneys. For this reason there is a tendency to give more
rather than less cobalamin, especially in patients with neurologic deficits.
Cobalamin has traditionally been given parenterally because deficiency is most often due to malabsorption, and
most cases of malabsorption are attributable to pernicious anemia with its lack of intrinsic factor.
13 14 , 15 16
High-dose oral cobalamin therapy is effective, feasible and cost-effective, but concerns about patient
17
compliance and the need for more attentive monitoring limit adoption of this approach in North America.
As a compromise:
administer parenteral cobalamin until all neurologic and hematologic findings resolve
provide maintenance therapy by the route that best fits the patient’s circumstances.
Where dietary deficiency is clearly the cause of the cobalamin deficiency and the patient has no neurologic
deficits, oral supplementation is adequate.

Folic Acid

Prophylaxis with folate before and during pregnancy is strongly recommended for the prevention of neural tube
defects. (See Endocrine and Metabolic Disorders: Nutritional Supplements for Adults for specific dosing
recommendations.)
Otherwise, folate should be given only for confirmed folate deficiency or in situations of increased demand,
such as hemolysis.
The oral route is sufficient to correct folate deficiency, even in patients with malabsorption syndromes.

Therapeutic Tips

A reticulocyte response should be evident within three to four days of beginning therapy, with improvement in
the Hgb level by about day ten. Full resolution of the anemia should occur within about two months.

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Therapeutic Choice
The rapid production of new hematopoietic cells leads to a potentially dramatic shift of potassium from
extracellular to intracellular compartments, which may cause profound hypokalemia.
monitor potassium carefully in the first few days of therapy; consider early and generous potassium
supplementation
older patients on diuretic therapy for heart failure are at particular risk
If the Hgb fails to respond as anticipated, consider that there may be:
a different or concurrent cause of anemia and/or an impaired erythropoietic response
concomitant iron deficiency may show itself with an MCV that shifts from the macrocytic to the
microcytic range
compliance issues, particularly in patients using oral supplements
Neurologic deficits may take six months or more to resolve; if severe, some deficits may persist.

Anemias Responsive to Pharmacologic Stimulation of Erythropoiesis

Investigations
Pharmacologic Choices
Therapeutic Tips

Most patients with nutritional anemias, hemolysis or bleeding have elevated levels of endogenous erythropoietin.
There are, however, a number of situations in which pharmacologic stimulation of red cell production is beneficial
including:

Chronic renal failure


18
HIV-infected patients receiving antiretroviral therapy
19
Chronic hepatitis C patients receiving ribavirin
Patients receiving chemotherapy for non-hematologic cancers20 , 21
20
Surgery patients
22
Low-risk myelodysplasia
23 , 24
Other clinical applications are beyond the scope of this discussion.

Investigations

Selection of patients is determined in part by baseline endogenous erythropoietin levels (approximately 3–30 IU/L in
healthy individuals).

For example:

A zidovudine-treated HIV patient is unlikely to respond if the baseline erythropoietin level is > 500 IU/L
A chemotherapy-treated cancer patient is unlikely to respond if the baseline erythropoietin level is > 200 IU/L
It is important to ensure an adequate iron supply in conjunction with erythropoietic stimulation.

Pharmacologic Choices (Table 2)

The choice of agent and dosage regimen varies according to the clinical situation. Both available agents may be
given by intravenous or subcutaneous injection. Epoetin alfa is a recombinant human erythropoietin with a
relatively short half-life that is typically given at least three times per week; daily in some circumstances.
Darbepoetin alfa is a synthetic erythropoietin analogue with a longer half-life that is typically given weekly or
biweekly, and monthly in some patients.

Therapeutic Tips

Erythropoietins have significant potential for toxicity and adverse consequences so they should be used
judiciously in patients who would otherwise require transfusion support.
Doses are titrated to achieve a gradual improvement in anemia, without overshooting the target Hgb.
25 , 26 , 27
in patients with renal failure, higher Hgb targets are not associated with better outcomes
survival was worse in patients treated to higher Hgb targets ( > 120 g/L) with erythropoietin as compared
with placebo in patients with head and neck cancer28 and those with breast cancer29

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Rapid and/or excessive correction of anemia may provoke hypertension and seizures in susceptible individuals;
erythrocytosis may predispose patients to thrombotic complications. Monitor blood pressure three times per
week initially, and after each dose thereafter.
Erythropoietins have been associated with the development of pure red cell aplasia (PRCA), a
potentially devastating complication in which neutralizing antibodies to the exogenous protein
cross-react with endogenous erythropoietin, resulting in profound anemia. Changes in the
formulation and handling of these proteins have greatly reduced the risk of PRCA.3 Nevertheless,
PRCA should be considered if a patient becomes refractory to therapy. Useful Info?

Figure 1-Evaluation of Anemia

Signs and symptoms of anemia occur when the oxygen-carrying capacity of the blood is unable to meet the oxygen
requirements of body tissues. Modified from Semin Oncol, Volume 25 (Suppl 7), Ludwig H, Fritz, E. Anemia in cancer patients,
pages 2–6, Copyright 1998, with permission from Elsevier Inc.

Figure 2-Diagnostic Algorithm for Microcytic Anemia

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Adapted with permission from: Tefferi A, Hanson DA, Inwards DJ. How to interpret and pursue an abnormal complete blood cell
count in adults. Mayo Clin Proc. 2005;80:923-936

Figure 3-Diagnostic Algorithm for Normocytic Anemia

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Abbreviations: AIHA = autoimmune hemolytic anemia; DIC = disseminated intravascular coagulation; SH = hereditary
spherocytosis; PBS = peripheral blood smear;
TTP/HUS = thrombotic thrombocytopenic purpura/hemolytic uremic syndrome

Adapted with permission from: Tefferi A, Hanson DA, Inwards DJ. How to interpret and pursue an abnormal complete blood cell
count in adults. Mayo Clin Proc. 2005;80:923-936

Figure 4-Diagnostic Algorithm for Macrocytic Anemia

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Abbreviations: MCV = mean cell volume; MDS = myelodysplastic syndrome

Adapted with permission from: Tefferi A, Hanson DA, Inwards DJ. How to interpret and pursue an abnormal
complete blood cell count in adults. Mayo Clin Proc. 2005;80:923-936

Table 1: Drugs for the Treatment of Iron-deficiency and Megaloblastic Anemias

Costa
Class Drug Dose Adverse Effects Comments

Iron ferrous fumarate 105–200 mg Gastrointestinal: There is no evidence that $


Supplements, Palafer, generics elemental iron nausea, dyspepsia, one preparation is more
oral (Fe) daily in three constipation and/or effective than another.
divided doses diarrhea. Avoid enteric-coated
preparations.

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Therapeutic Choice
a
Cost
Class Drug Dose Adverse Effects Comments
(100 mg Ameliorated by step-
elemental Fe/300 wise initiation of Vitamin C enhances
mg ferrous therapy (see text). absorption, but the effect is
fumarate) minimal and may aggravate
GI upset (not routinely
recommended).

Absorption is ↓ by food and


certain drugs: antacids,
calcium carbonate,
cholestyramine, levodopa,
methyldopa, penicillamine,
quinolones, sodium
bicarbonate, tetracyclines.
Separate administration by ~
2 hours.

Efficacy is delayed by
concomitant use of vitamin
E.

Iron ferrous gluconate 105–200 mg Gastrointestinal: There is no evidence that $


Supplements, generics elemental iron nausea, dyspepsia, one preparation is more
oral daily in three constipation and/or effective than another.
divided doses diarrhea. Avoid enteric-coated
(35 mg elemental Ameliorated by step- preparations.
Fe/300 mg wise initiation of
ferrous therapy (see text). Vitamin C enhances
gluconate) absorption, but the effect is
minimal and may aggravate
GI upset (not routinely
recommended).

Absorption is ↓ by food and


certain drugs: antacids,
calcium carbonate,
cholestyramine, levodopa,
methyldopa, penicillamine,
quinolones, sodium
bicarbonate, tetracyclines.
Separate administration by ~
2 hours.

Efficacy is delayed by
concomitant use of vitamin
E.

Iron ferrous sulfate 105–200 mg Gastrointestinal: There is no evidence that $


Supplements, Fer-In-Sol, elemental iron nausea, dyspepsia, one preparation is more
oral generics daily in three constipation and/or effective than another.
divided doses diarrhea. Avoid enteric-coated
(60 mg elemental Ameliorated by step- preparations.
Fe/300 mg wise initiation of
ferrous sulfate) therapy (see text). Vitamin C enhances
absorption, but the effect is
minimal and may aggravate
GI upset (not routinely
recommended).

Absorption is ↓ by food and


certain drugs: antacids,

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Therapeutic Choice
a
Cost
Class Drug Dose Adverse Effects Comments
calcium carbonate,
cholestyramine, levodopa,
methyldopa, penicillamine,
quinolones, sodium
bicarbonate, tetracyclines.
Separate administration by ~
2 hours.

Efficacy is delayed by
concomitant use of vitamin
E.

Iron polysaccharide- 105–200 mg Gastrointestinal: There is no evidence that $$


Supplements, iron complex elemental iron nausea, dyspepsia, one preparation is more
oral Triferexx daily in three constipation and/or effective than another.
divided doses diarrhea. Avoid enteric-coated
(150 mg Ameliorated by step- preparations.
elemental Fe/150 wise initiation of
mg therapy (see text). Vitamin C enhances
polysaccharide absorption, but the effect is
iron complex) minimal and may aggravate
GI upset (not routinely
recommended).

Absorption is ↓ by food and


certain drugs: antacids,
calcium carbonate,
cholestyramine, levodopa,
methyldopa, penicillamine,
quinolones, sodium
bicarbonate, tetracyclines.
Separate administration by ~
2 hours.

Efficacy is delayed by
concomitant use of vitamin
E.

Iron iron dextran Total dose Anaphylaxis (rare). Consult prescribing $$$$
Supplements, DexIron, Infufer infusion: Anaphylactoid information for dose
parenteral iv dose calculated reactions, calculation, dilution and
to restore iron hypotension (avoid administration details.
deficit in red cell rapid iv infusion). 0.9% NaCl is the preferred
mass and iron vehicle. D5W causes more
stores. Fever, chills, local irritation and phlebitis.
headache, myalgia,
In chronic dialysis arthralgia, urticaria, Give a 25 mg test dose one
patients: dizziness. May have h before the initial dose,
delayed onset, 24– with epinephrine available.
100 mg iv 1–3 48 hours after iv
×/wk for 10 infusion and 3–4 Side effects are more
doses or until days after im common with larger doses
replete; adjust as administration. and in underweight patients.
able to maintain
adequate iron
availability

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Therapeutic Choice

Costa
Class Drug Dose Adverse Effects Comments

Iron sodium ferric Chronic dialysis Anaphylaxis (rare). Test doses are no longer $$$$
Supplements, gluconate patients: Anaphylactoid recommended by the
parenteral Ferrlecit 125 mg iv 1–3 reactions, manufacturer.
×/wk × 8 doses; hypotension (avoid Incidence of life-threatening
adjust as able to rapid iv infusion). adverse effects is lower than
maintain with iron dextran.
adequate iron Fever, chills,
availability headache, myalgia,
arthralgia, urticaria,
dizziness. May have
delayed onset, 24–
48 hours after iv
infusion and 3–4
days after im
administration.

Iron iron sucrose Chronic dialysis Anaphylaxis (rare). Test doses are not $$$$
Supplements, Venofer patients: Anaphylactoid recommended by the
parenteral 100 mg iv 1–3 reactions, manufacturer.
×/wk until hypotension (avoid Lowest incidence of life-
replete; adjust as rapid iv infusion). threatening adverse effects
able to maintain among iv iron preparations.
adequate iron Fever, chills,
availability headache, myalgia,
arthralgia, urticaria,
dizziness. May have
delayed onset, 24–
48 hours after iv
infusion and 3–4
days after im
administration.

Vitamins cobalamin Pernicious Occasional Oral absorption is ↓ by $


(vitamin B12) anemia/other peripheral vascular anticonvulsants, colchicine,
chronic thrombosis, rash, metformin, neomycin and
malabsorption pruritus, headache, omeprazole.
disorders: 100 µg nausea and Consider generous
sc/im daily × 1 vomiting, diarrhea. potassium supplementation
wk; 200 µg Occasional heart with initiation of therapy.
sc/im/wk until failure.
Hgb normalizes Folate supplementation may
Life-long Possibility of mask hematologic findings
maintenance: profound of B12 deficiency, without
200 µg sc/im hypokalemia due to halting progression of the
monthly or 1000– intracellular neurologic deficits.
2000 µg po daily potassium shift.

Vitamins cyanocobalamin Pernicious Occasional Oral absorption is ↓ by $


generics anemia/other peripheral vascular anticonvulsants, colchicine,
chronic thrombosis, rash, metformin, neomycin and
malabsorption pruritus, headache, omeprazole.
disorders: 100 µg nausea and Consider generous
sc/im daily × 1 vomiting, diarrhea. potassium supplementation
wk; 200 µg Occasional heart with initiation of therapy.
sc/im/wk until failure.
Hgb normalizes Folate supplementation may
Life-long Possibility of mask hematologic findings
maintenance: profound of B12 deficiency, without

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Therapeutic Choice
a
Cost
Class Drug Dose Adverse Effects Comments
200 µg sc/im hypokalemia due to halting progression of the
monthly or 1000– intracellular neurologic deficits.
2000 µg po daily potassium shift.
Cobalamin has traditionally
been given parenterally
because deficiency is most
often due to malabsorption,
and most cases of
malabsorption are
attributable to pernicious
anemia with its lack of
intrinsic factor. High-dose
oral cobalamin therapy is
effective, feasible and cost-
effective, but concerns about
patient compliance and the
need for more attentive
monitoring limit adoption of
this approach in North
America.

Vitamins hydroxocobalamin Pernicious Occasional Oral absorption is ↓ by $


generics anemia/other peripheral vascular anticonvulsants, colchicine,
chronic thrombosis, rash, metformin, neomycin and
malabsorption pruritus, headache, omeprazole.
disorders: 100 µg nausea and Consider generous
sc/im daily × 1 vomiting, diarrhea. potassium supplementation
wk; 200 µg Occasional heart with initiation of therapy.
sc/im/wk until failure.
Hgb normalizes Folate supplementation may
Life-long Possibility of mask hematologic findings
maintenance: profound of B12 deficiency, without
200 µg sc/im hypokalemia due to halting progression of the
monthly or 1000– intracellular neurologic deficits.
2000 µg po daily potassium shift.

Vitamins folic acid (folate) 1 mg po daily Occasional allergic Available for iv use in $
generics reactions—rash, patients who are fasting.
pruritus, flushing,
bronchospasm.

a.
Cost of 30-day supply; includes drug cost only.

Legend: $ < $10 $$ $10–20 $$$ $20–250 $$$$ > $250

Table 2: Erythropoiesis-Stimulating Drugs

Class Drug Dose Adverse Effects Comments Cost

Erythropoietics epoetin alfa Chronic renal Hypertension, Usually given by sc $150/10 000 IU
a failure headache, seizures, injection. May be given
Eprex Initial: 50–100 thrombosis, iv if access already
IU/kg sc/iv 3×/wk, nausea, vomiting, established.
then: ↑ 25% Q4–8 diarrhea, Do not exceed target
wk to max 300 arthralgia, chest Hgb.
IU/kg/dose to pain, edema,
achieve Hgb of 120 cough. If no response to the
g/L Increases risk of maximum dose after 8
deep venous wk, discontinue.
thrombosis and

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Therapeutic Choice

Class Drug Dose Adverse Effects Comments Cost


As Hgb approaches other thrombotic If Hgb ↑ by more than
120 g/L, ↓ dose by complications in 10 g/L/2 wk, ↓ dose by
25% spine surgery 25%. Target Hgb ≤ 120 g/L.
patients. If no response to the
maximum dose after 8
HIV, on Pure red cell wk, discontinue.
antiretrovirals aplasia (rare)
(endogenous In patients with renal
erythropoietin failure, achievement of
level ≤ 500 higher Hgb targets is not
IU/L) associated with better
Initial: 100 IU/kg outcomes. Survival was
sc/iv 3×/wk, then: worse in patients treated
↑ by 50 IU/kg/dose Q4 to higher Hgb targets
–8wk to max 300 ( > 120 g/L) with
IU/kg/dose. erythropoietin as
compared with placebo
in patients with head
Cancer and neck cancer and in
chemotherapy those with breast
(endogenous cancer.
erythropoietin
level ≤ 200
IU/L)
Initial: 50 IU/kg
sc/iv 3×/wk, or
40 000 IU sc/iv
Qwk, then: ↑ by 50
IU/kg/dose Q8wk to
max 300
IU/kg/dose.

Chronic hepatitis
C, on ribavirin
40 000 IU sc/iv
weekly

Surgery
600 IU/kg sc/iv 21,
14 and 7 days
before surgery and
then on the day of
surgery

Erythropoietics darbepoetin Chronic renal Hypertension, May be able to shift to $283/ 100 µg
a failure hypotension, biweekly or monthly
alfa
Aranesp 0.45 µg/kg sc/iv headache, dosing in some patients.
Qwk, then: ↑ by thrombosis, Target Hgb ≤ 120 g/L
25% monthly if no nausea, vomiting, with ↑ limited to 10 g/L per
response. ↓ by 25% diarrhea, 2 wk.
as Hgb approaches constipation,
120 g/L arthralgia, myalgia, If excessive response, ↓
chest pain, dose by 40%. If still
arrhythmia, edema, excessive, hold dose until
Cancer dyspnea, cough. Hgb falls.
chemotherapy
(endogenous
erythropoietin
level ≤ 200
IU/L)

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Therapeutic Choice

Class Drug Dose Adverse Effects Comments Cost


2.25 µg/kg sc/iv
Qwk

If inadequate
response after 6
wk, ↑ to 4.5 µg/kg
sc/iv Qwk.

a.
Use the lowest dose that will gradually increase the Hgb concentration to the lowest level sufficient to avoid blood transfusions
(FDA update, Mar 9, 2007). Dosing recommendations are to be reassessed by the FDA Oncologic Drugs Advisory committee.

Suggested Readings

Kwong JC, Carr D, Dhalla IA et al. Oral vitamin B12 therapy in the primary care setting: a qualitative and
quantitative study of patient perspectives. BMC Fam Pract 2005;6(1):8.

Macdougall IC, Eckardt KU. Novel strategies for stimulating erythropoiesis and potential new treatments for
anaemia. Lancet 2006;368(9539):947-53.

Manning-Dimmitt LL, Dimmitt SG, Wilson GR. Diagnosis of gastrointestinal bleeding in adults. Am Fam Physician
2005;71(7):1339-46.

Nilsson M, Norberg B, Hultdin J et al. Medical intelligence in Sweden. Vitamin B12: oral compared with parenteral?
Postgrad Med J 2005;81(953):191-3.

Tefferi A, Hanson CA, Inwards DJ. How to interpret and pursue an abnormal complete blood cell count in adults.
Mayo Clin Proc 2005;80(7):923-36.

References

1. Culleton BF, Manns BJ, Zhang J et al. Impact of anemia on hospitalization and mortality in older adults. Blood
2006;107(10):3841-6.
2. Ross SD, Fahrbach K, Frame D et al. The effect of anemia treatment on selected health-related quality-of-life
domains: a systematic review. Clin Ther 2003;25(6):1786-805.
3. Macdougall IC, Eckardt KU. Novel strategies for stimulating erythropoiesis and potential new treatments for
anaemia. Lancet 2006;368(9539):947-53.
4. Tefferi A, Hanson CA, Inwards DJ. How to interpret and pursue an abnormal complete blood cell count in
adults. Mayo Clin Proc 2005;80(7):923-36.
5. Galloway M, Rushworth L. Red cell or serum folate? Results from the National Pathology Alliance
benchmarking review. J Clin Pathol 2003;56(12):924-6.
6. Solomon LR. Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin,
methylmalonic acid, and homocysteine testing. Blood 2005;105(3):978-85.
7. Metz J, McGrath K, Bennett M et al. Biochemical indices of vitamin B12 nutrition in pregnant patients with
subnormal serum vitamin B12 levels. Am J Hematol 1995;48(4):251-5.
8. Patterson AJ, Brown WJ, Roberts DC et al. Dietary treatment of iron deficiency in women of childbearing age.
Am J Clin Nutr 2001;74(5):650-6.
9. Rimon E, Kagansky N, Kagansky M et al. Are we giving too much iron? Low-dose iron therapy is effective in
octogenarians. Am J Med 2005;118(10):1142-7.
10. Green BT, Rockey DC. Gastrointestinal endoscopic evaluation of premenopausal women with iron deficiency
anemia. J Clin Gastroenterol 2004;38(2):104-9.
11. Makrides M, Crowther CA, Gibson RA et al. Efficacy and tolerability of low-dose iron supplements during
pregnancy: a randomized controlled trial. Am J Clin Nutr 2003;78(1):145-53.

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Therapeutic Choice
12. Dharmarajan TS, Adiga GU, Norkus EP. Vitamin B12 deficiency. Recognizing subtle symptoms in older adults.
Geriatrics 2003;58(3):30-4,37-8.
13. Vidal-Alaball J, Butler CC, Cannings-John R et al. Oral vitamin B12 versus intramuscular vitamin B12 for
vitamin B12 deficiency. Cochrane Database Syst Rev 2005;(3):CD004655.
14. Kwong JC, Carr D, Dhalla IA et al. Oral vitamin B12 therapy in the primary care setting: a qualitative and
quantitative study of patient perspectives. BMC Fam Pract 2005;6(1):8.
15. Nilsson M, Norberg B, Hultdin J et al. Medical intelligence in Sweden. Vitamin B12: oral compared with
parenteral? Postgrad Med J 2005;81(953):191-3.
16. van Walraven C, Austin P, Naylor CD. Vitamin B12 injections versus oral supplements. How much money could
be saved by switching from injections to pills? Can Fam Physician 2001;47:79-86.
17. Solomon LR. Oral vitamin B12 therapy: a cautionary note. Blood 2004;103(7):2863.
18. Henry DH, Volberding PA, Leitz G. Epoetin alfa for treatment of anemia in HIV-infected patients: past, present,
and future. J Acquir Immune Defic Syndr 2004;37(2):1221-7.
19. Sherman M, Cohen L, Cooper MA et al. Clinical recommendations for the use of recombinant human
erythropoietin in patients with hepatitis C virus being treated with ribavirin. Can J Gastroenterol 2006;20
(7):479-85.
20. [No authors listed]. Epoetins and darbepoetin alfa in malignant disease. Drug Ther Bull 2004;42(3):21-3.
21. Bokemeyer C, Oechsle K, Hartmann JT. Anaemia in cancer patients: pathophysiology, incidence and treatment.
Eur J Clin Invest 2005;35(Suppl 3):26-31.
22. Rizzo JD, Lichtin AE, Woolf SH et al. Use of epoetin in patients with cancer: evidence-based clinical practice
guidelines of the American Society of Clinical Oncology and the American Society of Hematology. Blood
2002;100(7):2303-20.
23. Corwin HL. The role of erythropoietin therapy in the critically ill. Transfus Med Rev 2006;20(1):27-33.
24. Henry DH, Bowers P, Romano MT et al. Epoetin alfa. Clinical evolution of a pleiotropic cytokine. Arch Intern
Med 2004;164(3):262-76.
25. Drueke TB, Locatelli F, Clyne N et al. Normalization of hemoglobin level in patients with chronic kidney
disease and anemia. N Engl J Med 2006;355(20):2071-84.
26. Phrommintikul A, Haas SJ, Elsik M et al. Mortality and target haemoglobin concentrations in anaemic patients
with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet 2007;369(9559):381-8.
27. Singh AK, Szczech L, Tang KL et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J
Med 2006;355(20):2085-98.
28. Henke M, Laszig R, Rube C et al. Erythropoietin to treat head and neck cancer patients with anaemia
undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003;362(9392):1255-
60.
29. Leyland-Jones B, Semiglazov V, Pawlicki M et al. Maintaining normal hemoglobin levels with epoetin alfa in
mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J
Clin Oncol 2005;23(25):5960-72.
30. Ludwig H, Fritz E. Anemia in cancer patients. Semin Oncol 1998;25(3 Suppl 7):2-6.

Therapeutic Choices. © Canadian Pharmacists Association, 2011. All rights reserved.

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Therapeutic Choice

Print Close

Cancer Chemotherapy Toxicity: Chemotherapy-induced Nausea and Vomiting

Date Prepared: March 2007


Date Revised: September 2009

Lynne Nakashima, PharmD

Goals of Therapy

Prevent or minimize acute (starting within 24 hours of chemotherapy), delayed (starting > 24 hours after
chemotherapy) and anticipatory (starting before chemotherapy as a conditioned response) nausea and vomiting
to help patient adherence with active treatment and to maintain quality of life
Decrease incidence of nausea and vomiting (once it has occurred) and maintain patient comfort1
Prevent complications such as esophageal tears, dehydration, anorexia, malnutrition, weight loss, pathological
bone fractures, metabolic alkalosis, chloride and potassium depletion1

Investigations

A thorough history including:


onset and duration of symptoms
timing of nausea and/or retching and/or vomiting
impact on the patient, e.g., weight loss, asthenia
description of the vomiting episodes
medications the patient is taking
Physical examination with particular attention to:
orthostatic hypotension
abdominal pain, distention, constipation, hemorrhage
neurologic assessment including cranial nerves, vestibular and pupillary function, extrapyramidal signs
Laboratory tests:
electrolytes: BUN, creatinine, sodium, potassium, chloride (to assess hydration status); calcium, albumin
(to assess for hypercalcemia)
drug screening, such as for digoxin if suspected as a cause of nausea and vomiting
Although medication is the most likely cause of nausea and vomiting in a patient receiving chemotherapy, other
potential causes (e.g., fluid/electrolyte abnormalities, bowel obstruction, CNS or hepatic metastases, infections and
radiation therapy) should be ruled out. Other drugs (e.g., opioids, digoxin, antibiotics) may cause or exacerbate
nausea and vomiting so a thorough medication history is essential. Some chemotherapeutic agents are more likely
to cause nausea and vomiting than others (Table 1). Therefore it is important to consider both the emetogenic
potential and the expected pattern of emesis of the chemotherapy regimen when choosing antiemetics.3 , 4 , 5 , 6 , 7

Table 1: Emetogenic Potential of Chemotherapy Agentsa

High (> 60%)

carmustine cytarabine (> 500 mg/m2) lomustine


cisplatin (> 50 mg/m2) dacarbazine mechlorethamine
cyclophosphamide (> 550 mg/m2) dactinomycin (> 1.5 g/m2) streptozocin

Moderate (30–60%)

capecitabine epirubicin methotrexate (dose-dependent)


carboplatin ifosfamide oxaliplatin
daunorubicin irinotecan procarbazine
doxorubicin vinblastine

Low (< 30%)

altretamine (hexamethylmelamine) fludarabine rituximab


amsacrine gemcitabine 6-thioguanine
androgens hydroxyurea tamoxifen
aromatase inhibitors L-asparaginase teniposide

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bevacizumab melphalan thiotepa


bleomycin mercaptopurine topotecan
bortezomib mitomycin trastuzumab
busulfan mitoxantrone vincristine
cetuximab paclitaxel vindesine
chlorambucil pemetrexed vinorelbine
docetaxel progestins
estramustine ralitrexed
estrogens
etoposide
5-fluorouracil

a. Slowing infusion rate of certain chemotherapeutic agents (e.g., cisplatin) may decrease emesis.2

Patient-specific factors such as age less than 50 years, female gender, previous motion sickness or pregnancy-
related nausea and vomiting, limited alcohol use and nausea and vomiting with previous chemotherapy regimens
may predispose the patient to nausea and vomiting; therefore, antiemetic regimens must also be tailored to the
individual patient.

Therapeutic Choices (Figure 1 - Management of Chemotherapy-induced Nausea and


Vomiting (low emetogenic potential))

Nonpharmacologic Choices1 , 8 , 9 , 10

Dietary adjustments
try small, light meals several times daily.
avoid foods high in fat or those with a heavy aroma.
try dry, starchy foods such as crackers.
if unable to tolerate solid foods, try ice chips and small sips of clear liquids.
avoid food preparation because the smell of food cooking often worsens nausea.
Behavioural methods
relaxation techniques may help decrease physiologic arousal and anxiety.
individualized exercise programs may help decrease anxiety and depression.
systemic desensitization may be helpful for anticipatory nausea and vomiting.
Other
keep movement to a minimum; rest in bed or a chair to avoid vestibular stimulation.
acupuncture and acupressure have been shown to have some effect on chemotherapy-induced emesis.11
sleep has been shown to protect against chemotherapy-induced nausea and vomiting.12

Pharmacologic Choices (Figure 1 - Management of Chemotherapy-induced Nausea and


Vomiting (low emetogenic potential), Table 2)

Phenothiazines

The most commonly used is prochlorperazine. Considered moderately effective, it is usually used in low
emetogenic regimens or as rescue medication.3 , 13 The availability of a wide variety of dosage forms (tablet,
suppository, injectable) facilitates prochlorperazine use, especially for outpatients.

Metoclopramide

Metoclopramide blocks the dopaminergic receptors in the chemoreceptor trigger zone and has serotonin antagonistic
activity at higher doses. Low doses (10– 20 mg) are generally as effective as prochlorperazine; however, in high
doses (1– 3 mg/kg), metoclopramide provides significantly higher antiemetic activity.3 , 14 When metoclopramide is
compared to serotonin antagonists for acute antiemetic efficacy against highly emetogenic chemotherapy, serotonin
antagonists are superior and have fewer side effects.15 , 16 , 17 , 18 For delayed nausea and vomiting,
metoclopramide plus a corticosteroid are as effective as a serotonin antagonist plus a corticosteroid
and are more cost effective.15,19 A limitation to metoclopramide use is the development of
extrapyramidal side effects. Useful Info?

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Corticosteroids

Dexamethasone is the most commonly used corticosteroid, although several others including
methylprednisolone have been studied.20 The actual mechanism of action is unknown, but the efficacy of
corticosteroids is documented. They appear to be effective as single agents, in combination with other antiemetics
and for delayed nausea and vomiting.20 , 21 Dexamethasone in combination with a serotonin antagonist is the
most effective antiemetic regimen for acute nausea and vomiting.19 , 22 , 23 Dexamethasone alone or in combination
with metoclopramide appears to be the most effective regimen for delayed nausea and vomiting.21 , 24 , 25 , 26
The optimal dose has not been identified; the usual range is from 6 to 60 mg daily.20

Serotonin Antagonists

The serotonin antagonists dolasetron, granisetron and ondansetron are equivalent in efficacy and toxicity.27 , 28
Two newer serotonin antagonists are now available in the US: palonosetron and tropisetron.29 , 30 Single agent
efficacy is reported, but when used in combination with corticosteroids, efficacy is improved. The combination is
recommended for the prevention of acute nausea and vomiting unless the patient has a contraindication to
corticosteroids.22 , 23 Serotonin antagonists plus corticosteroids are no more effective for delayed nausea and
vomiting than metoclopramide plus corticosteroids or corticosteroids alone.24 , 25 These drugs are well tolerated. At
equivalent doses, oral formulations are equally effective and as safe as intravenous.31 The major drawback to their
use is cost. However, because of their superior efficacy, serotonin antagonists should be used for the prophylaxis of
acute nausea and vomiting for moderately and highly emetogenic regimens. Choose serotonin antagonist based on
cost.

Benzodiazepines

Benzodiazepines provide useful antianxiety, amnesic and sedating effects. Lorazepam and alprazolam are the
most commonly used, and have been studied in cases of anticipatory nausea.32 , 33 They are usually used in
combination with other antiemetics.

Butyrophenones

Haloperidol has reported efficacy and is generally used as an alternative to high-dose metoclopramide or
ondansetron in refractory nausea and vomiting.34 , 35

Cannabinoids

Nabilone and dronabinol are of limited use because they are available only as oral formulations and are
associated with several side effects including mood alterations, hallucinations, delusions and increases in heart rate
and blood pressure.3 , 36 , 37 , 38 They are generally used in refractory nausea and vomiting or in combination with
other antiemetics.3 , 36

Dimenhydrinate

An antihistamine useful for treating vomiting due to motion sickness, dimenhydrinate is considered no more
effective than placebo against chemotherapy-induced nausea and vomiting.39

Scopolamine

Available as a transdermal system placed behind the ear, scopolamine can prevent vomiting related to motion
sickness but is generally ineffective in managing nausea and vomiting associated with chemotherapy.39 , 40

Propofol

Propofol is an anesthetic agent with antiemetic properties.5 Several studies suggest that a continuous infusion at
low doses ( 1 mg/kg/hour) is effective in patients with cisplatin-induced nausea and vomiting that is refractory to
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Therapeutic Choice

serotonin antagonists combined with corticosteroids.41 , 42 , 43 Its use is still considered investigational; however,
propofol use may be considered in severe, refractory vomiting. Expertise in administration is required.

Neurokinin-1 Receptor Antagonists

Neurokinin-1 (NK1) receptor antagonists bind to substance P, found in the brainstem and GI tract. Aprepitant is an
oral NK1 receptor antagonist while its pro-drug, fosaprepitant, is used intravenously. When added to a serotonin
antagonist plus dexamethasone regimen for highly emetogenic chemotherapy, it improves prevention of acute and
delayed emesis.44 , 45 Aprepitant is a moderate inhibitor of CYP3A4, and interacts with corticosteroids. Therefore the
dose of dexamethasone as an antiemetic should be decreased. Aprepitant appears to be well tolerated, with
asthenia/fatigue and hiccoughs being the most commonly reported side effects.46

Therapeutic Tips

Prevention of acute nausea and vomiting is the best way to prevent delayed nausea and vomiting.
Use antiemetic therapy to prevent anticipatory nausea and vomiting, which usually worsens with each cycle; up
to 30% of patients refuse further chemotherapy because of intolerable nausea and vomiting.3 , 4
Regularly scheduled and administered antiemetics (i.e., not PRN) are more effective at preventing nausea and
vomiting.
If the patient can tolerate oral antiemetics, this is the recommended route of administration. However, rectally
administered antiemetics such as prochlorperazine are especially useful in patients who are vomiting or unable
to take oral medications and who are at home. For hospitalized patients, the iv route of administration is
recommended in patients who are vomiting.

Figure 1- Management of Chemotherapy-induced Nausea and Vomiting (low emetogenic potential)

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Figure 2- Management of Chemotherapy-induced Nausea and Vomiting (moderate/high emetogenic


potential)

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Table 2: Drugs Used for Chemotherapy-induced Nausea and Vomiting

Costa
Class Drug Dose Adverse Effects Drug Interactions

Benzamides metoclopramide Low: 10–20 mg Sedation (up to 80%), Sedating po:$


generics po Q6H dose-related diarrhea medications. Additive iv:
High: 1–3 mg/kg (up to 45%), sedation occurs with,
po/iv Q3H extrapyramidal effects for example, opioid $$$$$
(3%). analgesics,
hypnotics, alcohol;
avoid or minimize
use if possible.
Anticholinergic
agents antagonize
effects of
metoclopramide on
GI motility.

Benzodiazepines lorazepam Sedation (up to 80%). Sedating $


Ativan, generics 1 mg po/sl pre- medications. Additive
chemo, then 1– sedation occurs with,
4 mg Q4H PRN for example, opioid
analgesics,
hypnotics, alcohol;
avoid or minimize
use if possible.

Butyrophenones haloperidol 1–2 mg po/im Sedation, Sedating $


generics pre-chemo and extrapyramidal effects. medications. Additive
Q8H sedation occurs with,
for example, opioid
analgesics,
hypnotics, alcohol;
avoid or minimize
use if possible.

Cannabinoids nabilone Sedation (4–89%), Sedating $


Cesamet 1 mg po BID dizziness, ataxia (12– medications. Additive
65%), psychotropic sedation occurs with,

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Costa
Class Drug Dose Adverse Effects Drug Interactions

effects (“high”) (27%), for example, opioid


tachycardia (7%), analgesics,
orthostatic hypotension hypnotics, alcohol;
(10%), dry mouth (6– avoid or minimize
62%). use if possible.

Cannabinoids dronabinol Sedation (4–89%), Sedating $b


Marinol 5 mg/m 2 po Q2– dizziness, ataxia (12– medications. Additive
4H 65%), psychotropic sedation occurs with,
Max 6 doses/day. effects (“high”) (27%), for example, opioid
May ↑ by tachycardia (7%), analgesics,
2.5 mg/m2 to orthostatic hypotension hypnotics, alcohol;
max (10%), dry mouth (6– avoid or minimize
62%). use if possible.
10 mg/m2 per
dose

Corticosteroids dexamethasone 4–10 mg po pre- Mood changes, $


Dexasone, generics chemo and Q6– increased appetite, GI
12H irritation, ulceration,
8–20 mg iv pre- fluid retention, weight
chemo and Q6– gain, may mask signs
12H of infection.
In combination
with aprepitant:
Highly
emetogenic
chemotherapy:
12 mg po day 1
then 8 mg po
days 2–4

Moderately
emetogenic
chemotherapy:
12 mg po on first
day only

Corticosteroids methylprednisolone 0.5–1 mg/kg po Mood changes, po:$


Medrol, Solu- or iv pre-chemo increased appetite, GI iv:$$
and Q4 and 8H irritation, ulceration,
Medrol, generics
post-chemo fluid retention, weight
(max 4 mg/kg gain, may mask signs
total dose) of infection.

May also give as


single
4 mg/kg dose 30
min pre-chemo

Neurokinin-1 aprepitant Day 1: 125 mg Asthenia/fatigue, Contraindicated with $$$$$


Receptor Emend po 1 h before diarrhea, dizziness, cisapride, pimozide.
Antagonists chemotherapy dyspepsia, hiccoughs. ↑ levels of drugs
Day 2 & 3: 80 metabolized by
mg po in the CYP3A4 (e.g.,
morning dexamethasone,
midazolam).
Administered in ↓ levels of drugs
combination with metabolized by

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Therapeutic Choice

Costa
Class Drug Dose Adverse Effects Drug Interactions

dexamethasone CYP2C9 (e.g.,


and a serotonin phenytoin,
antagonist tolbutamide,
warfarin).

↑ levels of aprepitant
with CYP3A4
inhibitors (e.g.,
clarithromycin,
ketoconazole).

↓ levels of aprepitant
with CYP3A4
inducers
(carbamazepine,
phenytoin, rifampin).
Possible ↓
effectiveness of oral
contraceptives.

Neurokinin-1 fosaprepitant Day 1: 115 mg iv Asthenia/fatigue, Contraindicated with $$$


Receptor Emend IV 30 min before diarrhea, dizziness, cisapride, pimozide.
Antagonists chemotherapy dyspepsia, hiccoughs. ↑ levels of drugs
Administered in metabolized by
combination with CYP3A4 (e.g.,
dexamethasone dexamethasone,
and a serotonin midazolam).
antagonist ↓ levels of drugs
metabolized by
CYP2C9 (e.g.,
phenytoin,
tolbutamide,
warfarin).

↑ levels of aprepitant
with CYP3A4
inhibitors (e.g.,
clarithromycin,
ketoconazole).

↓ levels of aprepitant
with CYP3A4
inducers
(carbamazepine,
phenytoin, rifampin).
Possible ↓
effectiveness of oral
contraceptives.

Phenothiazines prochlorperazine PO: Sedation, Sedating $


Apo-Prochlorazine, 10 mg Q6–8H anticholinergic effects medications. Additive
other generics PR: 10 mg Q6– (dry mouth, blurred sedation occurs with,
8H vision, constipation, for example, opioid
nasal congestion, analgesics,
IM: 10 mg Q8– urinary retention), hypnotics, alcohol;
12H extrapyramidal effects, avoid or minimize
hypotension, use if possible.
hypersensitivity
(1.4%), rare

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Therapeutic Choice

Costa
Class Drug Dose Adverse Effects Drug Interactions

pancytopenia.

Serotonin dolasetron Headache (6–43%), Potential interaction po:$$


Antagonists Anzemet 1.8 mg/kg iv pre- constipation (4–19%), with other drugs that iv:$
chemo or 100 mg diarrhea (1–16%), prolong QTc
po pre-chemo sedation (4–10%), intervals.
transient ↑ in LFTs (< Blood levels ↑ when
1–19%), bradycardia coadministered with
(4%), dizziness (3%). cimetidine and ↓
ECG interval changes when coadministered
have been reported. with rifampin.

Serotonin granisetron Headache (6–43%), $$


Antagonists Kytril, Apo- 10 µg/kg iv or constipation (4–19%),
Granisetron, other 2 mg po pre- diarrhea (1–16%),
generics chemo or sedation (4–10%),
1 mg pre-chemo transient ↑ in LFTs (<
and 12 h post 1–19%), bradycardia
(4%), dizziness (3%).

Serotonin ondansetron Headache (6–43%), po:$


Antagonists Zofran, generics 8 mg po/iv pre- constipation (4–19%), iv:
chemo diarrhea (1–16%),
In combination sedation (4–10%), $$$$
with aprepitant: transient ↑ in LFTs (<
Highly 1–19%), bradycardia
emetogenic (4%), dizziness (3%).
chemotherapy: Transient ECG changes
32 mg iv pre- have been reported.
chemo

Moderately
emetogenic
chemotherapy:
8 mg po pre-
chemo and 8 h
post

a. Cost of 1-day supply (except 3 days for aprepitant) based on 50 kg body weight; includes drug cost only.
b. Cost for dronabinol based on 5 mg TID.

Dosage adjustment may be required in renal impairment; see Appendices: Dosage Adjustment in Renal Impairment.

Abbreviations: LFTs=liver function tests

Legend: $ < $15 $$ $15–30 $$$ $30–45 $$$$ $45–60 $$$$$ > $60

Suggested Readings

American Society of Clinical Oncology; Kris MG, Hesketh PJ et al. American Society of Clinical Oncology guideline
for antiemetics in oncology: update 2006. J Clin Oncol 2006;24(18):2932-47.

ESMO recommendations for prophylaxis of chemotherapy-induced nausea and vomiting (NV). Ann Oncol 2001;12
(8):1059-60.

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Therapeutic Choice
Ioannidis JP, Hesketh PJ, Lau J. Contribution of dexamethasone to control of chemotherapy-induced nausea and
vomiting: a meta-analysis of randomized evidence. J Clin Oncol 2000;18(19):3409-22.

Jordan K, Kasper C, Schmoll HJ. Chemotherapy-induced nausea and vomiting: current and new standards in the
antiemetic prophylaxis and treatment. Eur J Cancer 2005;41(2):199-205.

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14. Gralla RJ. Metoclopramide. A review of antiemetic trials. Drugs 1983;25(Suppl 1):63-73.
15. De Mulder PH, Seynaeve C, Vermorken JB et al. Ondansetron compared with high-dose metoclopramide in
prophylaxis of acute and delayed cisplatin-induced nausea and vomiting. A multicenter, randomized, double-
blind, crossover study. Ann Intern Med 1990;113(11):834-40.
16. Roila F. Ondansetron plus dexamethasone compared to the 'standard' metoclopramide combination. Oncology
1993;50(3):163-7.
17. Marty M, Pouillart P, Scholl S et al. Comparison of the 5-hydroxytryptamine3 (serotonin) antagonist
ondansetron (GR 38032F) with high-dose metoclopramide in the control of cisplatin-induced emesis. N Engl J
Med 1990;322(12):816-21.
18. [No authors listed]. Ondansetron versus granisetron, both combined with dexamethasone, in the prevention of
cisplatin-induced emesis. Italian Group of Antiemetic Research. Ann Oncol 1995;6(8):805-10.
19. Mitchelson F. Pharmacological agents affecting emesis. A review (Part I). Drugs 1992;43(3):295-315.
20. Aapro MS. Corticosteroids as antiemetics. Recent Results Cancer Res 1988;108:102-11.
21. Ioannidis JP, Hesketh PJ, Lau J. Contribution of dexamethasone to control of chemotherapy-induced nausea
and vomiting: a meta-analysis of randomized evidence. J Clin Oncol 2000;18(19):3409-22.
22. Roila F, Tonato M, Cognetti F et al. Prevention of cisplatin-induced emesis: a double-blind multicenter
randomized crossover study comparing ondansetron and ondansetron plus dexamethasone. J Clin Oncol

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1991;9(4):675-8.
23. Roila F, Tonato M, Basurto C et al. Ondansetron. Eur J Cancer 1993;29A(Suppl 1):S16-21.
24. Gebbia V, Testa A, Valenza R et al. Oral granisetron with or without methylprednisolone versus
metoclopramide plus methylprednisolone in the management of delayed nausea and vomiting induced by
cisplatin-based chemotherapy. A prospective randomized trial. Cancer 1995;76(10):1821-8.
25. [No authors listed]. Persistence of efficacy of three antiemetic regimens and prognostic factors in patients
undergoing moderately emetogenic chemotherapy. Italian Group for Antiemetic Research. J Clin Oncol
1995;13(9):2417-26.
26. [No authors listed]. Dexamethasone alone or in combination with ondansetron for the prevention of delayed
nausea and vomiting induced by chemotherapy. The Italian Group for Antiemetic Research. N Engl J Med
2000;342(21):1554-9.
27. Hesketh P, Navari R, Grote T et al. Double-blind, randomized comparison of the antiemetic efficacy of
intravenous dolasetron mesylate and intravenous ondansetron in the prevention of acute cisplatin-induced
emesis in patients with cancer. Dolasetron Comparative Chemotherapy-induced Emesis Prevention Group. J
Clin Oncol 1996;14(8):2242-9.
28. del Giglio A, Soares HP, Caparroz C et al. Granisetron is equivalent to ondansetron for prophylaxis of
chemotherapy-induced nausea and vomiting: results of a meta-analysis of randomized controlled trials.
Cancer 2000;89(11):2301-8.
29. Gralla R, Lichinitser M, Van Der Vegt S et al. Palonosetron improves prevention of chemotherapy-induced
nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized
phase III trial comparing single doses of palonsetron with ondansetron. Ann Oncol 2003;14(10):1570-7.
30. Eisenberg P, Figueroa-Vadillo J, Zamora R et al. Improved prevention of moderately emetogenic
chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5 HT3 receptor
antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer 2003;98(11):2473-82.
31. American Society of Clinical Oncology; Kris MG, Hesketh PJ et al. American Society of Clinical Oncology
guideline for antiemetics in oncology: update 2006. J Clin Oncol 2006;24(18):2932-47.
32. Malik IA, Khan WA, Qazilbash M et al. Clinical efficacy of lorazepam in prophylaxis of anticipatory acute and
delayed nausea and vomiting induced by high doses of cisplatin. A prospective randomized trial. Am J Clin
Oncol1995;18(2):170-5.
33. Razavi D, Delvaux N, Farvacques C et al. Prevention of adjustment disorders and anticipatory nausea
secondary to adjuvant chemotherapy: a double-blind, placebo-controlled study assessing the usefulness of
alprazolam. J Clin Oncol 1993;11(7):1384-90.
34. Plotkin DA, Plotkin D, Okun R. Haloperidol in the treatment of nausea and vomiting due to cytotoxic drug
administration. Curr Ther Res Clin Exp 1973;15(9):599-602.
35. Tornetta FJ. Double-blind evaluation of haloperidol for antiemetic activity. Anesth Analg 1972;51(6):964-7.
36. Ward A, Holmes B. Nabilone. A preliminary review of its pharmacological properties and therapeutic use.
Drugs 1985;30(2):127-44.
37. Vincent BJ, McQuiston DJ, Einhorn LH et al. Review of cannabinoids and their antiemetic effectiveness. Drugs
1983;25(Suppl 1):52-62.
38. Tramer MR, Carroll D, Campbell FA et al. Cannabinoids for control of chemotherapy induced nausea and
vomiting: quantitative systematic review. BMJ 2001;323(7303):16-21.
39. Wood CD. Antimotion sickness and antiemetic drugs. Drugs 1979;17(6):471-9.
40. Longo DL, Wesley M, Howser D et al. Results of a randomized double-blind crossover trial of scopolamine
versus placebo administered by transdermal patch for the control of cisplatin-induced emesis. Cancer Treat
Rep 1982;66(11):1975-6.
41. Scher CS, Amar D, McDowall RH et al. Use of propofol for the prevention of chemotherapy-induced nausea
and emesis in oncology patients. Can J Anaesth 1992;39(2):170-2.
42. Borgeat A, Wilder-Smith OH, Wilder-Smith CH et al. Propofol improves patient comfort during cisplatin
chemotherapy. A pilot study. Oncology 1993;50(6):456-9.
43. Borgeat A, Wilder-Smith OH, Saiah M et al. Subhypnotic doses of propofol possess direct antiemetic
properties. Anesth Analg 1992;74(4):539-41.
44. Hesketh PJ, Grunberg SM, Gralla RJ et al. The oral neurokinin-1 antagonist aprepitant for the prevention of
chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled
trial in patients receiving high-dose cisplatin-The Aprepitant Protocol 052 Study Group. J Clin Oncol 2003;21
(22):4112-9.
45. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD et al. Addition of the neurokinin 1 receptor antagonist
aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting:
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results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer 2003;97(12):3090-
8.
46. Dando TM, Perry CM. Aprepitant: a review of its use in the prevention of chemotherapy-induced nausea and
vomiting. Drugs 2004;64(7):777-94.

Therapeutic Choices. © Canadian Pharmacists Association, 2011. All rights reserved.

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Therapeutic Choice

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Cancer Chemotherapy Toxicity: Management of Side Effects of Chemotherapy and


Radiation Therapy

Date Prepared: April 2007


Date Revised: February 2009

Pierre Fortin, MD, FACP, FRCPC

Cancer therapy encompasses three modalities of treatment: surgery, systemic therapies (chemotherapy, targeted
agents, hormones) and radiation therapy. An initial decision regarding the goal of therapy has to be made: curative
or palliative. Usually a combination of modalities is used in the treatment plan. Surgery remains the mainstay of
curative treatments, with chemo- and/or radiotherapy reserved for neoadjuvant therapies to downstage the tumor
before the surgery, or for adjuvant therapies in order to sterilize the surgical bed from suspected residual
microscopic disease. If surgery is not feasible as in the case of hematologic malignancies, then chemotherapy with
or without radiation is employed with curative or palliative intent.
If a decision is made to palliate the patient’s symptoms, radiation is usually used to control the disease locally,
while chemotherapy or other systemic agents are used to decrease the tumor burden throughout the whole body.
Surgery can also be used with palliative intent. These therapies are less intense and the goal is an acceptable quality
of life for the patient.

The following discussion will focus on managing the adverse effects of chemotherapy (Table 1 and Table 2) and
radiation therapy (Table 3).1 These tables outline treatments that are generally initiated by the oncology treatment
team but include issues that may be encountered by generalists when following cancer patients.

Side Effects of Chemotherapy

Cancer cells grow and divide faster than normal cells. This difference is exploited when using chemotherapy. The
drugs usually affect fast-growing cells during replication, killing more cancer cells than normal cells.

This characteristic also explains many of the side effects of chemotherapy. Fast-growing cells like the hematopoietic
cells, the skin and its appendages and the epithelium of the intestine often suffer adverse effects of chemotherapy.

Table 1: Acute Side Effects of Antineoplastic Drugs

Acute Side Effect Management Prevention

Extravasation Optimal management is unknown. Stop the Take all possible precautions to ensure
Vesicant drugs: infusion and aspirate any residual drug good blood return from and fluid flow
amsacrine remaining in tissues. Local measures such as into the iv line before injection.
bleomycin topical dimethylsulfoxide (DMSO),2 , 3 Be aware of potential damage to
carmustine subcutaneous injections of saline, steroids, tendons. Avoid dorsum of the hand or
cisplatin hyaluronidase or bicarbonate may be cubital fossa.
dactinomycin helpful. There is weak evidence that ice
daunorubicin packs may worsen the skin toxicity with
doxorubicin vinca alkaloids.
epirubicin Severe cases may require plastic surgery
etoposide intervention.
idarubicin
mechlorethamine
melphalan
mitomycin
mitoxantrone
plicamycin
streptozocin
vinblastine
vincristine
vindesine
vinorelbine

Hypersensitivity Stop chemotherapy infusion. Administer Premedicate with antihistamines (H1-

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Acute Side Effect Management Prevention

Reactions antihistamines, steroids, and H2-blockers) and corticosteroids.


Seen especially with vasoconstrictors. Use slower infusion rates.
etoposide and taxanes. Supportive care.
Also seen with
rituximab, trastuzumab
and other biologics.

Tumor Lysis Syndrome Rapid release of intracellular contents into IV hydration, allopurinol
the blood stream, resulting in hyperuricemia, 300–600 mg/day until normal uric acid
hyperkalemia, hyperphosphatemia and levels. Close monitoring of serum
hypocalcemia. Seen in diseases with large electrolytes with accordant adjustments
tumor burden and exquisitely sensitive to of contents of iv fluids.
chemotherapy, e.g., leukemia, lymphomas. Rasburicase is a uricolytic that may
be used at a dose of
0.20 mg/kg/day for up to seven days in
the treatment and prophylaxis of
hyperuricemia. Since it is a protein it
may induce allergic responses. When
administered to patients with G-6-PD
deficiency it can cause severe
hemolysis.

Table 2: Specific Side Effects of Antineoplastic Drugs

Side Effect Management Prevention

Alopecia Cosmetic intervention using wigs, hats or Cryotherapy caps or scalp


scarves. tourniquets are not effective and may
Hair usually begins regrowth 1–2 months be unsafe.
after completion of chemotherapy.

Anemia Packed red blood cells given to patients Decrease doses of chemotherapy for
with hemoglobin < 80 g/L, chest pain or subsequent cycles.
shortness of breath with little exertion.
Although these agents have significant
potential for toxicity, in select patients
erythropoetin as epoetin alfa or
darbepoetin may reduce the need for
transfusions.
Hemoglobin targets of > 120 g/L were
associated with increased risk of death and
serious adverse events.4

Cardiotoxicity Treat symptomatically with nitrates. Avoid administration in patients with


5-FU, capecitabine cause Discontinue therapy if necessary. known coronary artery disease.
coronary vasospasms,
mimicking a myocardial
infarct.

Trastuzumab can cause Left ventricular function should be


cardiac dysfunction including evaluated at baseline and during therapy.
severe heart failure. Manage clinically significant cardiac
dysfunction symptomatically.
Discontinuation of trastuzumab usually
recommended.

Anthracyclines can cause Perform ECG and serial ejection fractions. Limit cumulative doses of
acute inflammation Treat symptomatically. Discontinue therapy anthracyclines. Consider
(myocarditis/pericarditis if necessary. discontinuing anthracyclines if serial

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Side Effect Management Prevention

syndrome). Chronically, a ejection fraction is ↓ 25% from


dose-dependent congestive baseline. Dexrazoxane is a
myopathy may develop. cardioprotective agent used at a dose
of 500 mg/m2 to reduce the
incidence and severity of
cardiotoxicity associated with
doxorubicin. Dexrazoxane may add
to the myelosuppressive effects
caused by chemotherapeutic agents.
As a result, blood counts and hepatic
function tests should be performed
regularly. Cardiac function should
also be monitored.

Taxanes may cause Observe patient.


bradycardia. Treat symptomatically.

Carcinogenesis Case specific. Use the least amount of


chemotherapy possible to control the
disease.

Diarrhea IV hydration and supportive care if Decrease the dose of chemotherapy


Seen with irinotecan, 5-FU, dehydration secondary to diarrhea. in subsequent cycles or change the
antimetabolites. Loperamide and/or diphenoxylate PRN chemotherapy regimen.
or octreotide.5

Gonadal Toxicity Discuss assisted reproduction techniques Sperm banking. Use chemotherapy
with patients. with the least effect on
spermatogenesis or ovarian
function.

Hepatotoxicity Perform LFTs and bilirubin measurement. Avoid offending agent or decrease
Seen with methotrexate, Discontinue chemotherapy depending on doses.
azathioprine, cytarabine, extent of damage.
nitrosoureas, etoposide.

Mucositis Rule out infectious causes. Educate patients on basic oral


Avoid “magic mouthwash” with topical hygiene. Treat pre-existing oral
steroids and antihistamines that can problems before starting
increase chances of fungal infection or chemotherapy. Avoid alcohol and
sensitization. Combinations of spicy foods, which are irritating to
xylocaine viscous, sucralfate, nystatin, the mucosa. Ice chips reduce the
fluconazole, antacids and sodium incidence and severity of 5-FU-
bicarbonate are used in local induced mucositis.7
institutions. For severe mucositis in Withhold offending agent until
patients with hematologic episode resolves.
malignancies receiving myelotoxic
therapy and requiring stem cell
support, the growth factor palifermin
can be used at a dose of 60 µg/kg/day
for 3 days before and 3 days after
chemotherapy.6 Adverse effects
include mild to moderate taste
alteration, mouth and tongue
disorders, rash and edema.

Useful Info?

Myelosuppression/ Febrile Start oral antibiotics in those at low risk of Growth factors such as filgrastim or
Neutropenia complications. Ciprofloxacin or pegfilgrastim used to increase the
amoxicillin-clavulanate are commonly rate of neutrophil count recovery can

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Side Effect Management Prevention

used. be administered to allow


Those at higher risk of complications chemotherapy to be given without
include those with septic shock or signs of delays or decreasing doses. It can
organ failure, neutropenia for > 6 days, improve quality of life and decrease
signs of infections in lines, temperature ≥ hospitalization. CBC must be
39°C and receiving bacterial/fungal performed regularly during G-CSF
prophylaxis.8 These high-risk patients (filgrastim) therapy. Bone pain
should receive broad gram-negative and related to these agents can generally
antipseudomonal coverage with two agents. be controlled with nonopioid
Add vancomycin if gram-positive infection analgesics. Serious allergic or
suspected (see Infectious Diseases: anaphylactic reactions have occurred
and require discontinuation of G-
Infections in the Cancer Patient). Perform
CSF.
cultures and adjust antibiotics according to
results.8

Nausea/Vomiting See Cancer Chemotherapy Toxicity:


Chemotherapy-induced Nausea and
Vomiting

Nephrotoxicity IV hydration to achieve urine output of > 3 Mesna is a uroprotectant used to


L/24 h while administering chemotherapy. prevent hemorrhagic cystitis
Monitor creatinine, BUN and serum uric secondary to cyclophosphamide or
acid. ifosfamide. Most adverse effects of
mesna are immediate and include
nausea and vomiting, headache and
urticaria.
Allopurinol 300–600 mg/day po
starting 24–48 h before
chemotherapy for uric acid
nephropathy.

Neurotoxicity Dose reduction may be necessary with For vinca alkaloid constipation, use
Peripheral nerve damage is severe toxicity, or the drugs may have to stool softeners or stimulant
common with the vinca be avoided altogether. laxatives if necessary. Suggest
alkaloids, platinum-based Rule out other causes such as CNS increased physical activity and
chemotherapy and metastases or leptomeningeal disease. hydration if possible. Anticholinergic
taxanes. It can be drugs may help.
irreversible.
Neurotoxicity can present as
peripheral or central
neuropathy, impotence,
urinary retention. It can lead
to muscle atrophy, motor
weakness or loss of deep
tendon reflexes.
Autonomic neuropathy from
vinca alkaloids presents with
constipation and abdominal
pain.
High-dose methotrexate
may cause transient cerebral
dysfunction.

Ocular Discontinuation of the offending agent may For conjunctivitis, corticosteroid


Blepharitis, epiphora, tear be necessary. eye drops or artificial tears may
duct stenosis; conjunctivitis be preventative.
with 5-FU and taxanes.

Ototoxicity Can be irreversible. Reduce doses or avoid Audiograms every 3–4 cycles.
Seen with platinum completely if possible.

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Therapeutic Choice

Side Effect Management Prevention

compounds.

Pulmonary Rule out infectious causes. Withhold Avoid offending agent.


Interstitial pneumonitis and offending agent; supportive care, steroids
fibrosis with methotrexate, (prednisone 50 mg/day with tapering
bleomycin, anthracyclines, doses). Ventilatory support may be
vinca alkaloids, alkylating necessary.
agents. Acute respiratory
distress syndrome with
gemcitabine.

Teratogenicity Contraception necessary while patient Avoid pregnancy while on


receiving chemotherapy. chemotherapy.

Side Effects of Radiation Therapy

Radiation treatment is used to control the disease locally, not unlike surgery. A target, whether the tumor itself or
the surgical bed, is acquired with the help of a CT scan, and treatment fields are designed to encompass it. When
the x-rays are delivered, they travel through the tissues from an entry point to an exit point. The enormous quantity
of energy carried by the x-rays damage chromosomes either directly or indirectly by the production of free radicals
in the neighbourhood of the chromosomes. As with chemotherapy, the cell cannot divide and dies. A normal
inflammatory reaction ensues, producing the common side effects of radiation.

Contrary to chemotherapy, where the side effects are generally seen in a matter of minutes to days, the side effects
of radiation are seen many days to weeks and even years after the treatment. Acute side effects in this context
means within 30 days of the end of the treatments, subacute within 6 months and late side effects over 6 months
after the completion of the therapy.

Side effects could be decreased by lowering the total radiation dose or its fractionation or keeping the field size as
small as possible. However, the whole tumor has to be treated in order to control the disease appropriately.

Table 3: Organ-specific Side Effects of Radiation Therapy9

Organ/System Side Effect Management

CNS/Spinal Cord Edema Steroids, typically dexamethasone 4 mg po QID.

ENT/Esophagus Mucositis/ esophagitis Mouthwashes containing nystatin, fluconazole, sucralfate,


xylocaine viscous may help symptoms. Amifostine is a
cytoprotectant that may be used to reduce xerostomia. It may
cause hypotension that can lead to dizziness or fainting. Monitor
blood pressure and consider holding antihypertensives for 24 h
prior to amifostine administration. Prophylactic serotonin
antagonists may be used to reduce nausea and vomiting caused by
amifostine.
Systemic analgesics can be used for pain.

Heart Pericarditis NSAIDs.

Lungs Pneumonitis Prednisone (starting dose 1 mg/kg/day, to taper over weeks).

Skin Desquamation/itchiness If dry desquamation, use glaxal base or other moisturizers (e.g.,
Lubriderm, plain Keri Lotion) or vitamin E cream. If itchiness, use
hydrocortisone 0.5% cream. If moist desquamation, use silver
sulfadiazine cream.

Small Intestine/ Enteritis/proctitis Medical support: fluid replacement by po or iv route, loperamide,


Colon/Rectum diphenoxylate. Topical steroids by enema or suppository.
Antispasmodics such as hyoscine butylbromide (Buscopan) or
pinaverium may provide symptomatic relief.

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Organ/System Side Effect Management

Stomach Nausea Antiemetics, e.g., ondansetron, granisetron, dolasetron,


dimenhydrinate, prochlorperazine, metoclopramide.10

Suggested Readings

Schuchter LM, Hensley ML, Meropol NJ et al. 2002 update of recommendations for the use of chemotherapy and
radiotherapy protectants: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol
2002;20(12):2895-903.

Smith TJ, Khatcheressian J, Lyman GH et al. 2006 update of recommendations for the use of white blood cell growth
factors: an evidence-based clinical practice guideline. J Clin Oncol 2006;24(19):3187-205.

References

1. DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 7th ed. Philadelphia
(PA): Lippincott, Williams & Wilkins; 2005.
2. Olver IN, Aisner J, Hament A et al. A prospective study of topical dimethylsulfoxide for treating anthracycline
extravasation. J Clin Oncol 1988;6(11):1732-5.
3. Bertelli G, Gozza A, Forno GB et al. Topical dimethylsulfoxide for the prevention of soft tissue injury after
extravasation of vesicant cytotoxic drugs: a prospective clinical study. J Clin Oncol 1995;13(11):2851-5.
4. Health Canada endorsed important safety information on Erythropoiesis-Stimulating Agents (ESAs): Aranesp
(darbepoetin alfa) and Eprex (epoetin alfa). Ottawa (ON): Health Canada; 2007. Available from:
http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/public/_2007/aranesp_eprex_pc-cp-eng.php.
Accessed February 24, 2009.
5. Harris AG, O'Dorisio TM, Woltering EA et al. Consensus statement: octreotide dose titration in secretory
diarrhea. Diarrhea Management Consensus Development Panel. Dig Dis Sci 1995;40:1464-73.
6. Keefe DM, Schubert MM, Elting LS et al. Updated clinical practice guidelines for the prevention and treatment
of mucositis. Cancer 2007;109(5):820-31.
7. Worthington HV, Clarkson JE, Eden OB. Interventions for preventing oral mucositis for patients with cancer
receiving treatment. Cochrane Database Syst Rev 2006;(2):CD000978.
8. Hughes WT, Armstrong D, Bodey GP et al. 2002 guidelines for the use of antimicrobial agents in neutropenic
patients with cancer. Clin Infect Dis 2002;34(6):730-51.
9. Perez CA, Brady LW, editors. Principles and practice of radiation oncology. 3rd ed. Philadelphia (PA):
Lippincott-Raven; 1998.
10. Kris MG, Hesketh PJ, Somerfield MR et al. American Society of Clinical Oncology guideline for antiemetics in
oncology: update 2006. J Clin Oncol 2006;24(18):2932-47.

Therapeutic Choices. © Canadian Pharmacists Association, 2011. All rights reserved.

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Therapeutic Choice

Print Close

Cardiovascular Disorders: Acute Coronary Syndromes

Date Prepared: January 2011

Michelle Graham, MD, FRCPC

The term “acute coronary syndrome” (ACS) refers to any clinical symptoms compatible with acute myocardial
ischemia, from ST segment elevation myocardial infarction (STEMI) to non-ST segment elevation myocardial
infarction and unstable angina. Centres should have a standardized approach to ACS patients to ensure the most rapid
assessment and initiation of treatment possible.

The following discussion relates to ACS that are associated with primary coronary events caused by plaque erosion
and/or rupture, fissuring or dissection.

Unstable Angina and Non-ST Segment Elevation Myocardial Infarction (NSTEMI)

Goals of Therapy
Investigations
Therapeutic Choices
Nonpharmacologic Choices
Pharmacologic Choices
Therapeutic Tips

Goals of Therapy

Decrease mortality and complications


Reduce the severity or eliminate episodes of ischemia
Prevent further myocardial injury

Investigations

Careful history with special attention to pain (quality, severity, location, radiation, precipitating and relieving
factors), duration of symptoms, previous cardiac history, cardiac risk factors (smoking status, diabetes mellitus,
hyperlipidemia, hypertension, family history of first-degree relative with myocardial infarction before age 55 if
male or 65 if female) and effect of nitroglycerin
Physical examination, with attention to the presence of hypertension, heart failure or valvular heart disease
Laboratory tests:
ECG, CBC, electrolytes, glucose, creatinine and lipid profile (within 24 hours of presentation)
troponin, creatine kinase (if troponin is unavailable). Troponin is a highly accurate, sensitive and specific
indicator of myocardial injury.1 Its measurement allows reliable stratification of risk and prediction of
outcomes in individual patients.2 , 3 Elevation of cardiac troponin levels may result from pulmonary embolus
or non-ischemic mechanisms of myocardial injury, such as increased wall stress (e.g., myocarditis, severe
heart failure, left ventricular hypertrophy), or cardiac trauma. Additionally, troponins are elevated in 30–50%
of patients with pericarditis as a result of epicardial inflammation, and have also been reported in critical
illness, sepsis, neurological events, hypothyroidism, chemotherapy-induced myocardial toxicity and renal
insufficiency.
A careful search for secondary causes of ischemia, e.g., anemia, fever, infection, arrhythmia, thyroid disease
Echocardiography can be used early when clinical history and ECG are nondiagnostic—the presence of regional
wall motion abnormalities with chest pain is suggestive of underlying ischemia
The TIMI (Thrombolysis in Myocardial Infarction) Risk Score is a risk stratification tool for patients with NSTEMI or
unstable angina, using clinical features present at the time of initial assessment in the emergency department (Table
1). It predicts the risk of both death and early recurrent ischemic events and is used to target different evidence-
based therapies to appropriate patients. As the risk score increases, so too do adverse outcomes; for example, there
is a 5% risk of major adverse cardiac events in patients with a risk score of 0 or 1, and a 41% risk in those with a risk
score of 6 or 7.4

Table 1: Clinical Features Used to Calculate TIMI Risk Score4

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One point is assigned for each of the following clinical features:


• age >65 y
• ≥3 cardiac risk factors (hypercholesterolemia, hypertension, diabetes mellitus, current smoker, family history of
coronary artery disease)
• ≥50% coronary artery stenosis
• any ASA use within 7 d
• ≥2 episodes of angina within the last 24 h
• elevation in cardiac markers (troponin or creatine kinase-myocardial band)
• ST segment deviation ≥0.5 mm on ECG

The Global Registry of Acute Coronary Events (GRACE) score is a more comprehensive risk stratification tool
(www.outcomes-umassmed.org/grace/acs_risk/acs_risk_content.html ). While more complicated, it is a web-based
tool that can be easily used to improve risk calculation. When compared to the TIMI Risk Score, GRACE has been
found to better discriminate risk for 1-month and 1-year mortality in ACS patients.5

Therapeutic Choices (Figure 1 - Early Management of UA/NSTEMI)

The management of patients with NSTEMI or unstable angina has evolved significantly. Evidence from randomized
clinical trials now strongly supports the use of the “invasive strategy”—early, urgent coronary angiography followed if
possible by revascularization with percutaneous coronary intervention (PCI) or bypass surgery in all high-risk
patients. Patients are at high risk if they have one or more of the following features: positive cardiac enzymes, ST
segment changes, TIMI Risk Score ≥3, recurrent ischemic symptoms, heart failure, hemodynamic instability,
sustained ventricular tachycardia or a prior revascularization procedure—coronary artery bypass graft (CABG) or PCI.6

Nonpharmacologic Choices

All patients admitted with NSTEMI or unstable angina should be placed on bedrest while ischemia is ongoing, then
gradually mobilized when symptoms have stabilized. Use supplemental oxygen in patients with inadequate arterial
oxygen saturation to keep the SaO2 above 90%. Continuous ECG monitoring for potentially lethal arrhythmias and ST
segment shifts (if available) is indicated in all high-risk patients.

Pharmacologic Choices (Table 2)

Nitrates

Initial attempts at symptom relief should involve the use of nitroglycerin, first with sublingual tablets or spray.
Intravenous nitroglycerin is indicated in patients whose symptoms are not relieved promptly (within 15–20 minutes).
Longer acting oral or topical nitrates can be used when patients are symptom free to prevent recurrent episodes of
ischemia. The use of sildenafil, tadalafil or vardenafil in the previous 24 hours or the presence of significant
hypotension is a contraindication to the use of nitrates.

Beta-blockers and Calcium Channel Blockers

Start beta-blockers as soon as possible in all patients without contraindications: reactive airways disease;
bradycardia, i.e., heart rate (HR) ≤50 beats per minute (BPM); second- or third-degree heart block without a
functioning pacemaker; hypotension (SBP <100 mm Hg). The dose should be titrated to a resting HR of 50–60 BPM. I
anginal pain is ongoing at presentation, beta-blockers are initially administered intravenously followed by oral dosing

Calcium channel blockers can be used to control ongoing symptoms of ischemia in patients who are receiving
maximum tolerated doses of beta-blockers and adequate doses of nitrates. In addition, these agents are used in
patients who cannot tolerate beta-blockers, and in those with variant angina (coronary spasm). Avoid immediate-
release nifedipine because controlled trials suggest increased adverse outcomes such as stroke.

Angiotensin Converting Enzyme (ACE) Inhibitors

ACE inhibitors reduce mortality in patients with recent myocardial infarction, left ventricular systolic dysfunction or
clinical heart failure, diabetes and a broad spectrum of patients with high-risk chronic coronary artery disease.7 , 8

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Therapeutic Choice
Therefore, use these agents in all of these patient groups and in patients with hypertension not controlled with beta-
blockers and nitrates.

Antiplatelet and Anticoagulation Therapy

ASA

ASA provides a striking benefit in patients with acute coronary syndromes. If patients with suspected UA/NSTEMI
are not already receiving ASA, it should be initiated promptly and continued long term.

Thienopyridines

In the CURE (Clopidogrel in Unstable angina to prevent Recurrent ischemic Events) trial, clopidogrel (plus ASA)
significantly reduced the incidence of major adverse cardiac events in ACS patients compared with ASA alone, and
reduced the incidence of recurrent ischemia, an effect which was evident within a few hours.9 The benefit of
clopidogrel was consistent among patients regardless of TIMI Risk Score.10 The major benefits were noted at 30
days, with small additional benefits observed over the subsequent treatment period (average 8 months). There was
an excess of both major and minor bleeding in the clopidogrel group during the trial, with an insignificant trend
towards an increase in life-threatening bleeding. Bleeding risks increase with increasing ASA dose.11 Because of this
risk, many hospitals with cardiac catheterization facilities do not initiate clopidogrel until it is clear that bypass
surgery is not needed for appropriate revascularization. Clopidogrel should be held for a minimum of 5 days in
patients scheduled for bypass surgery.9 , 10 Clopidogrel is the preferred agent in this class due to its more rapid
onset of action and better safety profile compared with ticlopidine.

The FDA issued a black-box warning on clopidogrel due to the diminished effectiveness of this drug in patients who
are unable to convert it to active form.12 Patients with diminished CYP 2C19 function due to genetic
polymorphisms metabolize clopidogrel poorly and have higher cardiovascular event rates, both
following an ACS and after percutaneous coronary intervention. Tests are available to identify these
individuals and modified dosing strategies or an alternative agent can be considered. However, routine
genetic testing is not recommended at this time.13 Useful Info?

Prasugrel is a more potent platelet inhibitor than clopidogrel, and in a large clinical trial was associated with lower
ischemic event rates including stent thrombosis. However, there was a significant increase in bleeding events,
particularly in those older than age 75, those having body weight <60 kg and in patients with a history of stroke or
transient ischemic attack.14 The use of prasugrel should be considered in those patients with ACS undergoing stent
implantation who are at higher risk for stent thrombosis (previous stent thrombosis, STEMI, history of diabetes
mellitus).

Unfractionated Heparin (UFH) or Low Molecular Weight Heparins (LMWH)

Heparin is a key component in the successful management of patients with ACS. Studies of ASA with either UFH or
LMWH have shown a 3–3.5% absolute reduction (50–60% relative reduction) in the rate of death or MI in the first
week.15 , 16 UFH has important limitations due to significant variability in anticoagulant response. LMWH have the
advantage of ease of administration, predictable anticoagulant response and lack of need for monitoring. Clinical
trials have demonstrated the superiority of enoxaparin over UFH, but have shown neutral or unfavourable trends
with other LMWH (dalteparin and nadroparin).17 , 18 , 19 , 20 A direct comparison favoured enoxaparin over
tinzaparin.21 Enoxaparin is therefore the preferred agent in patients with UA/NSTEMI who do not have significant
renal dysfunction (estimated creatinine clearance >30 mL/min). In those with an estimated creatinine clearance ≤30
mL/min, UFH is appropriate.

Fondaparinux, a direct inhibitor of factor Xa, is as effective as enoxaparin in patients with non-ST segment
elevation ACS and is associated with a lower incidence of major bleeding according to the results of a large
randomized trial.22

Glycoprotein IIb/IIIa Inhibitors

Numerous trials have demonstrated the efficacy of these agents in the treatment of high-risk patients with
UA/NSTEMI undergoing coronary angiography and subsequent PCI. Clinical trials support the use of eptifibatide
and tirofiban at the time of admission or immediately before PCI.23 , 24 , 25 , 26 , 27 Abciximab is also effective,

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Therapeutic Choice
but its expense limits its use to the cardiac catheterization laboratory. The benefit of these agents is less clear for
patients for whom an initial conservative management approach is planned. Patients receiving any of these agents
must be carefully monitored for bleeding. However, the combined use of glycoprotein IIb/IIIa inhibitors and heparin
does appear to be safe.28 Thrombocytopenia is an unusual complication of treatment with these agents.

Direct Thrombin Inhibitors

Bivalirudin, a reversible direct thrombin inhibitor with a quick onset of action and short half-life, has a predictable
antithrombotic response. Clinical studies demonstrate positive outcomes in ACS patients. Bivalirudin use is considered
a reasonable strategy in patients with ACS undergoing PCI with concomitant thienopyridine and/or glycoprotein
IIb/IIIa inhibitor use.

Therapeutic Tips

The standard dose of ASA is 325 mg daily. This dose can be decreased to 81 mg enteric-coated tablet in those
patients receiving long-term clopidogrel.
Discontinue clopidogrel 5 days prior to bypass surgery to decrease the risk of bleeding.

ST Segment Elevation Myocardial Infarction (STEMI)

Goals of Therapy
Investigations
Therapeutic Choices
Nonpharmacologic Choices
Pharmacologic Choices

Patients with STEMI represent the extreme of the acute coronary syndrome spectrum, are considered to be a medical
emergency and, therefore, require urgent assessment and treatment.

Goals of Therapy

Decrease mortality and complications


Reduce or contain infarct size
Salvage functioning myocardium and prevent remodelling
Re-establish patency of the infarct-related artery

Investigations

Rapid, targeted history and physical examination, with particular attention to onset of symptoms,
contraindications to use of thrombolytic agents (see Table 2) and evidence of high-risk features (tachycardia,
hypotension, heart failure)
ECG STAT, then every 8 hours for the first 24 hours, then daily for 3 days. In addition, repeat the ECG with each
recurrence of chest pain
Baseline troponin STAT, (creatine kinase if troponin is unavailable) and then every 8 hours until enzymatic
confirmation of the diagnosis (see Investigations; Unstable Angina and Non-ST Segment Elevation Myocardial
Infarction (NSTEMI) for more discussion of troponin)
CBC to rule out the presence of anemia, baseline electrolytes, creatinine, fasting lipid profile (within 24 hours of
presentation) and liver function tests
Portable chest x-ray (CXR) STAT
Echocardiography to assess LV function after stabilization and treatment. Echocardiography is also used
emergently when there is suspicion of acute mechanical complications post-MI

Therapeutic Choices (Figure 2 - Early Management of STEMI)

Nonpharmacologic Choices

Place all patients on bedrest with supplemental oxygen and continuous ECG monitoring. Begin gradual mobilization
after stabilization provided there is no evidence of complications.

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Therapeutic Choice

Primary Percutaneous Coronary Intervention (PCI)

Urgent coronary angiography with PCI is an excellent alternative to thrombolytics if appropriate high-volume cardiac
catheterization facilities are available. Primary PCI is indicated in patients with contraindications to thrombolytic
therapy and in those with cardiogenic shock, and is preferred in patients over the age of 75 because of a higher risk
of intracranial hemorrhage and higher overall early mortality seen with thrombolytic agents in this age group.29 ,
30 , 31

Pharmacologic Choices (Table 2)

Thrombolytic Therapy

Thrombolytic therapy administered early in the course of STEMI substantially reduces morbidity and mortality,
particularly if the patient presents within 6 hours of symptom onset. The benefit is reduced for patients who present
6–12 hours after the onset of symptoms, and evidence of benefit is much less clear for those who present more than
12 hours after the onset of symptoms. The greatest absolute benefit is seen where the risk of mortality is highest
(anterior MI, previous MI).

Heparins

Give intravenous unfractionated heparin to all STEMI patients receiving alteplase, tenecteplase or reteplase.
Enoxaparin is an alternative, and has been shown to be superior to heparin in patients treated with tenecteplase,
but must be used with caution in patients older than 75 (dosage adjustment required) or those with renal
insufficiency (estimated ClCr <30 mL/min) because of an increased risk of bleeding.32 Heparin should be continued
for a minimum of 48 hours and use can be extended in patients with high-risk features. The indications for heparin
after streptokinase are unclear, but its use can be considered in patients with an anterior MI, atrial fibrillation, heart
failure or a history of embolism.

ASA

ASA provides a significant benefit in patients with STEMI. If patients are not already receiving ASA, it should be
initiated promptly and continued long term.33

Beta-blockers

These agents are recommended in all STEMI patients without contraindications, and are particularly useful when
sinus tachycardia and hypertension are present. They should be initiated once hemodynamic stability is achieved.
Titrate doses to a resting heart rate of 50–60 BPM.

Calcium Channel Blockers

Calcium channel blockers increase morbidity and mortality in patients with STEMI and are not recommended.34 They
may be used cautiously to relieve ischemia or to achieve rate control in patients with atrial fibrillation if beta-
blockers are contraindicated. Consider a low dose of diltiazem with heart rate monitored closely.

Nitroglycerin

Unlike NSTEMI or unstable angina, IV, oral or topical nitrates should be used in patients with STEMI only if ischemia
is persistent or recurrent, or if the patient has a large anterior MI, hypertension or heart failure.35

ACE Inhibitors and Angiotensin Receptor Blockers

ACE inhibitors are routinely recommended, unless contraindicated, in all patients post-STEMI and should ideally be
started within 24 hours of the event unless the patient is hypotensive (SBP <100 mm Hg). Doses should be
increased every 24 hours as tolerated for inpatients and at 1- to 2-week intervals for outpatients. Based on the
results of the HOPE trial, it is reasonable to continue an ACE inhibitor indefinitely even in patients with preserved LV

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Therapeutic Choice

function.8 An angiotensin receptor blocker should be used in STEMI patients who cannot tolerate an ACE inhibitor
and have either clinical or radiological signs of heart failure or documented LV dysfunction.

Aldosterone Antagonists

Long-term use of an aldosterone antagonist such as spironolactone or eplerenone reduces morbidity and
mortality in STEMI patients with clinical evidence of heart failure, LV ejection fraction <40% or both, based on the
results of 2 randomized trials.36 , 37 Caution must be used in patients with renal insufficiency or pre-existing
hyperkalemia, and in those receiving ACE inhibitors concomitantly.36 , 37

Clopidogrel

In patients with STEMI treated with fibrinolysis, clopidogrel increases patency of the infarct-related artery and
decreases ischemic complications according to the results of 2 randomized trials;38 , 39 therefore routine use should
be considered in these patients.

Complications of STEMI

Recurrent or Ongoing Ischemia

Optimize anti-anginal therapy, and consider urgent coronary angiography and possible revascularization for all
patients with recurrent or ongoing ischemia.

Heart Failure

Treat heart failure aggressively (see Cardiovascular Disorders: Heart Failure). In addition, consider angiography and
possible revascularization in patients with LV ejection fraction <40% after MI.

Arrhythmias

Asymptomatic premature ventricular contractions (PVCs) do not require therapy. Symptomatic ectopy may require
therapy, usually with a beta-blocker. Class IC agents are contraindicated. Patients with sustained ventricular
arrhythmias require investigation to rule out recurrent ischemia and may require subsequent electrophysiologic
assessment.40 Consider urgent electrical or pharmacologic cardioversion in patients with atrial fibrillation causing
ischemia or heart failure. Treat all patients with atrial fibrillation to control ventricular rate (usually with a beta-
blocker or digoxin if there is concomitant heart failure) and consider oral anticoagulant therapy.

Patients with an ejection fraction <30% 1 month post-MI or 3 months post-revascularization should be referred for
automatic implantable cardioverter-defibrillator therapy (AICD).41

Pericarditis

Pericarditis, although uncommon, usually presents within 72 hours post-MI, and symptoms usually resolve within 3–
4 days. Symptomatic pericarditis can be treated by increasing the dose of ASA to 650 mg QID for 1–2 weeks. If
ASA is ineffective, a nonsteroidal anti-inflammatory drug (NSAID) or corticosteroid can be added. Discontinuation
of anticoagulants is unnecessary if pericarditis occurs early post-infarction, but caution is required if a patient
presents with pericarditis weeks or months after MI (Dressler’s syndrome) because of the risk of pericardial bleeding
and tamponade.42

Mechanical Complications

Ruptured papillary muscle (and severe mitral regurgitation), ventricular septal defects or ventricular free wall
rupture are infrequent but devastating problems that can present with acute cardiac arrest or cardiogenic shock.
Patients should be considered for emergency angiography and surgical intervention, but even with urgent treatment
the mortality rate associated with these conditions is very high.

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Therapeutic Choice
Clopidogrel Use in Percutaneous Coronary Intervention

Pretreatment with clopidogrel prior to PCI reduced the risk of death, MI and repeat revascularization in the PCI-CURE
substudy.43 Therapy must be continued for at least 1 month post-procedure, particularly if a coronary stent is used.
However, if drug-eluting stents are used, the duration of thienopyridine therapy must be extended due to delayed
endothelialization and an increased risk of late stent thrombosis. It is recommended that clopidogrel be continued
for 1 year. Under urgent circumstances that prevent the use of clopidogrel for a full year, the drug should be
continued for a minimum of 3 months in patients with a sirolimus-eluting stent and for 6 months in those with a
paclitaxel-eluting stent.44 Elective surgery should be postponed until after the course of clopidogrel has been
completed in patients with stents. If surgery cannot be postponed, continue clopidogrel throughout the perioperative
period if possible. Early discontinuation of clopidogrel results in a high risk of acute stent thrombosis with high
morbidity and mortality.

Therapeutic Tips

The goal for thrombolytic treatment is a door-to-needle time of 30 minutes or less.


The goal for primary PCI is a door-to-dilatation time of 90 minutes or less.
Careful attention to maximum pain relief is important.
In patients with right ventricular infarcts:
avoid nitrates and diuretics
use fluids and inotropes to treat hypotension
Administer beta-blockers early to all patients without contraindications. Increase the dose every 12 hours (every
24 hours for once-daily beta-blockers), if tolerated (monitor blood pressure and heart rate), until the patient
has reached adequate beta-blockade (HR ≤55–65 BPM).
Start ACE inhibitors early. The choice of agent can depend on practitioner preference, hospital formulary or
financial constraints for the individual patient.
In smokers, reinforce early (within 24 hours) and frequently the need to quit smoking.
Stool softeners are often used in the immediate post-MI period to prevent straining with bowel movements.
Anxiolytics are often used on an as-needed basis in the immediate post-MI period.

Figure 1- Early Management of UA/NSTEMI

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Therapeutic Choice

Figure 2-Early Management of STEMI

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Therapeutic Choice

Table 2: Drugs Used in Acute Coronary Syndromes

Drug
Class Drug Dose Adverse Effects Interactions Costa

Beta1- acebutolol Initial: Bronchospasm, HF, Enhanced $


adrenergic Rhotral, Sectral, 100–200 mg BID po hypotension, sleep cardiodepressant
Antagonists, Apo-Acebutolol, Usual: disturbances, effect with
selective with other generics 400 mg BID po dizziness, fatigue, calcium channel
ISA anorexia, nausea, AV blockers,
block, bradycardia, antiarrhythmics,
claudication, anesthetics.
Raynaud's, lethargy, Increased
drowsiness. bradycardia with
digoxin.
Hypertension with
alpha-agonists.

Beta1- atenolol Initial: Bronchospasm, HF, Enhanced $


adrenergic Tenormin, 50 mg/day po hypotension, sleep cardiodepressant
Antagonists, generics Usual: disturbances, effect with
selective 100 mg/day po dizziness, fatigue, calcium channel

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Therapeutic Choice

Drug
Class Drug Dose Adverse Effects Interactions Costa

without ISA anorexia, nausea, AV blockers,


block, bradycardia, antiarrhythmics,
claudication, anesthetics.
Raynaud's, lethargy, Increased
drowsiness. bradycardia with
digoxin.
Hypertension with
alpha-agonists.

Beta1- metoprolol iv: Bronchospasm, HF, Enhanced $


adrenergic Betaloc, Lopresor, 5 mg over 1–2 min hypotension, sleep cardiodepressant
Antagonists, generics repeat Q5 min disturbances, effect with
selective (maximum 15 mg) dizziness, fatigue, calcium channel
without ISA Initial: anorexia, nausea, AV blockers,
25–50 mg QID po block, bradycardia, antiarrhythmics,
Usual: claudication, anesthetics.
100 mg BID po Raynaud's, lethargy, Increased
po can be started drowsiness. bradycardia with
15 min after iv digoxin.
Hypertension with
alpha-agonists.

Beta1- nadolol Initial: Bronchospasm, HF, Enhanced $


adrenergic generics 40–80 mg/day po hypotension, sleep cardiodepressant
Antagonists, Usual: disturbances, effect with
nonselective 160 mg/day po dizziness, fatigue, calcium channel
without ISA anorexia, nausea, AV blockers,
block, bradycardia, antiarrhythmics,
claudication, anesthetics.
Raynaud's, lethargy, Increased
drowsiness. bradycardia with
digoxin.
Hypertension with
alpha-agonists.

Beta1- propranolol Initial: Bronchospasm, HF, Enhanced $


adrenergic generics 40 mg BID/TID po hypotension, sleep cardiodepressant
Antagonists, Usual: disturbances, effect with
nonselective 60 mg QID po dizziness, fatigue, calcium channel
without ISA anorexia, nausea, AV blockers,
block, bradycardia, antiarrhythmics,
claudication, anesthetics.
Raynaud's, lethargy, Increased
drowsiness. bradycardia with
digoxin.
Hypertension with
alpha-agonists.

Beta1- timolol Initial: Bronchospasm, HF, Enhanced $


adrenergic Apo-Timol, other 5–10 mg BID po hypotension, sleep cardiodepressant
Antagonists, generics Usual: disturbances, effect with
nonselective 10 mg BID po dizziness, fatigue, calcium channel
without ISA anorexia, nausea, AV blockers,
block, bradycardia, antiarrhythmics,
claudication, anesthetics.
Raynaud's, lethargy, Increased
drowsiness. bradycardia with
digoxin.
Hypertension with
alpha-agonists.

Calcium amlodipine Hypotension, flushing, $$


Channel Norvasc, GD- 5–10 mg/day po marked peripheral
Blockers edema.

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Therapeutic Choice

Drug
Class Drug Dose Adverse Effects Interactions Costa

amlodipine,
other generics

Calcium diltiazem Bradycardia, heart Additive effect $-$$$


Channel Cardizem CD, 120–360 mg/day po block, edema, with β-blockers,
Blockers Give IR formulations hypotension. digoxin,
Tiazac, Tiazac XC,
TID or QID; CD and XC amiodarone.
generics
once daily Monitor for
excessive
bradycardia.

Calcium verapamil Bradycardia, heart Additive effect $-$$$


Channel Isoptin SR, 180–480 mg/day po block, hypotension, with β-blockers,
Blockers generics Give IR formulations constipation, flushing, digoxin,
TID; SR BID edema. amiodarone.
Monitor for
excessive
bradycardia.

Nitrates isosorbide Initial: 30–90 mg/day Headache (up to 50%; Potential $


dinitrate, IR po tolerance may hypotensive effect
generics IR: give TID (allow a develop), tachycardia, with vasodilators.
12 h nitrate-free palpitation, Contraindicated
period) hypotension, syncope with recent
(rare), dizziness, (<24 h) use of
nausea, flushing, sildenafil,
weakness. tadalafil or
vardenafil; use
with caution when
hypotension
present.

Nitrates isosorbide-5- Headache (up to 50%; Potential $


mononitrate 30–60 mg daily po tolerance may hypotensive effect
develop), tachycardia, with vasodilators.
Imdur, generics
palpitation, Contraindicated
hypotension, syncope with recent
(rare), dizziness, (<24 h) use of
nausea, flushing, sildenafil,
weakness. tadalafil or
vardenafil; use
with caution when
hypotension
present.

Nitrates nitroglycerin Initial: Frequent BP Potential $b


intravenous 10–150 µg/min iv monitoring is required hypotensive effect
generics (titrate to symptoms for iv nitroglycerin. with vasodilators.
and blood pressure) Headache (up to 50%; Contraindicated
tolerance may with recent
develop), tachycardia, (<24 h) use of
palpitation, sildenafil,
hypotension, syncope tadalafil or
(rare), dizziness, vardenafil; use
nausea, flushing, with caution when
weakness. hypotension
present.

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Therapeutic Choice

Drug
Class Drug Dose Adverse Effects Interactions Costa

Nitrates nitroglycerin Headache (up to 50%; Potential $-$$


transdermal 0.2–0.8 mg/h patch tolerance may hypotensive effect
applied daily for 10–12 develop), tachycardia, with vasodilators.
Minitran, Nitro-
h palpitation, Contraindicated
Dur, Transderm- hypotension, syncope with recent
Nitro, Trinipatch (rare), dizziness, (<24 h) use of
nausea, flushing, sildenafil,
weakness. tadalafil or
Contact dermatitis. vardenafil; use
with caution when
hypotension
present.

ACE Inhibitors captopril Initial: Proteinuria (1%), ↑ risk of $$


Capoten, generics 6.25 mg Q8H po neutropenia (rare), neutropenia with
Target: rash, angioedema, antiarrhythmics,
50 mg Q8H po hypotension, allopurinol,
alterations in taste, corticosteroids.
nausea, anorexia, Hyperkalemia
dizziness, with
hyperkalemia, dry spironolactone,
cough (common). triamterene,
Caution in patients amiloride.
with renovascular Hypotension with
hypertension, renal diuretics.
insufficiency, bilateral
renal artery stenosis Avoid concurrent
or single kidney with therapy with
renal artery stenosis. lithium.

ACE Inhibitors cilazapril Initial: Proteinuria (1%), ↑ risk of $


Inhibace, 0.5 mg daily po neutropenia (rare), neutropenia with
generics Target: rash, angioedema, antiarrhythmics,
2.5 mg daily po hypotension, allopurinol,
alterations in taste, corticosteroids.
nausea, anorexia, Hyperkalemia
dizziness, with
hyperkalemia, dry spironolactone,
cough (common). triamterene,
Caution in patients amiloride.
with renovascular Hypotension with
hypertension, renal diuretics.
insufficiency, bilateral
renal artery stenosis Avoid concurrent
or single kidney with therapy with
renal artery stenosis. lithium.

ACE Inhibitors enalapril Initial: Proteinuria (1%), ↑ risk of $$


Vasotec, generics 2.5 mg BID po neutropenia (rare), neutropenia with
Target: rash, angioedema, antiarrhythmics,
10 mg BID po hypotension, allopurinol,
alterations in taste, corticosteroids.
nausea, anorexia, Hyperkalemia
dizziness, with
hyperkalemia, dry spironolactone,
cough (common). triamterene,

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Therapeutic Choice

Drug
Class Drug Dose Adverse Effects Interactions Costa

Caution in patients amiloride.


with renovascular Hypotension with
hypertension, renal diuretics.
insufficiency, bilateral
renal artery stenosis Avoid concurrent
or single kidney with therapy with
renal artery stenosis. lithium.

ACE Inhibitors fosinopril Initial: 5 mg daily po Proteinuria (1%), ↑ risk of $


Monopril, Target: neutropenia (rare), neutropenia with
generics 20 mg daily po rash, angioedema, antiarrhythmics,
hypotension, allopurinol,
alterations in taste, corticosteroids.
nausea, anorexia, Hyperkalemia
dizziness, with
hyperkalemia, dry spironolactone,
cough (common). triamterene,
Caution in patients amiloride.
with renovascular Hypotension with
hypertension, renal diuretics.
insufficiency, bilateral
renal artery stenosis Avoid concurrent
or single kidney with therapy with
renal artery stenosis. lithium.

ACE Inhibitors lisinopril Initial: 2.5 mg daily po Proteinuria (1%), ↑ risk of $


Zestril, Prinivil, Target: neutropenia (rare), neutropenia with
generics 20 mg daily po rash, angioedema, antiarrhythmics,
hypotension, allopurinol,
alterations in taste, corticosteroids.
nausea, anorexia, Hyperkalemia
dizziness, with
hyperkalemia, dry spironolactone,
cough (common). triamterene,
Caution in patients amiloride.
with renovascular Hypotension with
hypertension, renal diuretics.
insufficiency, bilateral
renal artery stenosis Avoid concurrent
or single kidney with therapy with
renal artery stenosis. lithium.

ACE Inhibitors quinapril Initial: 5 mg daily po Proteinuria (1%), ↑ risk of $


Accupril Target: neutropenia (rare), neutropenia with
20 mg daily po rash, angioedema, antiarrhythmics,
hypotension, allopurinol,
alterations in taste, corticosteroids.
nausea, anorexia, Hyperkalemia
dizziness, with
hyperkalemia, dry spironolactone,
cough (common). triamterene,
Caution in patients amiloride.
with renovascular Hypotension with
hypertension, renal diuretics.
insufficiency, bilateral
renal artery stenosis Avoid concurrent
or single kidney with therapy with
renal artery stenosis. lithium.

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Therapeutic Choice

Drug
Class Drug Dose Adverse Effects Interactions Costa

ACE Inhibitors ramipril Initial: 1.25–2.5 mg Proteinuria (1%), ↑ risk of $


Altace, generics BID po neutropenia (rare), neutropenia with
Target: rash, angioedema, antiarrhythmics,
5 mg BID or hypotension, allopurinol,
10 mg daily po alterations in taste, corticosteroids.
nausea, anorexia, Hyperkalemia
dizziness, with
hyperkalemia, dry spironolactone,
cough (common). triamterene,
Caution in patients amiloride.
with renovascular Hypotension with
hypertension, renal diuretics.
insufficiency, bilateral
renal artery stenosis Avoid concurrent
or single kidney with therapy with
renal artery stenosis. lithium.

Aldosterone spironolactone Initial: 12.5 mg daily Rash, urticaria, Hyperkalemia $


Antagonists Aldactone, po gynecomastia, nausea, with ACE
generics Target 25–50 mg daily vomiting, diarrhea, inhibitors,
po confusion, digoxin, NSAIDs.
hyperkalemia,
agranulocytosis, SLE.

Antiplatelet ASA Gastritis, Heparin, warfarin $


Agents Aspirin, Coated 80–325 mg/day po gastric/duodenal (bleeding risk
ulceration (rarely with heparin is
Aspirin,
bronchospasm). low); other
Asaphen/Asaphen
Nausea, vomiting, GI NSAIDs.
EC, Entrophen,
hemorrhage, tinnitus,
generics
vertigo,
hypersensitivity.

Antiplatelet clopidogrel Loading dose pre-PCI Bleeding, rash, Caution with $$$$
Agents Plavix or STEMI: 300–600 mg, purpura. Similar NSAIDs. PPI use
then 75 mg daily po tolerability to ASA. may reduce
clopidogrel
efficacy.45

Antiplatelet prasugrel Loading dose: 60 mg, Increased risk of Caution with $$$$
Agents Effient then 10 mg daily po bleeding. Caution in NSAIDs.
patients >75 y, body
weight <60 kg.
Contraindicated if
history of ischemic
stroke.

Antiplatelet ticlopidine Diarrhea, rash, Caution with $$


Agents generics 250 mg BID po neutropenia, purpura. NSAIDs. May ↑
Measure neutrophils theophylline
Q2 wk × 3 mo levels.
initially.

Heparin, heparin sodium Bleeding, ASA, warfarin $b


Unfractionated Hepalean, 60–70 U/kg iv bolus thrombocytopenia. (bleeding risk
Maximum: 5000 U then with ASA is low);
Heparin LEO,
aPTT response
generics

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Therapeutic Choice

Drug
Class Drug Dose Adverse Effects Interactions Costa

12–15 U/kg/h. may be blunted


Adjust to maintain aPTT with concurrent iv
at 1.5–2 × control. nitroglycerin
First aPTT 4 h after (controversial).
bolus

Post-thrombolytic:
bolus
60 U/kg iv
Maximum: 4000 U then
12 U/kg/h.

Adjust to maintain aPTT


at 1.5–2 × control.
First aPTT 6 h after
bolus

Heparins, Low dalteparin Hematoma at injection ASA, warfarin $b


Molecular Fragmin 120 IU/kg BID sc site, bleeding, (bleeding risk
Weight Maximum: thrombocytopenia; with ASA is low).
10 000 IU/dose caution if ClCr <30
mL/min.

Heparins, Low enoxaparin 1 mg/kg BID sc Hematoma at injection ASA, warfarin $b


Molecular Lovenox Maximum: site, bleeding, (bleeding risk
Weight 100 mg/dose thrombocytopenia; with ASA is low).
caution if ClCr <30
Post-thrombolytic: 30 mL/min.
mg iv bolus in addition Caution in elderly
to first sc dose patients and those
with renal
When ≥75 y, omit insufficiency.
bolus and reduce dose
to 0.75 mg/kg BID (75 Preferred LMWH in
mg maximum for first 2 ACS.
doses)

Specific Factor fondaparinux 2.5 mg daily sc Bleeding, allergic Use caution with $b
Xa Inhibitors Arixtra First dose iv if STEMI reactions (rare). other drugs that
Not recommended as affect hemostasis.
sole agent in patients
undergoing PCI due to
risk of catheter
thrombosis.

Direct bivalirudin Bolus: 0.75 mg/kg iv, Bleeding, allergic Use caution with $447
Thrombin Angiomax then 1.75 mg/kg/h reactions (rare). other drugs that (250 mg
Inhibitors affect hemostasis. vial)b

Thrombolytics alteplase Bolus: 15 mg iv, then Bleeding (can be $2746


Activase rt-PA 0.75 mg/kg × 30 min fatal). (100 mg
(maximum 50 mg), Absolute vial)b
then 0.5 mg/kg × 60 contraindications:
min (maximum 35 mg) previous intracranial
Maximum dose 100 mg hemorrhage; known
malignant intracranial

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Therapeutic Choice

Drug
Class Drug Dose Adverse Effects Interactions Costa

Start heparin with neoplasm, known


infusion cerebral vascular
lesion, ischemic stroke
within 3 mo EXCEPT
acute stroke within 3
h; suspected aortic
dissection; active
bleeding or bleeding
diathesis (excluding
menses); significant
closed head or facial
trauma within 3 mo.

Relative
contraindications:
history of chronic
severe, poorly
controlled HTN, severe
uncontrolled HTN (BP
>180/110 mm Hg)c;
prior CVA greater than
3 mo or known
intracerebral
pathology not covered
above; traumatic or
prolonged (>10 min)
CPR or major surgery
(<3 wk);
noncompressible
venous punctures;
recent (2–4 wk)
internal bleeding;
pregnancy; active
peptic ulcer; current
use of anticoagulants.

Thrombolytics streptokinase 1.5 million units iv over Bleeding (can be $730


Streptase 1h fatal). (1.5 MU
Absolute vial)b
contraindications:
previous intracranial
hemorrhage; known
malignant intracranial
neoplasm, known
cerebral vascular
lesion, ischemic stroke
within 3 mo EXCEPT
acute stroke within 3
h; suspected aortic
dissection; active
bleeding or bleeding
diathesis (excluding
menses); significant
closed head or facial
trauma within 3 mo.

Relative
contraindications:
history of chronic
severe, poorly
controlled HTN, severe

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Therapeutic Choice

Drug
Class Drug Dose Adverse Effects Interactions Costa

uncontrolled HTN (BP


>180/110 mm Hg)c;
prior CVA greater than
3 mo or known
intracerebral
pathology not covered
above; traumatic or
prolonged (>10 min)
CPR or major surgery
(<3 wk);
noncompressible
venous punctures;
recent (2–4 wk)
internal bleeding;
pregnancy; active
peptic ulcer; current
use of anticoagulants.

Thrombolytics tenecteplase <60 kg: Bleeding (can be $2746


TNKase 30 mg iv × 1 fatal). (50 mg
60–69 kg: Absolute vial)b
35 mg iv × 1 contraindications:
70–79 kg: previous intracranial
40 mg iv × 1 hemorrhage; known
80–89 kg: malignant intracranial
45 mg iv × 1 neoplasm, known
≥90 kg: cerebral vascular
50 mg iv × 1 lesion, ischemic stroke
Given as iv bolus over within 3 mo EXCEPT
5s acute stroke within 3
h; suspected aortic
dissection; active
bleeding or bleeding
diathesis (excluding
menses); significant
closed head or facial
trauma within 3 mo.

Relative
contraindications:
history of chronic
severe, poorly
controlled HTN, severe
uncontrolled HTN (BP
>180/110 mm Hg)c;
prior CVA greater than
3 mo or known
intracerebral
pathology not covered
above; traumatic or
prolonged (>10 min)
CPR or major surgery
(<3 wk);
noncompressible
venous punctures;
recent (2–4 wk)
internal bleeding;
pregnancy; active
peptic ulcer; current
use of anticoagulants.

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Therapeutic Choice

Drug
Class Drug Dose Adverse Effects Interactions Costa

Glycoprotein eptifibatide Bolus: 180 µg/kg iv Bleeding (risk of Use caution with $$$$ b
IIb/IIIa Integrilin over 1–2 min, then serious bleeding other drugs that
Inhibitors 2 µg/kg/min appears to be low), affect hemostasis.
Maximum: primarily at puncture
15 mg/h sites.
ClCr <50 mL/min: Thrombocytopenia.
infuse at 1 µg/kg/min
Allergic reactions.

Glycoprotein tirofiban Bleeding (risk of Use caution with $$$$ b


IIb/IIIa Aggrastat 0.4 µg/kg/min iv × 30 serious bleeding other drugs that
Inhibitors min then appears to be low), affect hemostasis.
0.1 µg/kg/min × primarily at puncture
48–72 h sites.
ClCr Thrombocytopenia.
<30 mL/min:
0.2 µg/kg/min iv × 30 Allergic reactions.
min then
0.05 µg/kg/min × 72 h

a. Cost of 30-day supply, includes drug cost only except where noted.
b. Cost of average 1-day supply.
c. Could be an absolute contraindication in low-risk patients with STEMI.

Dosage adjustment may be required in renal impairment; see Appendices: Dosage Adjustment in Renal Impairment.

Abbreviations: aPTT=activated partial thromboplastin time; HF=heart failure; CVA=cerebrovascular accident; DBP=diastolic
blood pressure; GI=gastrointestinal; GU=genitourinary; HTN=hypertension; IR=immediate-release; ISA=intrinsic
sympathomimetic activity; NSAIDs=nonsteroidal anti-inflammatory drugs; NTG=nitroglycerin; PCI=percutaneous coronary
intervention; PPI=proton pump inhibitor; SBP=systolic blood pressure; SCr=serum creatinine; SR=slow-
release; TTP=thrombotic thrombocytopenic purpura; U=units

Legend: $ < $25 $-$$ < $25–50 $$ $25–50 $-$$$ < $25–75 $$$ $50–75 $$$$ $75–100

Suggested Readings

Antman EM, Anbe DT, Armstrong PW et al. ACC/AHA guidelines for the management of patients with ST-elevation
myocardial infarction--executive summary: a report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management
of Patients With Acute Myocardial Infarction). Circulation 2004;110(5):588-636.

Boersma E, Harrington RA, Moliterno DJ et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes:
a meta-analysis of all major randomised clinical trials. Lancet 2002;359(9302):189-98.

Braunwald E, Antman EM, Beasley JW et al. ACC/AHA guideline update for the management of patients with unstable
angina and non-ST-segment elevation myocardial infarction—2002: summary article: a report of the American
College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management
of Patients With Unstable Angina). Circulation 2002;106(14):1893-900.

References

1. Alpert JS, Thygesen K, Antman E et al. Myocardial infarction redefined—a consensus document of The Joint

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Therapeutic Choice
European Society of Cardiology/American Collegeof Cardiology Committee for the redefinition of myocardial
infarction. J Am Coll Cardiol 2000;36(3):959-69.
2. Heidenreich PA, Alloggiamento T, Melsop K et al. The prognostic value of troponin in patients with non-ST
elevation acute coronary syndromes: a meta-analysis. J Am Coll Cardiol 2001;38(2):478-85.
3. Ottani F, Galvani M, Nicolini FA et al. Elevated cardiac troponin levels predict the risk of adverse outcome in
patients with acute coronary syndromes. Am Heart J 2000;140(6):917-27.
4. Antman EM, Cohen M, Bernink PJ et al. The TIMI risk score for unstable angina/non-ST elevation MI: a
method for prognostication and therapeutic decision making. JAMA 2000;284(7):835-42.
5. Yan AT, Yan RT, Tan M et al. Risk scores for risk stratification in acute coronary syndromes: useful but simpler
is not necessarily better. Eur Heart J 2007;28(9):1072-8.
6. Cannon CP, Weintraub WS, Demopoulos LA et al. Comparison of early invasive and conservative strategies in
patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J
Med 2001;344(25):1879-87.
7. Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of
individual data from 100,000 patients in randomized trials. ACE Inhibitor Myocardial Infarction Collaborative
Group. Circulation 1998;97(22):2202-12.
8. Yusuf S, Sleight P, Pogue J et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on
cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N
Engl J Med 2000;342(3):145-53.
9. Yusuf S, Zhao F, Mehta SR et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary
syndromes without ST-segment elevation. N Engl J Med 2001;345(7):494-502.
10. Budaj A, Yusuf S, Mehta SR et al. Benefit of clopidogrel in patients with acute coronary syndromes without
ST-segment elevation in various risk groups. Circulation 2002;106(13):1622-6.
11. Mehta SR, Yusuf S, Peters RJ et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term
therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358
(9281):527-33.
12. U.S. Food and Drug Administration. FDA Drug Safety Communication: Reduced effectiveness of Plavix
(clopidogrel) in patients who are poor metabolizers of the drug. Available from:
www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htm.
Accessed January 18, 2011.
13. ACCF/AHA clopidogrel clinical alert: approaches to the FDA “boxed warning”: a report of the American College
of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the American Heart
Association. Circulation 2010;122(5):537-57.
14. Wiviott SD, Braunwald E, McCabe CH et al. Prasugrel versus clopidogrel in patients with acute coronary
syndromes. N Engl J Med 2007;357(2):2001-15.
15. Holdright D, Patel D, Cunningham D et al. Comparison of the effect of heparin and aspirin versus aspirin alone
on transient myocardial ischemia and in-hospital prognosis in patients with unstable angina. J Am Coll Cardiol
1994;24(1):39-45.
16. Theroux P, Ouimet H, McCans J et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med
1988;319(17):1105-11.
17. Comparison of two treatment durations (6 days and 14 days) of a low molecular weight heparin with a 6-day
treatment of unfractionated heparin in the initial management of unstable angina or non-Q wave myocardial
infarction: FRAX.I.S. (FRAxiparine in Ischaemic Syndrome). Eur Heart J 1999;20(21):1553-62.
18. Antman EM, McCabe CH, Gurfinkel EP et al. Enoxaparin prevents death and cardiac ischemic events in unstable
angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B
trial. Circulation 1999;100(15):1593-601.
19. Cohen M, Demers C, Gurfinkel EP et al. A comparison of low-molecular-weight heparin with unfractionated
heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave
Coronary Events Study Group. N Engl J Med 1997;337(7):447-52.
20. Klein W, Buchwald A, Hillis SE et al. Comparison of low-molecular-weight heparin with unfractionated heparin
acutely and with placebo for 6 weeks in the management of unstable coronary artery disease. Fragmin in
unstable coronary artery disease study (FRIC). Circulation 1997;96(1):61-8.
21. Michalis LK, Katsouras CS, Papamichael N et al. Enoxaparin versus tinzaparin in non-ST-segment elevation
acute coronary syndromes: the EVET trial. Am Heart J 2003;146(2):304-10.
22. Yusuf S, Mehta SR, Chrolavicius S et al. Comparison of fondaparinux and enoxaparin in acute coronary
syndromes. N Engl J Med 2006;354(14):1464-76.
23. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. Platelet Receptor
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Therapeutic Choice
Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators. N Engl J Med 1998;338(21):1498-
505.
24. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave
myocardial infarction. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by
Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. N Engl J Med 1998;338(21):1488-97.
25. Labinaz M, Kilaru R, Pieper K et al. Outcomes of patients with acute coronary syndromes and prior coronary
artery bypass grafting: results from the platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression
using integrilin therapy (PURSUIT) trial. Circulation 2002;105(3):322-7.
26. Moliterno DJ, Yakubov SJ, DiBattiste PM et al. Outcomes at 6 months for the direct comparison of tirofiban
and abciximab during percutaneous coronary revascularisation with stent placement: the TARGET follow-up
study. Lancet 2002;360(9330):355-60.
27. O'Shea JC, Hafley GE, Greenberg S et al. Platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in
coronary stent intervention: the ESPRIT trial: a randomized controlled trial. JAMA 2001;285(19):2468-73.
28. Braunwald E, Antman EM, Beasley JW et al. ACC/AHA guidelines for the management of patients with unstable
angina and non-ST-segment elevation myocardial infarction. A report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of
Patients With Unstable Angina). J Am Coll Cardiol 2000;36(3):970-1062.
29. Grines CL, Browne KF, Marco J et al. A comparison of immediate angioplasty with thrombolytic therapy for
acute myocardial infarction. The Primary Angioplasty in Myocardial Infarction Study Group. N Engl J Med
1993;328(10):673-9.
30. Hochman JS, Sleeper LA, White HD et al. One-year survival following early revascularization for cardiogenic
shock. JAMA 2001;285(2):190-2.
31. Thiemann DR, Coresh J, Schulman SP et al. Lack of benefit for intravenous thrombolysis in patients with
myocardial infarction who are older than 75 years. Circulation 2000;101(19):2239-46.
32. Antman EM, Morrow DA, McCabe CH et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-
elevation myocardial infarction. N Engl J Med 2006;354(14):1477-88.
33. Antman EM, Anbe DT, Armstrong PW et al. ACC/AHA guidelines for the management of patients with ST-
elevation myocardial infarction--executive summary: a report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the
Management of Patients With Acute Myocardial Infarction). Circulation 2004;110(5):588-636.
34. Yusuf S, Held P, Furberg C. Update of effects of calcium antagonists in myocardial infarction or angina in light
of the second Danish Verapamil Infarction Trial (DAVIT-II) and other recent studies. Am J Cardiol 1991;67
(15):1295-7.
35. Yusuf S, Collins R, MacMahon S et al. Effect of intravenous nitrates on mortality in acute myocardial
infarction: an overview of the randomised trials. Lancet 1988;1(8594):1088-92.
36. Pitt B, Zannad F, Remme WJ et al. The effect of spironolactone on morbidity and mortality in patients with
severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341(10):709-
17.
37. Pitt B, Remme W, Zannad F et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular
dysfunction after myocardial infarction. N Engl J Med 2003;348(14):1309-21.
38. Chen ZM, Jiang LX, Chen YP et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial
infarction: randomised placebo-controlled trial. Lancet 2005;366(9497):1607-21.
39. Sabatine MS, Cannon CP, Gibson CM et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for
myocardial infarction with ST-segment elevation. N Engl J Med 2005;352(12):1179-89.
40. Moss AJ, Zareba W, Hall WJ et al. Prophylactic implantation of a defibrillator in patients with myocardial
infarction and reduced ejection fraction. N Engl J Med 2002;346(12):877-83.
41. Gregoratos G, Abrams J, Epstein AE et al. ACC/AHA/NASPE 2002 guideline update for implantation of cardiac
pacemakers and antiarrhythmia devices: summary article: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to
Update the 1998 Pacemaker Guidelines). Circulation 2002;106(16):2145-61.
42. Berman J, Haffajee CI, Alpert JS. Therapy of symptomatic pericarditis after myocardial infarction:
retrospective and prospective studies of aspirin, indomethacin, prednisone, and spontaneous resolution. Am
Heart J 1981;101(6):750-3.
43. Mehta SR, Yusuf S, Peters RJ et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term
therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358
(9281):527-33.
44. Popma JJ, Berger P, Ohman EM et al. Antithrombotic therapy during percutaneous coronary intervention: the
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Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126( 3 Suppl):576S-
599S.
45. Lau WC, Gurbel PA. The drug-drug interaction between proton pump inhibitors and clopidogrel. CMAJ
2009;180(7):699-700.

Therapeutic Choices. © Canadian Pharmacists Association, 2011. All rights reserved.

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Therapeutic Choice

Print Close

Cardiovascular Disorders: Acute Stroke

Date Prepared: May 2009

Stephen J. Phillips, BSc, MBBS, FRCPC

Gord Gubitz, BSc, MD, FRCPC (Edin)

Stroke, recognized clinically as the sudden onset of a focal disturbance of central nervous system function, may be
caused by cerebral infarction (ischemic stroke, responsible for about 85% of all strokes) or intracerebral
hemorrhage.1 Warning signs promoted by the Heart and Stroke Foundation that suggest the presence of stroke are
shown in Table 1. The third main stroke subtype, subarachnoid hemorrhage, more often causes sudden onset severe
headache with or without impaired consciousness.

There is no acute-phase intervention of proven value for intracerebral hemorrhage. Post-acute treatment of primary
intracerebral hemorrhage is similar to that of ischemic stroke except that antithrombotic drugs are avoided.
Treatment of subarachnoid hemorrhage is primarily nonpharmacologic (i.e., ablation of the bleeding source). Refer
patients with suspected subarachnoid hemorrhage to a neurosurgical centre.

Table 1: Warning Signs of Stroke

Weakness − sudden loss of strength or numbness in the face, arm or leg

Difficulty with speech − sudden confusion or trouble speaking

Vision problems − sudden trouble with vision

Headache − sudden severe and unusual headache

Dizziness − loss of balance, especially with any of the above signs

Goals of Therapy 2 , 3 , 4

Minimize brain damage


Prevent complications
Reduce risk of recurrence
Restore function of the individual

Investigations

The evaluation of patients with suspected stroke is highly time dependent. Specific stroke treatments (alteplase) can
only be provided within the first 4.5 hours of symptom onset in patients with ischemic stroke (see Figure 1 -
Emergency Department Management of Patients with Suspected Stroke).

Use the clinical history, physical examination, imaging studies and other ancillary investigations to confirm the
diagnosis and exclude stroke mimics such as subdural hematoma, Todd's paresis (post seizure), brain abscess,
herpes simplex encephalitis, hypoglycemia, brain tumour (primary or secondary), multiple sclerosis, migraine and
conversion disorder.

History
time of onset, symptoms at onset, course of symptoms since onset
antecedent trauma or illness, previous neurovascular events
vascular comorbidity (angina, MI, heart failure, atrial fibrillation, peripheral and renal vascular disease)
vascular disease risk factors (hypertension, smoking, diabetes mellitus, dyslipidemia, excessive alcohol
intake, body mass index, exercise, family history of vascular disease or hemostatic disorders)
other health problems (particularly peptic ulcer disease or other disorders that predispose to bleeding)
pre-stroke cognitive and functional status
family history of premature vascular disease
place of residence and social supports
medications (particularly warfarin, ASA and other antiplatelet drugs)
Physical examination
to localize the lesion by brain region and vascular territory
to determine stroke syndrome, severity and cause

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Therapeutic Choice
to assess comorbid conditions
Laboratory and radiological tests
CBC, INR, PTT, glucose (to rule out hypoglycemia as a stroke mimic), electrolytes, urea, creatinine, liver
function tests, albumin
fasting glucose, hemoglobin A1c, cholesterol panel (for risk factor modification)
ECG (to look for atrial fibrillation, MI and left ventricular hypertrophy)
chest x-ray (to look for heart disease, lung cancer)
CT (or MR) brain scan is required immediately2 for all patients to rule out intracerebral hemorrhage and
stroke mimics. For patients who are found to have intracranial hemorrhage, the location of the hemorrhage
determines subsequent treatment (see Figure 2 - Approach to a Finding of Intracranial Hemorrhage on CT
Scan)
lumbar puncture if subarachnoid hemorrhage suspected and CT scan negative for blood
urgent (same or next day) vascular imaging (duplex carotid ultrasonography, CT angiography or MR
angiography) to determine the degree of carotid stenosis in patients with nondisabling carotid territory
strokes who are fit for carotid endarterectomy2
echocardiography (transthoracic +/− transesophageal) to search for a cardiac source of emboli in patients
with a recent history of MI or cardiac surgery, and any patient with a large-vessel territory (nonlacunar)
stroke and neurovascular imaging studies showing no large-vessel disease, provided anticoagulation is not
contraindicated
other investigations if indicated:
blood cultures to rule out endocarditis
inflammatory markers (ESR, CRP, ANA) as a screen for vasculitis
syphilis serology
antiphospholipid antibodies, protein C, protein S, antithrombin, factor V Leiden and prothrombin gene
mutation if hypercoagulable state suspected
malignancy work-up (CT chest, abdomen, pelvis)

Therapeutic Choices

I. Minimize Brain Damage

Ischemic Stroke

Alteplase should be administered (iv) as soon as possible following stroke onset for patients who meet
strict eligibility criteria2,5 (Figure 1 - Emergency Department Management of Patients with Suspected
Stroke, Table 2, Table 3, Table 4). A meta-analysis concluded that thrombolysis within 3 hours
provided a significant reduction (odds ratio 0.71, 95% confidence interval 0.52–0.96) in the chance of
death and dependency 3–6 months after ischemic stroke.6 Health Canada currently approves
administration within 3 hours of stroke onset, though evidence from randomized trials demonstrates
benefit up to 4.5 hours.2 Useful Info?

Intra-arterial administration of thrombolytic agents is presently of limited clinical application, except in highly
specialized centres, where randomized trials are ongoing.

Nonpharmacologic methods of achieving recanalization are under investigation. Mechanical clot-retrieving devices
have been approved for removing thrombus (but not for treating stroke) in the United States, but not in Canada.

Subarachnoid Hemorrhage

Nimodipine 60 mg po/ng Q4H for 3 weeks reduces the risk of secondary vasospasm and cerebral infarction.7 Use
30 mg po/ng Q2H in patients who are very sensitive to the blood pressure lowering effects (Table 5).

Neurosurgical Intervention

Ischemic stroke
Decompressive craniectomy may be performed on patients with massive hemispheric infarcts whose level of
consciousness is declining. Evidence from a pooled analysis of 3 smaller randomized trials found an increase in
survival for these patients when treated with craniectomy. However, survivors did incur significant amounts of
disability.8 Consensus opinion is that patients with large cerebellar infarcts may benefit from surgical
decompression.

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Table 2: Alteplase in Acute Ischemic Stroke: Treatment Criteria

Treatment criteria
Ischemic stroke in a patient ≥ 18 years
Stroke onset > 1 h and ≤ 4.5 h before alteplase administration
Stroke deficit that is disabling or measurable on the NIH Stroke Scale
No intracranial hemorrhage on CT or MRI scan

Exclusion criteria
Time of stroke onset unknown or > 4.5 h
Any hemorrhage on brain CT or MRI scan
Symptoms suggestive of subarachnoid hemorrhage
CT or MRI signs of acute hemispheric infarction involving more than 1/3 of the middle cerebral artery territory
(Alberta Stroke Program Early CT Score < 5)
History of intracranial hemorrhage
Stroke or serious head or spinal trauma within the preceding 3 mo
Seizure at stroke onset
Systolic blood pressure ≥ 185 mm Hg or diastolic blood pressure ≥ 110 mm Hg or aggressive treatment
(intravenous medication) necessary to reduce blood pressure to these limits
Recent major surgery
Arterial puncture at a noncompressible site within the previous 7 days
Elevated activated partial thromboplastin time
International normalized ratio > 1.7
Platelet count < 100 × 109/L
Blood glucose concentration < 2.7 or > 22 mmol/L
Any other condition that could increase the risk of hemorrhage after alteplase administration

Adapted with permission from “Canadian best practice recommendations for stroke care (updated 2008)”, CMAJ December
2008;179(12 Suppl), pages E1-93. [Online English Version] © 2008 Canadian Medical Association.

Abbreviations: CT=computed tomography; NIH=National Institutes of Health; MRI=magnetic resonance imaging

Intracerebral hemorrhage (see Figure 2 - Approach to a Finding of Intracranial Hemorrhage on CT Scan)


Patients with cerebellar hemorrhage should have an urgent neurosurgical consultation for consideration of
craniotomy and evacuation of the hemorrhage.2 There is no specific acute-phase neurosurgical intervention of
proven value for supratentorial intracerebral hemorrhage.9 Patients with supratentorial intracerebral hemorrhage
should be cared for on a stroke unit.2 The medical treatment of patients with intracerebral hemorrhage is similar
to that of ischemic stroke, except that antithrombotic drugs and statins are avoided.10

Subarachnoid hemorrhage (see Figure 2 - Approach to a Finding of Intracranial Hemorrhage on CT Scan)


Refer patients with suspected subarachnoid hemorrhage immediately to a neurosurgical centre.2

Table 3: Alteplase in Acute Ischemic Stroke: Monitoring5

Blood Pressure and Neurological Signs


• Baseline, then Q15min × 2 h after starting alteplase
• Then Q30min × 6 h
• Then Q1H until 24 h after starting alteplase
• Call MD if the systolic BP is > 180 mm Hg or if the diastolic BP is > 110 mm Hg on 2 or more occasions taken
5–10 min apart
• Stop the infusion, obtain emergency CT scan and notify MD if there is neurologic deterioration, severe headache,
or new onset of nausea or vomiting

Blood Glucose
• Call MD if glucose > 12 mmol/L

Lines and Tubes


• Delay placement of nasogastric tubes, indwelling catheters or intra-arterial pressure catheters

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Medications
• No ASA, ticlopidine, clopidogrel, heparin or warfarin for 24 h
• Acetaminophen 650 mg po or pr Q4H if body temperature is ≥ 38°C or for analgesia
• O2 via nasal prongs or face mask to keep O2 saturation > 90%
• After the alteplase infusion is completed, continue iv normal saline (with or without KCl)

Investigations
• CT brain scan after 24 h

II. Prevent Complications

General Supportive Care

Expert nursing care and early mobilization are the mainstays of treatment.
Use oxygen if pulse oximetry shows desaturation (SaO2 < 90%).5
Elevated body temperature is associated with poor outcome after stroke.11 , 12 , 13 Symptomatic treatment of
pyrexia (and investigation of its cause) is recommended.2
Hyperglycemia is associated with poor outcome after stroke and should be treated,2 but there is no definitive
clinical trial data to support the use of intravenous insulin.14

Aspiration Pneumonia and Malnutrition2

Review the nutritional status (pre-albumin, weight) on admission to identify patients who were malnourished
before their stroke.
Give nothing by mouth if any of the following are present: reduced level of consciousness, severe dysarthria,
wet voice, weak cough, impaired palatal sensation, inability to sit, suspected aspiration.
Monitor recovery of dysphagia using serial bedside swallowing assessments, best performed by an experienced
dysphagia team.
A videofluoroscopic examination (modified barium swallow) may be required to exclude significant aspiration
when the results of the bedside examination are ambiguous.
Tube feeding may be required if significant aspiration is demonstrated or suspected. Initially, this is usually
done via a nasogastric tube. If swallowing does not recover, tube feeding via percutaneous endoscopic
gastrostomy (PEG) may be necessary. The results of the FOOD trial did not support a policy of early initiation of
PEG feeding in dysphagic stroke patients.15
Parenteral nutrition is required only in exceptional circumstances.
Give a texture-modified diet for dysphagic patients at lower risk of aspiration. Additional iv fluids are often
necessary for these patients.

Venous Thromboembolism2

Early mobilization (even if only up in a chair) is recommended (i.e., within the first day of admission to
hospital).
Maintain adequate hydration.
ASA (80–325 mg daily) reduces the risk of thromboembolism.16
In the absence of contraindications, the following interventions may also be used for patients with acute
ischemic stroke at high risk of venous thromboembolism (patients with inability to move one or both lower
limbs and those patients unable to mobilize independently):
graduated compression stockings.
low molecular weight heparin or unfractionated heparin in prophylactic doses (see Cardiovascular
Disorders: Venous Thromboembolism).
For patients with hemorrhagic stroke use graduated compression stockings and avoid antithrombotic drugs.

III. Reduce the Risk of Stroke Recurrence

Aneurysmal subarachnoid hemorrhage

Ablation of the aneurysm reduces the risk of rebleeding. Endovascular coiling is superior to neurosurgical clipping

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for ruptured intracranial aneurysm anatomically suitable for either procedure.17

Carotid endarterectomy (CEA)2

Patients with carotid territory transient ischemic attack or nondisabling stroke and ipsilateral 70–95% internal
carotid artery stenosis (measured on a catheter angiogram or by 2 concordant non-invasive imaging modalities)
should be offered carotid endarterectomy within 2 weeks of the incident transient ischemic attack or stroke unless
contraindicated. CEA is also appropriate for selected patients with moderate (50–69%) symptomatic stenosis. These
patients should be evaluated by a physician with expertise in stroke management. Carotid stenting may be
considered for patients who are not CEA candidates for technical, anatomical or medical reasons.

Antithrombotic Drug Treatment

Avoid in patients with hemorrhagic stroke.

Antiplatelet therapy2

If intracranial hemorrhage is excluded by CT scan, but alteplase is not indicated, give ASA 160 mg immediately.
This is followed by ASA 80–325 mg daily.
When alteplase is used, wait until intracranial hemorrhage is excluded by CT scan 24 hours later and give ASA
160 mg once. This is followed by ASA 80–325 mg daily.
Administer ASA as a suppository or via nasogastric tube to dysphagic patients. Use enteric-coated formulation
for patients who can swallow. No evidence supports the use of ASA doses greater than 325 mg/day for
secondary stroke prevention. The GI side effects of ASA are dose related.
For patients who were taking ASA prior to their stroke, consider other antiplatelet agents, such as clopidogrel
75 mg daily or a combination of ASA and sustained-release dipyridamole 25/200 mg twice daily,
although these regimens have not been tested in acute stroke.
The combination of ASA and clopidogrel is not recommended for long-term secondary stroke prevention.

Anticoagulant therapy2

Immediate systemic anticoagulation with unfractionated heparin, low molecular weight heparin, heparinoids or
specific thrombin inhibitors is not recommended in the setting of acute ischemic stroke, not even for patients in
atrial fibrillation (AF), because there is no evidence of short- or long-term benefit. Specifically, reduction in
early recurrent ischemic stroke is completely offset by an increase in major intracranial and extracranial
bleeding.18
ASA is as effective as warfarin for secondary stroke prevention in patients in normal sinus rhythm, and does not
require laboratory monitoring.
For patients in AF, use warfarin at a dose to maintain the INR in the range 2.0 to 3.0, provided there are no
contraindications to anticoagulation. For patients who cannot take warfarin, use enteric-coated ASA 80–325 mg
daily.
The best time to initiate anticoagulant therapy is unclear. For patients with minor strokes, start warfarin as soon
as intracranial hemorrhage has been excluded by CT scan. For patients with major strokes, delay warfarin until
a CT scan done about a week or two after the stroke has excluded hemorrhagic transformation of the infarct.
For post-acute antithrombotic treatment, carotid endarterectomy and risk-factor modification, see Cardiovascular
Disorders: Prevention of Ischemic Stroke.

Blood pressure lowering treatment2

Randomized controlled trials have not defined the optimal time to initiate blood pressure lowering therapy after
stroke.19 Oral blood pressure lowering treatment should be initiated (or modified) prior to discharge from hospital
in patients whose blood pressure is ≥ 140/90.

IV. Restore Function of the Individual2

Outcomes are optimized by care on a stroke unit provided by a coordinated interdisciplinary team (see Figure 3
- General Management of the Stroke Patient).
Start rehabilitation as soon as the patient is medically stable.
Family and community supports are important for social reintegration.

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Therapeutic Tips

The effectiveness of thrombolytic therapy with alteplase is exquisitely time dependent; delays of any sort should
not be tolerated. A minority of patients present to hospital within the first 90 minutes of stroke onset, leaving
limited time to act. Immediate contact with the patient, rapid triage, and (most importantly) staying with the
patient continuously during the clinical assessment, CT scan, blood tests and consent procedures are vital in
ensuring that the appropriate steps are being taken as rapidly as possible prior to alteplase administration. For
example, it is not necessary to wait for hospital porters to take the patient to the CT scanner.
Determining the time of stroke onset is critical in deciding to use alteplase, but checking the clock is not a
natural reaction in the setting of an acute stroke. Encourage patients and families to think of “time
anchors” (e.g., what was on the radio or TV at the time, or at what point in the patient's daily routine did the
symptoms first occur).
Patients with acute stroke are often unable to communicate. When possible, the next-of-kin should travel with
the patient to hospital (or between hospitals if the patient is transferred) to provide collateral history and
consent for treatment before the time window for intervention closes.
If the patient is referred to a tertiary care hospital, have the stat blood work (CBC, INR) drawn at the community
hospital and the results faxed to the referral centre as soon as possible.
Point-of-care INR testing , if available, can provide results quickly.
Signs of infarction on a CT scan done within 4.5 hours of stroke onset are usually subtle. If the CT scan of a
patient being considered for treatment with alteplase shows a very definite infarct in a location that explains the
presenting clinical symptoms and signs, recheck the time of onset.

Figure 1- Emergency Department Management of Patients with Suspected Stroke

a. Notify neurosurgeon if cerebellar infarct with mass effect on 4th ventricle (see text).

Abbreviations: CBC = complete blood count; CT = computed tomography; CXR = chest x-ray;
ECG = electrocardiogram; INR = International Normalized Ratio; PTT = partial thromboplastin time

Adapted with permission from Nova Scotia Guidelines for Stroke Care. Halifax (NS): Cardiovascular Health Nova Scotia; 2008.

Figure 2- Approach to a Finding of Intracranial Hemorrhage on CT Scan

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Abbreviations: CT = computed tomography

Adapted with permission from Nova Scotia Guidelines for Stroke Care. Halifax (NS): Cardiovascular Health Nova Scotia;
2008.

Figure 3- General Management of the Stroke Patient

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a. Hematoma volume (cm3) = A+B+C/2 where A = largest diameter (cm) on CT scan, B = diameter (cm) perpendicular to A, C =

number of scan slices (cm) showing hematoma.20 , 21


b. Hemiparesis and hemianopia with either aphasia or visuospatial deficit.22

Table 4: Drugs Used for Acute Ischemic Stroke

Class Drug Dose Adverse Effects Comments Costa

Antiplatelet ASA Initial: 160 mg Nausea, vomiting, If alteplase is to be < $1


Agents Aspirin, Maintenance: 80– hemorrhage, administered, wait 24 h
Bufferin, 325 mg daily hypersensitivity reactions before initiating ASA. If
(rarely bronchospasm). alteplase is not used, start
Coated
ASA as soon as
Aspirin, intracranial hemorrhage is
generics excluded by CT scan.
Use enteric-coated
formulations for patients
who can swallow.

Give via a nasogastric


tube or as a suppository
to dysphagic patients.

Fibrinolytic alteplase 0.9 mg/kg (max 90 Superficial bleeding, Review inclusion and $2746/100
Agents Activase mg) iv over 60 internal bleeding (i.e., exclusion criteria before mg vial

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Class Drug Dose Adverse Effects Comments Costa

rt-PA min. Give 10% of gastrointestinal, administering (Table 2).


the total dose as an genitourinary, respiratory No ASA, clopidogrel,
initial bolus over 1 tract, retroperitoneal), ticlopidine, heparin or
min. intracranial hemorrhage. warfarin for 24 h after
Cerebral edema, cerebral administration.
herniation, seizures and
new onset ischemic
stroke may occur and be
life threatening.

a. Cost of a 1-day supply; includes drug cost only.

Table 5: Drugs Used for Subarachnoid Hemorrhage

Costa
Class Drug Dose Adverse Effects Comments

Calcium nimodipine 60 mg Hypotension (5%), Crushing tablets for nasogastric $2600


Channel Q4H for nausea, bradycardia administration is not recommended since
Blockers Nimotop 21 days and rash. bioavailability reduces with time. If
necessary, crush and administer immediately.

a. Cost of 21-day supply; includes drug cost only.

Suggested Readings

Donnan GA, Fisher M, Macleod M et al. Stroke. Lancet 2008;371(9624):1612-23.

Internet Stroke Center at Washington University School of Medicine. Stroke trials registry. Available from:
www.strokecenter.org/trials/. Accessed July 22, 2010.

Lindsay P, Bayley M, Hellings C et al. Canadian best practice recommendations for stroke care (updated 2008). CMAJ
2008;179(12 Suppl):E1-93. Available from: www.cmaj.ca/cgi/data/179/12/S1/DC1/1. Accessed July 22, 2010.

Stroke Unit Trialists' Collaboration. Organised inpatient (stroke unit) care for stroke. Cochrane Database Syst Rev
2007;(4):CD000197.

Wardlaw JM, Murray V, Berge E et al. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2009;
(4):CD000213.

References

1. Warlow C, Sudlow S, Dennis M et al. Stroke. Lancet 2003;362(9391):1211-24.


2. Lindsay P, Bayley M, Hellings C et al. Canadian best practice recommendations for stroke care (updated 2008).
CMAJ 2008;179(12 Suppl): E1-93. Available from: www.cmaj.ca/cgi/data/179/12/S1/DC1/1. Accessed July
22, 2010.
3. Lindsay P, Bayley M, McDonald A et al. Toward a more effective approach to stroke: Canadian best practice
recommendations for stroke care. CMAJ 2008;178(11):1418-25.
4. Bayley M, Lindsay P, Hellings C et al. Balancing evidence and opinion in stroke care: the 2008 best practice
recommendations. CMAJ 2008;179(12):1247-9.
5. Adams HP, del Zoppo G, Alberts MJ et al. Guidelines for the early management of adults with ischemic stroke:
a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical

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Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral
Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American
Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation
2007;115(20):e478-534.
6. Wardlaw JM, Murray V, Berge E et al. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev
2009;(4):CD000213.
7. Rinkel GJ. Medical management of patients with aneurysmal subarachnoid hemorrhage. Int J Stroke 2008;3
(3):193-204.
8. Vahedi K, Hofmeijer J, Juettler E et al. Early decompressive surgery in malignant infarction of the middle
cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol 2007;6(3):215-22.
9. Broderick JP. The STICH trial: what does it tells us and where do we go from here? Stroke 2005;36(7):1619-
20.
10. Goldstein LB, Amarenco P, Szarek M et al. Hemorrhagic stroke in the Stroke Prevention by Aggressive
Reduction in Cholesterol Levels study. Neurology 2008;70(24 Pt 2):2364-70.
11. Jorgensen HS, Reith J, Pedersen PM et al. Body temperature and outcome in stroke patients. Lancet 1996;348
(9021):193.
12. Jorgensen HS, Reith J, Nakayama H et al. What determines good recovery in patients with the most severe
strokes? The Copenhagen Stroke Study. Stroke 1999;30(10):2008-12.
13. Reith J, Jorgensen HS, Pedersen PM et al. Body temperature in acute stroke: relation to stroke severity, infarct
size, mortality and outcome. Lancet 1996;347(8999):422-5.
14. Gray CS, Hildreth AJ, Sandercock PA et al. Glucose-potassium-insulin infusions in the management of post-
stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK). Lancet Neurol 2007;6(5):397-406.
15. Dennis MS, Lewis SC, Warlow C et al. Effect of timing and method of enteral tube feeding for dysphagic stroke
patients (FOOD): a multicentre randomised controlled trial. Lancet 2005;365(9461):764-72.
16. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy
for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324(7329):71-86.
17. Molyneux A, Kerr R, Stratton I et al. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical
clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised
trial. Lancet 2002;360(9342):1267-74.
18. Sandercock PA, Counsell C, Kamal AK. Anticoagulants for acute ischemic stroke. Cochrane Database Syst Rev
2008;(4):CD000024.
19. Sare GM, Geeganage C, Bath PM. High blood pressure in acute stroke: to treat or not to treat? Int J Stroke
2007;2(3):172-3.
20. Broderick JP, Brott TG, Duldner JE et al. Volume of intracerebral hemorrhage. A powerful and easy-to-use
predictor of 30-day mortality. Stroke 1993;24(7):987-93.
21. Broderick JP, Brott TG, Grotta JC. Intracerebral hemorrhage volume measurement. Stroke 1994;25(5):1081.
22. Bamford J, Sandercock P, Dennis M et al. Classification and natural history of clinically identifiable subtypes of
cerebral infarction. Lancet 1991;337(8756):1521-6.

Pharmacoeconomic Considerations: Acute Ischemic Stroke


Date of preparation: 2007-06-30
Nicole Mittmann, MSc, PhD

Epidemiology

Country (Year) Incidence and Prevalence (%)

Canada (2002)1 40 000–50 000 strokes per year


300 000 individuals live with the effects of stroke

Cost of Illness Data

Country and Year of Estimate Direct Costsa Indirect Costsb

Canada $529 million $328 million


(Ontario 1994-95)2

Canada $27 500 for acute stroke admission Not reported


(Ontario 1991-92)3

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Canada $9763 for acute stroke admission Not reported


(Ontario 1996)4

Commentary

Ischemic stroke is a significant disease in the aging population. From an economic perspective, the impact of
stroke on society will increase significantly as the population ages. Of every 100 people hospitalized for stroke,
50 will be discharged home, 20 will die before leaving the hospital, 15 will require long-term care and 10 will
enter an inpatient rehabilitation program. Stroke incidence is related to increased age and has an economic
impact on the patient, health care system and society.
Direct medical and nonmedical costs associated with stroke are significant. In acute stroke, hospitalization, length
of stay and rehabilitation are the cost drivers.5 Direct nonmedical costs including informal care, out-of-pocket
expenses and caregiver time are not well documented but have been estimated to be significant for informal
care.5 Indirect costs have not been well documented. Depending on the severity of the stroke, work productivity
and regular daily activities may be severely restricted. Long-term costs are significant.
Quality of life is significantly impaired by stroke.6 Predictors of poor quality of life included physical impairment,
disability and anxiety/depression.
Alteplase, which is used in patients with acute stroke, is expensive and must be administered expeditiously.
Researchers in Australia assessed the relative benefits of various interventions for acute stroke from a community
perspective.7 For every 1000 patients with stroke, death or dependency could be prevented in 46 individuals by
management in a stroke unit, in 6 individuals through use of ASA and in 11 individuals through use of alteplase
within 3 hours. The authors concluded that the greatest benefit to the community could be provided through the
establishment of dedicated stroke units.

a. Direct costs include those associated with physician services, nursing care, diagnostic procedures, drugs and hospitalization.
b. Indirect costs include those associated with lost productivity and days off work due to morbidity or premature mortality.

1. Heart and Stroke Foundation. Stroke statistics. Available from:


www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3483991/k.34A8/Statistics.htm. Accessed July 22, 2010.
2. Chan B, Hayes B. Cost of stroke in Ontario, 1994/95. CMAJ 1998;159(6 Suppl):S2-S8. Available from:
www.cmaj.ca/cgi/data/159/6/DC1/2. Accessed July 22, 2010.
3. Smurawska LT, Alexandrov AV, Bladin CF et al. Cost of acute stroke care in Toronto, Canada. Stroke 1994;25
(8):1628-31.
4. Tran C, Nadareishvili Z, Smurawska L et al. Decreasing costs of stroke hospitalization in Toronto. Stroke
1999;30(1):185-6.
5. Dewey HM, Thrift AG, Mihalopoulos C et al. Informal care for stoke survivors: results from the north east
Melbourne stroke incidence study (NEMESIS). Stroke 2002;33(4):1028-33.
6. Sturm JW, Donnan GA, Dewey HM et al. Quality of life after stroke: the North East Melbourne Stroke
Incidence Study (NEMESIS). Stroke 2004;35(10):2340-5.
7. Gilligan AK, Thrift AG, Sturm JW et al. Stroke units, tissue plasminogen activator, aspirin and
neuroprotection: which stroke intervention could provide the greatest community benefit? Cerebrovasc Dis
2005;20(4):239-44.

Therapeutic Choices. © Canadian Pharmacists Association, 2011. All rights reserved.

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Print Close

Cardiovascular Disorders: Dyslipidemias

Date Prepared: December 2010

Ghislaine O. Roederer, MD, PhD

The majority of dyslipidemias result from interaction between environmental and genetic factors. Understanding the contribution of
each factor in the dyslipidemic patient is beyond the scope of this chapter. Nevertheless, it is essential to rule out secondary causes of
dyslipidemia that, when identified and potentially eliminated, can prevent unnecessary treatment. In addition, the use of lipid-lowering
agents in the management of cardiovascular disease is increasingly emphasized.

Screening of the lipid-profile is recommended in children with a family history of hypercholesterolemia or chylomicronemia, men 40
years old and over, women older than 50 years or postmenopausal and all patients with the following conditions independent of age:
diabetes
hypertension
current cigarette smoking
obesity
family history of premature CAD (<60 years in first-degree relatives)
inflammatory diseases (SLE, RA, psoriasis)
chronic renal disease (eGFR <60 mL/min/1.73 m2)
evidence of atherosclerosis
HIV infection treated with HAART
clinical manifestations of hyperlipidemias (xanthomes, xanthelasmas, premature arcus cornealis)
erectile dysfunction

Goals of Therapy

Reduce risk of cardiovascular disease (CVD)


Prevent pancreatitis from severe hypertriglyceridemia

Investigations

Clinical evaluation should focus on:

Medical history
CVD (past or present): MI, angina, TIA, CVA, claudication, erectile dysfunction
possible causes of secondary dyslipidemia (Table 1)
major cardiovascular risk factors (Figure 1 - Management of Dyslipidemia1 , Figure 2 - Estimating the 10-year Risk of Total
Cardiovascular Disease (Framingham Heart Study)23 )
Family history:
premature CVD (before age 60) in first-degree relatives
dyslipidemia
Physical examination:
waist circumference
bilateral brachial blood pressure
funduscopy (lipemia retinalis, retinopathies)
cardiovascular evaluation (bruits, heart sounds, peripheral pulses)
hepatosplenomegaly
lipid deposits (premature arcus corneae, xanthomas, xanthelasmas)
Laboratory tests:
lipid and lipoprotein levels1

Note that the Friedewald equation, LDL-C=Total-C - (HDL-C+TG/2.2) cannot be used if triglyceride levels are >4.52 mmol/L, if
type III dysbetalipoproteinemia or if chylomicrons are present.
use the same laboratory for repeated measurements
a 12-hour fast is required for triglyceride levels
obtain 2 or 3 measurements at 4- to 6-week intervals to establish a baseline before initial diagnosis of a dyslipidemic
phenotype. At least one measurement should include a lipoprotein profile, i.e., high-density lipoprotein cholesterol (HDL-C)
and low-density lipoprotein cholesterol (LDL-C)
other lab investigations to rule out frequent causes of secondary dyslipidemias (Table 1) and establish baseline levels for CK
and liver transaminases
high-sensitivity C-reactive protein (hsCRP), a marker of inflammation: recommended in men older than 50 and
women older than 60, at moderate risk according to the Framingham Risk Score and who do not qualify for lipid-
lowering therapy (LDL <3.5 mmol/L). Two measurements at least 2 weeks apart are
recommended1 Useful Info?

Table 1: Common Causes of Secondary Hyperlipidemia

Conditions Medicationsa

Alcohol excess Beta-blockers without intrinsic sympathomimetic or alpha-blocking activity

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Conditions Medicationsa

Chronic renal failure Corticosteroids


Diabetes/Metabolic syndrome Highly active antiretroviral therapy (HAART)
Excess weight Hormone replacement therapy (HRT)
Hypothyroidism Oral contraceptives
Nephrotic syndrome Thiazide diuretics
Obstructive liver disease
Pregnancy

a. Medication-induced dyslipidemia should not preclude the use of these medications if clinically indicated.

Criteria for Intervention

Global cardiovascular risk assessment described in the 2009 recommendations from the Canadian Cardiovascular Society1 stratifies
patients into 1 of 3 categories of cardiovascular risk, using the Framingham Risk Score or the Reynolds Risk Score (RRS)
(www.reynoldsriskscore.org). While both scores include the same major CV risk factors, the RRS includes the family history and hsCRP
levels. This provides an optional tool to better stratify intermediate risk patients in whom hsCRP measurements are indicated. Based on
the risk score, the target lipid levels are shown in Figure 1 - Management of Dyslipidemia1 .

Optional targets, after reaching LDL-C goals may be:


TC/HDL-C ratio <4
Non-HDL-C <3.5 mmol/L
Triglycerides <1.7 mmol/L
Apolipoprotein B / apolipoprotein A ratio <0.8
hsCRP <2 mg/L

Table 2: International Diabetes Federation Classification of the Metabolic Syndrome2

Risk Factor Defining Level

Central obesitya Waist circumference:

Europids
Men ≥94 cm; Women ≥80 cm

South Asians
Men ≥90 cm; Women ≥80 cm

Chinese
Men ≥90 cm; Women ≥80 cm

Japanese
Men ≥90 cm; Women ≥80 cm

Ethnic South and Central Americans, First Nations Use South Asian recommendations until more specific data
are available

Eastern Mediterranean and Middle East (Arabic) populations, Sub- Use European data until more specific data are available
Saharan Africans

Triglyceride level ≥1.7 mmol/L

HDL-C level

Men <1.0 mmol/L


Women <1.3 mmol/L

Blood pressure ≥130/85 mm Hg

Fasting glucose level 5.7–7.0 mmol/L

a. Criteria: central obesity required, plus 2 or more other risk factors.

Abbreviations: HDL-C=high density lipoprotein cholesterol

Adapted with permission from the International Diabetes Federation.

Metabolic syndrome is an association of metabolic abnormalities. The classification used by the International Diabetes Federation is
suggested to reflect the ethnic make-up of Canada (Table 2). Management includes weight reduction, increased physical activity and
treatment of lipid and nonlipid risk factors.

Diabetics, end-stage renal disease and renal transplant patients are considered very high risk. High triglyceride levels (2.3–11.3

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mmol/L) are an additional CV risk factor when associated with atherogenic dyslipidemias, e.g., familial combined hyperlipidemia,
insulin resistance, diabetes, renal failure. Very high triglyceride levels (>10 mmol/L) are a risk factor for pancreatitis.

Therapeutic Choices

Nonpharmacologic Choices

Diet, aimed at reducing blood lipid levels and weight (if needed), should always be part of the treatment. For secondary prevention
and very high risk individuals, medication is introduced simultaneously. For primary prevention, a 6-month dietary trial (Table 3) is
recommended before considering medication; during this time, take 2 (ideally 3) lipid and lipoprotein measurements.
Encourage other lifestyle changes to further modify lipoprotein profile and reduce the risk of CVD, e.g., weight loss, physical
activity and smoking cessation. Smoking cessation can help raise HDL-C.

Table 3: Dietary Interventions

Step I Step II
Primary Prevention Secondary Preventiona
(patients with no previous CVD) (patients with prior CVD/atherosclerotic disease and/or at very high risk)

↓ dietary cholesterol intake to <300 mg/day Same as Step I, but further


Restrict fat intake to 30% of calories ↓ dietary cholesterol intake to <200 mg/day
Increase proportion of mono- and Restrict fat intake to 20% of calories and less than 7% of daily calories as saturated
polyunsaturated fats in diet fat and trans-fatty acids
Restrict saturated and trans-fatty acids in diet
Favour fruit and vegetable intake
Increase omega-3 fatty acids from fish and plant
sources
Favour high-fibre intake
Limit simple sugars to 8% of total calories
Limit alcohol consumption to 5% of total
calories

a. A dietitian's help is usually required to reach and maintain these goals.

Pharmacologic Choices (Table 6)

Table 4 summarizes the effects of lipid-lowering drugs on lipoproteins.

Table 4: Lipid-lowering Agents—Effect on Lipoproteins

LDL HDL TG

Resins ↓↓ ↑ ↑

HMG CoA reductase inhibitors ↓↓↓ ↑ ↓↔a

Niacin ↓↓ ↑↑ ↓↓↓

Fibrates ↓↔ ↑↑ ↓↓↓

Ezetimibe ↓↓ ↑↔ ↓↔

a. Atorvastatin and rosuvastatin have the greatest TG-lowering effect.

Resins

The bile acid-sequestering resins cholestyramine and colestipol reduce plasma LDL and can slightly increase HDL levels. They have
a strong safety record. Resins are appropriate lipid-lowering agents in children and in pregnant or breastfeeding women.

HMG CoA Reductase Inhibitors (Statins)

HMG CoA reductase inhibitors, the most potent LDL-lowering agents, interfere with the atherosclerotic disease process. Significant
reductions in CVD morbidity, CVD mortality and total deaths in both primary and secondary prevention have been associated with their
use.3 , 4 Initiating a statin for primary prevention depends on the individual’s global cardiovascular risk (Figure 2 - Estimating the 10-
year Risk of Total Cardiovascular Disease (Framingham Heart Study)23 ). For patients at high risk of coronary artery disease, statins
should be initiated at the recommended starting doses and titrated to reach targets (Figure 1 - Management of Dyslipidemia1 ).
However, different statins have different degrees of lipid-lowering potential 5 , 6 (Table 4). Some statins are indicated for use in children
>10 years old with heterozygous and homozygous familial hypercholesterolemia.7 , 8 Refer these patients for care by a specialist.

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Effect on HDL is modest. Statins differ in their structure, pharmacokinetics, in vitro properties and potency. Increasing the dose may
result in further decrease in LDL and global cardiovascular risk.9 Statin- and patient-related factors influencing potential myotoxic
effects must be considered to avoid this complication10 (Table 5). There are no consensual recommendations regarding the
management of myotoxic effects. An algorithm has been proposed by Sithasivam and Lecky10 that could prove very useful (Figure 3 -
Diagnosis and Management of Statin-induced Myopathy10 ).
Table 5: Patient- and Statin-related Factors That May Influence Myotoxic Effects

Patient Characteristics Concomitant Medications Statin Properties

Advanced age (>80 y) Amiodarone High bioavailability


Alcohol abuse Azole antifungals (itraconazole, Limited protein binding
Chronic renal insufficiency ketoconazole) Lipophilicity
Excessive grapefruit or Calcium channel blockers Membrane transporter affinity
cranberry juice intake (nondihydropyridine type) Potential for drug–drug interactions metabolized by cytochrome
Frailty, small body frame Cyclosporine P450 pathways, especially 3A4 and 2C9 (Table 6)
Hepatic dysfunction Fibrates (particularly gemfibrozil)
Hypothyroidism (untreated) HIV protease inhibitors
Inherited myopathies Macrolide antibiotics (erythromycin,
Intercurrent infections clarithromycin)
Perioperative periods Nicotinic acid (rarely)
Polypharmacy
Vigorous exercise
Women are more affected than
men

Nicotinic Acid (Niacin)

Niacin is a B vitamin that, at high doses, lowers triglycerides and LDL and raises HDL more than any other lipid-lowering agent. It
lowers lipoprotein(a), although the clinical significance of this effect is not yet known. The unpleasant side effects of niacin make
patient compliance difficult, limiting its usefulness. Slow-release formulations appear to be more hepatotoxic than standard-release
products.11 A “no-flush” formulation combining inositol and niacin purports to reduce this adverse effect. A “once a day at night”
extended-release formulation of niacin combined with a selective prostaglandin D(2) receptor-1 antagonist appears promising in terms
of rapid titration and tolerability.12 Further, it seems to have a lower rate of hepatotoxicity than other formulations. More clinical
experience with these formulations are nevertheless required. Glucose intolerance is not an absolute contraindication to the use of
niacin. Antihyperglycemic agents can be pre-emptively adjusted to maintain glycemic control.

Fibrates

Bezafibrate, fenofibrate and gemfibrozil lower triglyceride levels and raise HDL and may benefit patients with diabetic
dyslipidemias. The effect of fibrates on LDL is variable; bezafibrate and fenofibrate lower LDL more consistently. Except for gemfibrozil,
combining a fibrate with a statin can be safe. Fenofibrate was shown to significantly reduce total CVD events, particularly due to
reductions in nonfatal MI and coronary revascularization, without reducing fatal events in patients with type 2 diabetes.13 The
combination of a fibrate and a statin in this population is not routinely recommended, although it could be beneficial for patients with a
high baseline triglyceride level and low HDL.14

Cholesterol Absorption Inhibitors

Ezetimibe, which inhibits intestinal cholesterol absorption, is useful as monotherapy or in combination with statins. It is better
tolerated than resins, has low potential for drug interactions with cytochrome P450 substrates and does not affect the absorption of fat-
soluble vitamins.15 Hard end-point data using ezetimibe in combination with a statin should soon be available.

Combination Therapy

Agents from different classes can be combined to reach maximal efficacy with an acceptable level of safety, especially if a single drug
fails to achieve targets. However, since some combination therapies (such as fibrates and statins) carry an increased risk of drug
toxicity, consider referral for such patients.16

Nonprescription Agents

The only nonprescription agents that can be recommended are psyllium and omega-3 fatty acids. The American Heart Association
recommends patients with documented coronary heart disease consume about 1 gram of omega-3 fatty acids daily.17 Patients taking
more than 3 grams of omega-3 fatty acids from supplements should do so only under a physician’s care. High intakes could cause
excessive bleeding in some people.

Choices During Pregnancy and Breastfeeding

Due to hormonal changes, plasma lipids increase throughout the duration of pregnancy. Total cholesterol concentrations increase 25–
50% and total triglycerides by 2- to 4-fold. By mid-gestation, there is a 50% increase in LDL-C and a 30% rise in HDL-C, followed at

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term by a slight decrease in HDL-C.18

Risk factors for hyperlipidemia are also true for pregnancy and include obesity, weight gain, hypothyroidism, gestational and non-
gestational diabetes, alcohol consumption, prescription medications and genetic predisposition.19 Very severe forms of
hypertriglyceridemia may hence increase the risk of pancreatitis.20

Pre-pregnancy Considerations

Risk factor control is recommended throughout the pregnancy. The teratogenicity of lipid-lowering drugs in humans is not well
established but appears to be small, if present at all, with statins and termination of pregnancy is not warranted. However, in order to
reduce the risks as much as possible, it is advisable to discontinue all lipid-lowering drugs, with the exception of resins.21

Management During Pregnancy

Patients must be reassured that interrupting the treatment for the duration of the child-bearing period has little impact on the overall
cardiovascular risk. Although resins may be continued, their gastrointestinal effects may limit their use. If tolerated, lipid-soluble
vitamin supplementation should be implemented. In the very severe cases of pregnancy-induced hyperlipoproteinemia, other
nonpharmacologic extreme measures can be used.22

Management During Postpartum/Breastfeeding

Treatment may be resumed unless breastfeeding is considered. Lipid-lowering drugs are currently not recommended during
breastfeeding.

A discussion of general principles on the use of medications in these special populations can be found in Appendix: Drug Use During
Pregnancy and Appendix: Drug Use During Breastfeeding. Other specialized reference sources are also provided in these appendices.

Therapeutic Tips

Global cardiovascular management initially involves modification of health behaviours (smoking cessation, diet, weight reduction
and maintenance, exercise, stress management) in addition to lipid lowering medication.
Lipid-lowering drugs must always be an adjunct to, not a substitution for, diet therapy.
Treat to reach the target levels.
Try different agents within the same class in cases of intolerance or insufficient efficacy.
Long-term clinical and laboratory follow-up is essential to monitor lipid-lowering efficacy and safety of therapy. From the authors
experience, follow-up is suggested every 4 months for the first year, every 6 months for the second year and yearly thereafter,
unless some other condition requires closer monitoring.
Allow 3 months for a stabilized and representative plasma lipid profile after a major medical event. Acute coronary syndromes
require immediate statin therapy regardless of the lipid profile.
Doubling the dose of a statin will further reduce the LDL-C level by only 6% (Figure 1 - Management of Dyslipidemia1 , Figure 2 -
Estimating the 10-year Risk of Total Cardiovascular Disease (Framingham Heart Study)23 ).
It appears safe to lower target LDL-C levels to 1.8 mmol/L (<70 mg/dL) in individuals with overt coronary heart disease and
multiple risk factors.

Figure 1- Management of Dyslipidemia1

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Figure 2- Estimating the 10-year Risk of Total Cardiovascular Disease (Framingham Heart Study)23

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Adapted with permission from D'Agostino RB, Vasan RS, Pencina MJ et al. General cardiovascular risk profile for use in primary care: the Framingham
Heart Study. Circulation 2008;117(6):743-53.

Figure 3- Diagnosis and Management of Statin-induced Myopathy10

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Reproduced from Sathasivam S, Lecky B. Statin induced myopathy. BMJ 2008;337:a2286, with permission from BMJ Publishing Group Ltd.

Table 6: Drugs Used in the Management of Dyslipidemias

Class Drug Dose Adverse Effects Drug Interactions Comments Costa

Resins cholestyramine Adult: 4 g Common: Administer 1 h before Start with daily dosing $$$$$
generics BID–TID AC Constipation or 4–6 h after to improve tolerability.
po. Maximum (>10%), bloating, concurrent Recommend high-fibre
24 g divided abdominal fullness, medications due to diet and high water
in 3 flatulence, ↑ possible adsorption of intake to minimize
doses/day triglycerides, ↑ other drugs in the GI constipation. Monitor
Children: 240 transaminases tract. serum electrolytes
mg/kg/day (reversible). periodically. Long-term
divided in Rare: and high-dose use can
3 doses po hyperchloremic prevent the absorption
acidosis, of fat-soluble vitamins
cholecystitis, and folic acid. May be
cholelithiasis, mixed with juice, soups
pancreatitis, and applesauce. Can be
malabsorption used to lower
syndrome, GI cholesterol and LDL in
bleeding, peptic pregnancy and in
ulceration. children. Add granules
to at least 90 mL of
fluid.
Contraindications:
biliary obstruction,
dysbetalipoproteinemia,
TG >4.6 mmol/L;
phenylketonurics.

Resins colestipol Granules: 5 g Common: Administer 1 h before Start with daily dosing Granules:$$$$
Colestid BID–TID AC Constipation or 4–6 h after to improve tolerability. Tablets:$$
po. Maximum (>10%), bloating, concurrent Recommend high-fibre
30 g/day abdominal fullness, medications due to diet and high water
Tablets: 2 g flatulence, ↑ possible adsorption of intake to minimize
once daily– triglycerides, ↑ other drugs in the GI constipation. Monitor
BID po. transaminases tract. serum electrolytes

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Class Drug Dose Adverse Effects Drug Interactions Comments Costa

Maximum 16 (reversible). periodically. Long-term


g/day. Rare: and high-dose use can
hyperchloremic prevent the absorption
acidosis, of fat-soluble vitamins
cholecystitis, and folic acid. May be
cholelithiasis, mixed with juice, soups
pancreatitis, and applesauce. Can be
malabsorption used to lower
syndrome, GI cholesterol and LDL in
bleeding, peptic pregnancy and in
ulceration. children. Add granules
to at least 90 mL of
fluid.
Contraindications:
biliary obstruction,
dysbetalipoproteinemia,
TG >4.6 mmol/L;
phenylketonurics.

Cholesterol ezetimibe 10 mg once Well tolerated. Low potential for drug Monitor liver function $$$
Absorption Ezetrol daily po at Common: back pain, interactions. and CK.
Inhibitor any time arthralgia, diarrhea, Potential In general, can use in
abdominal pain, pharmacokinetic children ≥12 y. Not
fatigue, dizziness, interaction with recommended in
headache. cyclosporine. Exercise moderate to severe
caution when hepatic impairment.
Rare: myopathy, initiating ezetimibe in
rhabdomyolysis, patients receiving
hepatitis, acute cyclosporine,
pancreatitis, especially if severe
thrombocytopenia. renal insufficiency.

HMG CoA atorvastatin Adult: 10–80 Common: ↑ CK, ↑ Avoid with CYP3A4 Start with low doses $$
Reductase Lipitor, mg daily po transaminases inhibitors: macrolide and titrate up to reach
Inhibitors generics Children:b (reversible), mild antibiotics, targets while monitoring
10–20 mg upper GI gemfibrozil, grapefruit biochemical markers.
daily po disturbances, juice, azoles, protease Monitor liver function
myalgias (with and inhibitors, and CK at 3, 6 and 12
without CK amiodarone, mo, then yearly. If LFTs
elevation), sleep cyclosporine, (AST, ALT) >3 ×
disturbances, nondihydropyridine normal, discontinue
headache, rash. calcium channel statin. LFT elevations
Rare: myopathy, blockers, e.g., are dose dependent.
rhabdomyolysis, verapamil. Excellent safety profile.
peripheral
neuropathy, lupus- Use caution in patients
like symptoms, with moderate to severe
impotence. renal impairment
(<60 mL/min).

Contraindications:
active liver disease,
high alcohol
consumption,
pregnancy.

HMG CoA fluvastatin 20–80 mg po Common: ↑ CK, ↑ Avoid with CYP P450 Start with low doses $$
Reductase Lescol, Lescol with evening transaminases 2C9 inhibitors: and titrate up to reach
Inhibitors meal (reversible), mild amiodarone, targets while monitoring
XL
Give XL upper GI fluconazole, biochemical markers.
formulation disturbances, fluoxetine, Monitor liver function
once daily myalgias (with and fluvoxamine. and CK at 3, 6 and 12
anytime without CK mo, then yearly. If LFTs
elevation), sleep (AST, ALT) >3 ×
disturbances, normal, discontinue
headache, rash. statin. LFT elevations
Rare: myopathy, are dose dependent.
rhabdomyolysis, Excellent safety profile.
peripheral
neuropathy, lupus- Use caution in patients

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Class Drug Dose Adverse Effects Drug Interactions Comments Costa

like symptoms, with moderate to severe


impotence. renal impairment
(<60 mL/min).

Contraindications:
active liver disease,
high alcohol
consumption,
pregnancy.

HMG CoA lovastatin 20–80 mg po Common: ↑ CK, ↑ Avoid with CYP3A4 Start with low doses $$–$$$$$
Reductase Mevacor, with evening transaminases inhibitors: macrolide and titrate up to reach
Inhibitors generics meal. (reversible), mild antibiotics, targets while monitoring
Maximum 40 upper GI gemfibrozil, grapefruit biochemical markers.
mg BID disturbances, juice, azoles, protease Monitor liver function
myalgias (with and inhibitors, and CK at 3, 6 and 12
without CK amiodarone, mo, then yearly. If LFTs
elevation), sleep cyclosporine, (AST, ALT) >3 ×
disturbances, nondihydropyridine normal, discontinue
headache, rash. calcium channel statin. LFT elevations
Rare: myopathy, blockers, e.g., are dose dependent.
rhabdomyolysis, verapamil. Excellent safety profile.
peripheral
neuropathy, lupus- Use caution in patients
like symptoms, with moderate to severe
impotence. renal impairment
(<60 mL/min).

Contraindications:
active liver disease,
high alcohol
consumption,
pregnancy.

HMG CoA pravastatin 10–40 mg Common: ↑ CK, ↑ Not metabolized Start with low doses $$
Reductase Pravachol, QHS po transaminases through CYP P450 and titrate up to reach
Inhibitors generics (reversible), mild pathway, thus low targets while monitoring
upper GI potential for drug biochemical markers.
disturbances, interactions. Monitor liver function
myalgias (with and and CK at 3, 6 and 12
without CK mo, then yearly. If LFTs
elevation), sleep (AST, ALT) >3 ×
disturbances, normal, discontinue
headache, rash. statin. LFT elevations
Rare: myopathy, are dose dependent.
rhabdomyolysis, Excellent safety profile.
peripheral
neuropathy, lupus- Use caution in patients
like symptoms, with moderate to severe
impotence. renal impairment
(<60 mL/min).

Contraindications:
active liver disease,
high alcohol
consumption,
pregnancy.

HMG CoA rosuvastatin Adult: 10–40 Common: ↑ CK, ↑ Avoid with CYP P450 Start with low doses $$$
Reductase Crestor mg daily po transaminases 2C9 inhibitors: and titrate up to reach
Inhibitors Initial dose 10 (reversible), mild amiodarone, targets while monitoring
mg/day po upper GI fluconazole, biochemical markers.
except in disturbances, fluoxetine, Monitor liver function
Asian patients myalgias (with and fluvoxamine. and CK at 3, 6 and 12
and those without CK ↓ levels with mo, then yearly. If LFTs
receiving elevation), sleep concomitant use of (AST, ALT) >3 ×
cyclosporine. disturbances, magnesium/aluminum normal, discontinue
(Initial dose 5 headache, rash. hydroxide-containing statin. LFT elevations
mg/day po) Rare: myopathy, antacids. are dose dependent.
rhabdomyolysis, Excellent safety profile.

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Class Drug Dose Adverse Effects Drug Interactions Comments Costa

Children:b 5– peripheral
10 mg daily neuropathy, lupus- Use caution in patients
po like symptoms, with moderate to severe
impotence. renal impairment
(<60 mL/min).

Contraindications:
active liver disease,
high alcohol
consumption,
pregnancy.

Administer antacids 2 h
after rosuvastatin.

HMG CoA simvastatin Adult: 10–80 Common: ↑ CK, ↑ Avoid with CYP3A4 Start with low doses $$
Reductase Zocor, mg po with transaminases inhibitors: macrolide and titrate up to reach
Inhibitors generics evening meal (reversible), mild antibiotics, targets while monitoring
Children:b10– upper GI gemfibrozil, grapefruit biochemical markers.
40 mg po with disturbances, juice, azoles, protease Monitor liver function
evening meal myalgias (with and inhibitors, and CK at 3, 6 and 12
without CK amiodarone, mo, then yearly. If LFTs
elevation), sleep cyclosporine, (AST, ALT) >3 ×
disturbances, nondihydropyridine normal, discontinue
headache, rash. calcium channel statin. LFT elevations
Rare: myopathy, blockers, e.g., are dose dependent.
rhabdomyolysis, verapamil. Excellent safety profile.
peripheral
neuropathy, lupus- Use caution in patients
like symptoms, with moderate to severe
impotence. renal impairment
(<60 mL/min).

Contraindications:
active liver disease,
high alcohol
consumption,
pregnancy.

Niacin niacin, Start with 50 Common: hot Use caution if using Greatest HDL-raising $-$$
(Nicotinic immediate mg TID po; flushes and pruritus, with statins because effect.
Acid) double dose dry skin, acanthosis of potential Monitor blood glucose,
release
Derivatives Q5 days to nigricans hepatotoxicity and uric acid, transaminases
Niacin,
1.5–2 g/day. (reversible), myopathy. at 3, 6 and 12 months,
generics
If tolerated, reactivation of peptic then yearly.
maximum is 4 ulcer, GI
g/day after disturbances, ↑ Contraindications:
meals blood glucose, severe peptic ulcer
Usual dose: glucose intolerance, disease, uncontrolled
1.5–4 g/day uric acid and hyperglycemia, severe
divided TID transaminases. gout, hepatic disease.
po, PC Rare: torsades de
pointes, severe Flushing abates with
Reassure and hepatotoxicity (more time. Avoid hot drinks,
instruct the frequent with slow- hot showers, spicy
patient (see release formulation), food, alcohol for 1–2 h
comments) ↑ blood glucose, uric after a dose; uncoated
acid, transaminases. ASA 325 mg daily in the
first few weeks of
treatment or when
increasing the dose may
be helpful.

Tolerance develops
within several weeks.
Avoid missing a dose.

Niacin niacin, slow 0.5–2 g/day Same as niacin Use caution if using Similar to niacin $-$$
(Nicotinic release (SR) divided BID immediate release, with statins because immediate release,
Acid) po after meals although less of potential although fewer

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Class Drug Dose Adverse Effects Drug Interactions Comments Costa

Derivatives generics flushing. hepatotoxicity and measures required.


myopathy.
Common: hot Greatest HDL-raising
flushes and pruritus, effect.
dry skin, acanthosis Monitor blood glucose,
nigricans uric acid, transaminases
(reversible), at 3, 6 and 12 months,
reactivation of peptic then yearly.
ulcer, GI
disturbances, ↑ Contraindications:
blood glucose, severe peptic ulcer
glucose intolerance, disease, uncontrolled
uric acid and hyperglycemia, severe
transaminases. gout, hepatic disease.
Rare: torsades de
pointes, severe Flushing abates with
hepatotoxicity (more time. Avoid hot drinks,
frequent with slow- hot showers, spicy
release formulation), food, alcohol for 1–2 h
↑ blood glucose, uric after a dose; uncoated
acid, transaminases. ASA 325 mg daily in the
first few weeks of
Severe treatment or when
hepatotoxicity more increasing the dose may
frequent with slow- be helpful.
release formulation,
thus not Tolerance develops
recommended. within several weeks.
Avoid missing a dose.

Niacin niacin, Titrate the Similar adverse Use caution if using Less flushing because $$$–$$$$
(Nicotinic extended dose: 0.5 g effects to niacin with statins because taken at bedtime. Less
Acid) HS po after a immediate release, of potential hepatotoxic effects
release (ER)
Derivatives low-fat snack although less hepatotoxicity and relative to SR
Niaspan, × 1 month severe. myopathy. formulations.
Niaspan-FCT then 1 g HS x Common: hot
1 mo, then flushes and pruritus,
1.5 g HS. May dry skin, acanthosis
↑ to 2 g HS if nigricans
required (reversible),
reactivation of peptic
ulcer, GI
disturbances, ↑
blood glucose,
glucose intolerance,
uric acid and
transaminases.
Rare: torsades de
pointes, severe
hepatotoxicity (more
frequent with slow-
release formulation),
↑ blood glucose, uric
acid, transaminases.

Fibrates bezafibrate SR: 400 Upper GI Caution when Monitor CK, liver and $$$
Bezalip mg/day po disturbances combining with renal function at 3, 6
with evening (nausea, abdominal statins. and 12 mo, then yearly.
meal pain, flatulence), Monitor INR with Useful in diabetic
myalgias concomitant warfarin dyslipidemias.
↑ bile lithogenicity, ↑ use. Contraindications:
CK, ↑ creatinine (not hepatic impairment,
representative of ↑ ezetimibe levels. renal dysfunction, pre-
renal function Monitor for signs of existing gallbladder
deterioration). cholelithiasis. disease.

Fibrates fenofibrate 100 mg BID– Upper GI Caution when Monitor CK, liver and $$$–$$$$
Apo- QID po with disturbances combining with renal function at 3, 6
meals (nausea, abdominal statins. and 12 mo, then yearly.

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Class Drug Dose Adverse Effects Drug Interactions Comments Costa

Fenofibrate, pain, flatulence), Monitor INR with Useful in diabetic


other myalgias concomitant warfarin dyslipidemias.
generics ↑ bile lithogenicity, ↑ use. Contraindications:
CK, ↑ creatinine (not hepatic impairment,
representative of ↑ ezetimibe levels. renal dysfunction, pre-
renal function Monitor for signs of existing gallbladder
deterioration). cholelithiasis. disease.

Monitor renal function


with concomitant
cyclosporine use.

Fibrates fenofibrate 160 mg/day, Upper GI Caution when Monitor CK, liver and $$
microcoated once daily po disturbances combining with renal function at 3, 6
Lipidil Supra, with largest (nausea, abdominal statins. and 12 mo, then yearly.
generics meal pain, flatulence), Monitor INR with Useful in diabetic
myalgias concomitant warfarin dyslipidemias.
↑ bile lithogenicity, ↑ use. Contraindications:
CK, ↑ creatinine (not hepatic impairment,
representative of ↑ ezetimibe levels. renal dysfunction, pre-
renal function Monitor for signs of existing gallbladder
deterioration). cholelithiasis. disease.

Monitor renal function


with concomitant
cyclosporine use.

Fibrates fenofibrate 200 mg/day, Upper GI Caution when Monitor CK, liver and $$
micronized once daily po disturbances combining with renal function at 3, 6
Lipidil Micro, with largest (nausea, abdominal statins. and 12 mo, then yearly.
Apo-Feno- meal pain, flatulence), Monitor INR with Useful in diabetic
myalgias concomitant warfarin dyslipidemias.
Micro, other
↑ bile lithogenicity, ↑ use. Contraindications:
generics hepatic impairment,
CK, ↑ creatinine (not
representative of ↑ ezetimibe levels. renal dysfunction, pre-
renal function Monitor for signs of existing gallbladder
deterioration). cholelithiasis. disease.

Monitor renal function


with concomitant
cyclosporine use.

Fibrates fenofibrate 145 mg/day, Upper GI Caution when Monitor CK, liver and $$
nanocrystals once daily po disturbances combining with renal function at 3, 6
with or (nausea, abdominal statins. and 12 mo, then yearly.
Lipidil EZ, without food pain, flatulence), Monitor INR with Useful in diabetic
generics Recommended myalgias concomitant warfarin dyslipidemias.
starting dose ↑ bile lithogenicity, ↑ use. Contraindications:
for patients CK, ↑ creatinine (not hepatic impairment,
with renal representative of ↑ ezetimibe levels. renal dysfunction, pre-
impairment renal function Monitor for signs of existing gallbladder
and in the deterioration). cholelithiasis. disease.
elderly is 48
mg daily Monitor renal function
with concomitant
cyclosporine use.

Fibrates gemfibrozil 300–1200 Upper GI Not to be used in Monitor CK, liver and $–$$
Lopid, mg/day po disturbances combination with renal function at 3, 6
generics divided BID (nausea, abdominal statins. and 12 mo, then yearly.
30 min prior pain, flatulence), May increase Useful in diabetic
to meals myalgias repaglinide and dyslipidemias.
↑ bile lithogenicity, ↑ rosiglitazone levels; Contraindications:
CK, ↑ creatinine (not metabolized by hepatic impairment,
representative of CYP2C8. renal dysfunction, pre-
renal function existing gallbladder
deterioration). Monitor INR with disease.
concomitant warfarin

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Therapeutic Choice

Class Drug Dose Adverse Effects Drug Interactions Comments Costa

use.

Combination niacin, Dose is Niacin: Niacin:Use caution if Not recommended as $$$


products extended individualized. Similar adverse using with statins initial therapy. May
release / 500 mg/20 effects to niacin because of potential switch to combination
lovastatin mg or 1000 immediate release, hepatotoxicity and therapy when on stable
Advicor mg/20 mg po: although less myopathy. doses of lovastatin and
1 tab HS with severe. Lovastatin:Avoid with niacin, extended
low-fat snack CYP3A4 inhibitors: release.
Common: hot macrolide antibiotics, Less flushing because
flushes and pruritus, gemfibrozil, grapefruit taken at bedtime. Less
dry skin, acanthosis juice, azoles, protease hepatotoxic effects
nigricans inhibitors, relative to SR
(reversible), amiodarone, formulations.
reactivation of peptic cyclosporine,
ulcer, GI nondihydropyridine Start with low doses
disturbances, ↑ calcium channel and titrate up to reach
blood glucose, blockers, e.g., targets while monitoring
glucose intolerance, verapamil. biochemical markers.
uric acid and Monitor liver function
transaminases. and CK at 3, 6 and 12
Rare: torsades de mo, then yearly. If LFTs
pointes, severe (AST, ALT) >3 ×
hepatotoxicity (more normal, discontinue
frequent with slow- statin. LFT elevations
release formulation), are dose dependent.
↑ blood glucose, uric Excellent safety profile.
acid, transaminases.
Use caution in patients
Lovastatin:Common: with moderate to severe
↑ CK, ↑ renal impairment
transaminases (<60 mL/min).
(reversible), mild
upper GI Contraindications:
disturbances, active liver disease,
myalgias (with and high alcohol
without CK consumption,
elevation), sleep pregnancy.
disturbances,
headache, rash.
Rare: myopathy,
rhabdomyolysis,
peripheral
neuropathy, lupus-
like symptoms,
impotence.

a. Cost of 30-day supply; includes drug cost only.


b. Children aged 10 to 17 years (boys and post-menarchal girls).

Dosage adjustment may be required in renal impairment; see Appendices: Dosage Adjustment in Renal Impairment.

ALT=alanine transaminase; AST=aspartate transaminase; CK=creatine kinase; LFT=liver function test

Legend: $ <$20 $-$$ <$20–40 $$ $20–40 $$$ $40–60 $$$-$$$$ $40–80 $$$$ $60–80 $$-$$$$$ $20– >80 $$$$$
>$80

Suggested Readings

Genest J, McPherson R, Frohlich J et al. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of
dyslipidemia and prevention of cardiovascular disease in the adult–2009 recommendations. Can J Cardiol 2009;25(10):567-79.

Grundy SM, Cleeman JI, Merz CN et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult
Treatment Panel III guidelines. Circulation 2004;110(2):227-39.

Jialal I. A practical approach to the laboratory diagnosis of dyslipidemia. Am J Clin Pathol 1996;106(1):128-38.

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Therapeutic Choice
Kuoppala J, Lamminpaa A, Pukkala E. Statins and cancer: a systematic review and meta-analysis. Eur J Cancer 2008;44(15):2122-32.

Mattar M, Obeid O. Fish oil and the management of hypertriglyceridemia. Nutr Health 2009;20(1):41-9.

NACB LMPG Committee Members, Myers GL, Christenson RH et al. NACB LMPG Committee Members, National Academy of Clinical
Biochemistry Laboratory Medicine Practice guidelines: emerging biomarkers for primary prevention of cardiovascular disease. Clin Chem
2009;55(2):378-84.

Sathasivam S, Lecky B. Statin induced myopathy. BMJ 2008;337:a2286.

Seth Loomba R, Arora R. Fibrates: where are we now? Ther Adv Cardiovasc Dis 2009;3(1):91-6.

References

1. Genest J, McPherson R, Frohlich J et al. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and
treatment of dyslipidemia and prevention of cardiovascular disease in the adult–2009 recommendations. Can J Cardiol 2009;25
(10):567-79.
2. International Diabetes Federation. The IDF consensus worldwide definition of the metabolic syndrome. Brussels (BE); [2006].
Available from: www.idf.org/webdata/docs/MetSyndrome_FINAL.pdf. Accessed March 9, 2010.
3. Vrecer M, Turk S, Drinovec J et al. Use of statins in primary and secondary prevention of coronary heart disease and ischemic
stroke. Meta-analysis of randomized trials. Int J Clin Pharmacol Ther 2003;41(12):567-77.
4. Yusuf S, Lonn E, Bosch J. Lipid lowering for primary prevention. Lancet 2009;373(9670):1152-5.
5. Brugts JJ, Yetgin T, Hoeks SE et al. The benefits of statins in people without established cardiovascular disease but with
cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ 2009;338:b2376.
6. Beth Smith ME, Lee NJ, Haney E et al. Drug class review: HMG-CoA reductase inhibitors (statins) and fixed-dose combination
products containing a statin. Final Report Update 5. Portland (OR): Oregon Health & Science University; November 2009.
Available from: derp.ohsu.edu/final/Statins_final%20evidence%20tables_update%205_unshaded_NOV_09.pdf. Accessed March
4, 2010.
7. Kavey RE, Allada V, Daniels SR et al. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the
American Heart Association Expert Panel on Population and Prevention Science et al. Circulation 2006;114(24):2710-38.
8. Daniels SR, Greer FR; Committee on Nutrition. Lipid screening and cardiovascular health in childhood. Pediatrics 2008;122
(1):198-208.
9. LaRosa JC, Grundy SM, Waters DD et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N
Engl J Med 2005;352(14):1425-35.
10. Sathasivam S, Lecky B. Statin induced myopathy. BMJ 2008;337:a2286.
11. Guyton JR, Bays HE. Safety considerations with niacin therapy. Am J Cardiol 2007;99(6A):22C-31C.
12. Maccubbin D, Koren MJ, Davidson M et al. Flushing profile of extended-release niacin/laropiprant versus gradually titrated niacin
extended-release in patients with dyslipidemia with and without ischemic cardiovascular disease. Am J Cardiol 2009;104(1):74-
81.
13. Keech A, Simes RJ, Barter P et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2
diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366(9500):1849-61.
14. ACCORD Study Group, Ginsberg HN, Elam MB et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med
2010;362(17):1563-74.
15. Cannon CP, Giugliano RP, Blazing MA et al. Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin
Efficacy International Trial): comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in
patients with acute coronary syndromes. Am Heart J 2008;156(5):826-32.
16. Tenenbaum A, Fisman EZ, Motro M et al. Optimal management of combined dyslipidemia: what have we behind statins
monotherapy? Adv Cardiol 2008;45:127-53.
17. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation
2002;106(21):2747-57.
18. Lain KY, Catalano PM. Metabolic changes in pregnancy. Clin Obstet Gynecol 2007;50(4):938-48.
19. Basaran A. Pregnancy-induced hyperlipoproteinemia: review of the literature. Reprod Sci 2009;16(5):431-7.
20. Glueck CJ, Christopher C, Mishkel MA et al. Pancreatitis, familial hypertriglyceridemia, and pregnancy. Am J Obstet Gynecol
1980;136(6):755-61.
21. Kazmin A, Garcia-Bournissen F, Koren G. Risks of statin use during pregnancy: a systematic review. J Obstet Gynaecol Can
2007;29(11):906-8.
22. Klingel R, Gohlen B, Schwarting A et al. Differential indication of lipoprotein apheresis during pregnancy. Ther Apher Dial 2003;7
(3):359-64.
23. D’Agostino RB, Vasan RS, Pencina MJ et al. General cardiovascular risk profile for use in primary care: the Framingham Heart
Study. Circulation 2008;117(6):743-53.

Therapeutic Choices. © Canadian Pharmacists Association, 2011. All rights reserved.

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Print Close

Cardiovascular Disorders: Heart Failure

Date Prepared: May 2009

Simon de Denus, B. Pharm, MSc

Michel White, MD, FRCPC, FACC, FESC

Heart failure (HF) is associated with a 5-year mortality rate of 5–50% depending on the severity of symptoms.1 HF may
require frequent hospitalizations and significantly reduces quality of life and exercise tolerance.1 Typical symptoms of HF
include dyspnea, fatigue and fluid retention.1

HF is characterized by impaired left ventricular (LV) function and reduced LV reserve. HF is generally categorized as systolic
HF or HF with preserved systolic function (PSF).2 Less common types of HF will not be discussed. Systolic HF is characterized
by decreased pump function, dilatation of the left ventricle and decreased LV ejection fraction (LVEF ≤ 40%). Most clinical
trials have been conducted in patients with systolic HF. There is no strong consensus on the definition of HF with PSF or its
treatment.1 , 2 , 3 , 4 , 5 It is variably defined as the presence of signs and symptoms of HF with LVEF > 40 or 50%. HF with
PSF can be associated with many conditions (hypertension, arterial stiffness, diabetes mellitus), although abnormal
myocardial relaxation, hypertrophy and/or fibrosis are generally present.1 , 2 , 3 , 4 , 5

Goals of Therapy1 , 2 , 3 , 4 , 5

Treat risk factors


Prevent disease progression
Improve symptoms, exercise tolerance and quality of life
Reduce morbidity and mortality

Table 1: Laboratory Investigations for Evaluation of Patients with Heart Failure

All patients

Complete blood count


Serum creatinine, electrolytes, blood urea nitrogen and transaminase levels
Fasting plasma glucose and serum lipids
Thyroid function tests
Urinalysis

Select patients

Brain natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP)a


Iron studies, ferritin and transferrin
HIV test

a. BNP or NT-proBNP is potentially useful in the emergency care setting. Value in primary care is not definitive.

Investigations1 (Figure 1 - Evaluation of Patients with Heart Failure)

A history, physical examination and select laboratory tests should be performed to establish the diagnosis (Table 1)
Identify and correct modifiable risk factors and exacerbating factors (Table 2)
Determine ventricular size and function with transthoracic echocardiography or isotopic ventriculography in all patients
with suspected HF. Echocardiography allows for identification of valvular abnormalities and other myocardial problems
Additional tests should be performed in select individuals to identify the etiology of HF and to guide specific treatment
when appropriate
The New York Heart Association functional classification is commonly used to describe patients with HF (Table 3)

Table 2: Factors That Can Exacerbate Heart Failure

Patient-specific factors

Noncompliance with drug therapy or dietary restrictions


Anemia
Arrhythmias
Infections
Myocardial ischemia
Pulmonary embolism

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Renal dysfunction
Thyroid dysfunction
Uncontrolled hypertension
Valvular heart disease

Drugs

Drugs that cause sodium and fluid retention:


NSAIDs including selective COX-2 inhibitors and high-dose salicylates
Corticosteroids
Minoxidil
Androgens
Thiazolidinediones (pioglitazone, rosiglitazone)
Drugs with high sodium content
Licorice-containing products
Negative inotropes:
Antiarrhythmic agents except amiodarone and dofetilide
Beta-blockers at maintenance doses
Calcium channel blockers: diltiazem, nifedipine, verapamil, but not amlodipine or felodipine
Itraconazole
Cardiotoxic drugs
Alcohol
Anthracyclines (doxorubicin)
Cocaine
Cyclophosphamide
Imatinib
Trastuzumab

Table 3: New York Heart Association (NYHA) Functional Classification

Class Characteristics

I No symptoms

II Symptoms occur with ordinary activity

III Symptoms occur with less than ordinary activity

IV Symptoms occur at rest or with minimal activity

Therapeutic Choices

Nonpharmacologic Choices1 , 3 , 4 , 5

Control HF risk factors (hypertension, obesity, diabetes mellitus, supraventricular arrhythmia, dyslipidemia, coronary
artery disease and other vascular diseases).
Recommend moderate regular physical activity in stable patients.
Recommend no more than moderate alcohol consumption in all patients.
avoid completely in alcoholic cardiomyopathy
Restrict sodium intake in all patients (< 2–3 g/day; 1–2 g/day in those with severe HF).
Restrict fluid intake (< 1.5–2 L/day) in patients with fluid retention that is not easily controlled with diuretics, or in
patients with hyponatremia.
Annual influenza vaccination in all patients.
Pneumococcal vaccination in all patients.
Daily weight.
patients who gain 0.5 kg/day on several consecutive days or 2 kg in 3 days should alert their team or physician

Device Therapy

Given their high cost, the following devices should generally be reserved for patients who do not have significant
comorbidities that are expected to significantly limit survival.

Implantable cardioverter defibrillators (ICD) are recommended for stable patients with a history of sudden cardiac arrest,
ventricular fibrillation (VF) or hemodynamically unstable sustained ventricular tachycardia (VT) in the absence of
reversible factors; or coronary artery disease with or without mild to moderate symptoms and an LVEF ≤ 30%.1 An ICD
may also be considered for stable patients with nonischemic NYHA class II–III HF and an LVEF ≤ 30%; or ischemic HF
and a history of myocardial infarction, NYHA class II–III HF and an LVEF of 31–35% and inducible VT/VF during an

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electrophysiology study.
Cardiac resynchronization therapy (CRT) should be considered in patients with NYHA class III–IV HF despite optimal
medical therapy who are in sinus rhythm and have an LVEF ≤ 35% and a QRS interval ≥ 120 msec.1
Left ventricular assist devices (LVAD) should be used as a bridge to transplantation. Use of LVADs as a bridge to
recovery is controversial.6
Continuous positive airway pressure (CPAP) should be considered in patients with obstructive sleep apnea.4

Reperfusion and Surgery

Revascularization, either by percutaneous coronary intervention or coronary artery bypass surgery, should be performed
in select patients with symptomatic ischemia.1
Cardiac transplantation should be considered in patients with severe refractory HF, despite optimal therapy, who would
otherwise have a good life expectancy.1

Pharmacologic Choices

Systolic Heart Failure

In the absence of contraindications, the cornerstone of therapy for systolic HF in all patients with an LVEF ≤ 40% (NYHA
class I–IV) is long-term treatment with the combination of an angiotensin converting enzyme (ACE) inhibitor and a beta-
blocker (Figure 2 - Management of Systolic Heart Failure). Diuretics are used to control signs and symptoms of
hypervolemia. Digoxin, angiotensin II receptor blockers (ARBs), aldosterone antagonists or the combination of isosorbide
dinitrate/hydralazine are used in select individuals.5

Consideration should be given to the use of agents for which mortality and morbidity benefits have been established in large
randomized clinical trials (Table 4). Drugs used in the treatment of HF are presented in Table 5. Target doses are those used
in such trials.

Consider a patient’s comorbid conditions when contemplating the use of a particular class of medication, a specific agent and
the target dosage.

ACE Inhibitors

ACE inhibitors are recommended in all patients because they improve symptoms and reduce the risk of hospitalization,
myocardial infarction and death in patients with systolic HF.7 , 8 , 9 Start with a low dose and titrate the dose at 7- to 14-day
intervals to the target dose, or maximum tolerated dose if the target dose cannot be reached. Treatment with target doses is
more effective than low doses.10 Measure serum creatinine, potassium and blood pressure before initiating an ACE inhibitor
or increasing the dose and 7–14 days after any increase in dosage.5 An increase in serum creatinine of up to 30% is expected
and acceptable after initiation of an ACE inhibitor.1 Patients at greatest risk of hyperkalemia are those with moderate to
severe renal dysfunction, high baseline potassium, diabetes mellitus and those receiving potassium-sparing diuretics.11

Beta-blockers

Beta-blockers improve symptoms and reduce the risk of hospitalization and death in patients with systolic HF.12 , 13 , 14 , 15
They are recommended in all patients with an LVEF ≤ 40%.5 Only beta-blockers that have been shown to reduce mortality
should be used: carvedilol, bisoprolol and metoprolol succinate (not available in Canada).5 Metoprolol tartrate is
available in Canada, but has not been shown to reduce mortality in patients with HF. Titrate the dose at 2- to 4-week
intervals.5 Monitor blood pressure and heart rate before initiating a beta-blocker and before any increase in dose. Watch for
the signs and symptoms of HF decompensation when initiating or increasing the dose of a beta-blocker. Pay particular
attention to the daily morning weight.5 Beta-blockers should not be stopped abruptly.1 Refer patients with severe HF (NYHA
class III–IV) to an HF specialist for initiation of a beta-blocker.1

Diuretics

Diuretics are recommended to control signs and symptoms of congestion. Thiazide diuretics can be used in patients with
minimal fluid retention, but loop diuretics, usually furosemide, are required in most patients.1 , 3 , 4 , 5 Use of
ethacrynic acid is limited to patients with an allergy to furosemide. Thiazides have poor efficacy as monotherapy in patients
with creatinine clearance < 50 mL/min.16 Higher doses of furosemide are required in patients with renal dysfunction.16 The
lowest effective dose should be used.5 Serum creatinine and electrolytes should be measured before and 3–7 days after
initiation of a diuretic and then as indicated (until serum potassium and renal function are stable) after increasing the dose.

Thiazide and loop diuretics deplete potassium and magnesium. Serum potassium should be maintained at ≥ 4 mmol/L
because hypokalemia increases the risk of fatal ventricular arrhythmias and digoxin toxicity.1 In patients with refractory
volume overload, consider the addition of a low-dose thiazide intermittently (e.g., a few times/week) to a loop diuretic.1 , 3 ,

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4 , 5 This strategy should be used only by experienced clinicians with close monitoring of weight, renal function and serum

potassium because of the risk of severe and potentially fatal dehydration and electrolyte imbalances.1 , 3 , 4 , 5 When
prescribed once a day, diuretics should generally be taken in the morning. When prescribed twice daily or more, the last dose
should be taken before 4:00 p.m. to avoid diuresis during the night.

With the exception of spironolactone (see Aldosterone Antagonists below), the role of potassium-sparing diuretics is
limited to prevention of hypokalemia and hypomagnesemia in patients treated with thiazides or loop diuretics.3

Angiotensin II Receptor Blockers

Angiotensin II receptor blockers (ARBs) are an alternative to ACE inhibitors in patients with ACE inhibitor–induced cough or
angioedema. Patient education and follow-up are essential because ARB-induced angioedema has been reported.4 , 17 Similar
to ACE inhibitors, ARBs are associated with renal dysfunction and hyperkalemia; thus, ARBs should not be substituted for
ACE inhibitors specifically for these adverse events.18 Considerations for initiation, dosage titration and monitoring for ARBs
are the same as for ACE inhibitors.

Addition of an ARB may be considered in patients with persistent symptoms despite optimal therapy with an ACE inhibitor
and a beta-blocker.1 , 19 In this setting, candesartan reduced cardiovascular mortality and hospitalizations for HF.19
Reductions in morbidity but not mortality were obtained with valsartan in another trial.20 Limited data suggest that an ARB
may be a valuable addition to an ACE inhibitor in patients not receiving a beta-blocker.1 Close monitoring of vital signs,
serum creatinine and potassium is essential when combining an ACE inhibitor and an ARB. The combination of an ACE
inhibitor, an ARB and an aldosterone antagonist is not recommended because of the uncertainty regarding the benefit and
safety of this combination.1

Aldosterone Antagonists

Aldosterone antagonists reduce the risk of mortality and morbidity in patients with chronic severe HF (NYHA class III–IV and
LVEF < 35%) and in post-MI patients with an LVEF ≤ 40% and either clinical HF or diabetes mellitus.4 , 21 , 22 The benefit of
these agents in patients with stable mild to moderate symptoms is unknown.4 Aldosterone antagonists should not be used in
patients with a baseline potassium > 5 mmol/L, a serum creatinine > 221 µmol/L or a creatinine clearance < 30 mL/min.4
Start spironolactone at a dose of 12.5 mg daily or every other day. Alternatively use eplerenone at a dose of 25 mg daily
or every other day. Monitor vital signs, serum creatinine and potassium 3 days and 1 week after initiating or titrating the
dose of aldosterone antagonists and repeat as necessary until the potassium level and renal function are stable.5 Monitoring
should then be performed monthly for 3 months and then every 3 months.5

Eplerenone is a new selective aldosterone antagonist that does not produce gynecomastia.5 Currently available data with
this agent are limited to post-MI patients. In chronic heart failure its use should be restricted to patients who cannot tolerate
spironolactone because of gynecomastia. Eplerenone appears to have a similar risk of hyperkalemia and renal dysfunction as
spironolactone, so should not be used as a substitute in these situations.

Digoxin

Digoxin improves symptoms and reduces the risk of hospitalization for HF, but does not reduce mortality in patients with
moderate to severe persistent symptoms (NYHA class II–IV) despite optimal medical therapy.4 , 23 It may also be considered
for control of the ventricular rate in patients with atrial fibrillation that cannot be controlled by beta-blockers, or in patients
who cannot tolerate beta-blockers.5 The dosage is individualized based on the patient’s age, weight, renal function and
concomitant drugs, but usually ranges from 0.0625 to 0.25 mg daily. Lower doses may be appropriate in select patients.
Given the narrow therapeutic index of digoxin, particular attention should be devoted to identifying and preventing potential
drug interactions. Digoxin serum concentrations should be monitored when renal function changes significantly, an
interacting drug is added or discontinued, or when digoxin toxicity is suspected. Serum concentrations may also be
monitored once steady state is achieved after initiating digoxin, particularly in elderly patients and those with renal
dysfunction.4 , 24 Measure trough serum concentrations at least 8 hours after administration and adjust the dose to maintain
the serum concentration between 0.6 and 1 nmol/L, which is associated with greater reductions in hospitalization and,
possibly, a reduction in all cause and HF mortality.25 , 26

Nitrates/hydralazine

The combination of isosorbide dinitrate plus hydralazine reduces mortality and morbidity in black patients with NYHA class
III–IV HF and is recommended in addition to standard therapy in this setting.27 Use of this combination may also be
considered in black patients with NYHA class II HF1 , 4 , 27 and in other HF patients who do not tolerate ACE inhibitors and
ARBs.1

Nitrate monotherapy is valuable to treat symptoms of exercise-induced dyspnea or angina, paroxysmal nocturnal dyspnea
and orthopnea. Nitrates have not been shown to reduce mortality in the absence of hydralazine.1

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Omega-3 Polyunsaturated Fatty Acid Supplementation

Based on a recent trial that suggested a modest reduction of cardiovascular events with low-dose omega-3
polyunsaturated fatty acid (n-3 PUFA),28 the 2009 update of the Canadian Cardiovascular Society Guidelines
suggest that low-dose n-3 PUFA (1 g/day) may be considered in patients with mild to moderate
HF.29 Useful Info? The more recent joint American Heart Association and American College of Cardiology guideline has
not included a recommendation for or against the use of n-3 PUFA.5 Whether higher doses of n-3 PUFA are more effective is
unknown, but doses of more than 3 g/day have been associated with excessive bleeding.29 Monitoring the INR is suggested
in patients receiving warfarin following n-3 PUFA initiation.29 Finally, because n-3 PUFA are food supplements, patients
should consult their pharmacist to help in the selection of a reliable n-3 PUFA brand that most closely matches the
formulation studied in HF (850–882 mg eicosapentaenoic acid and docosahexaenoic acid as ethyl esters in an average ratio
of 1:1.2).

Calcium Channel Blockers

Felodipine and amlodipine are safe, but do not reduce mortality or morbidity in patients with systolic HF.30 , 31 They may
be useful in select patients with persistent angina despite the use of beta-blockers (and nitrates) or in patients with
uncontrolled hypertension despite the use of an ACEI, ARB, beta-blocker and a diuretic.3

Avoid use of diltiazem and verapamil in patients with systolic HF because of their negative inotropic effects.1 , 3 , 4 , 5 Avoid
nifedipine because of the lack of data and availability of safe alternatives.

Antiarrhythmics4

Consider amiodarone to maintain sinus rhythm in select patients with atrial fibrillation. Amiodarone also reduces the
frequency of repetitive ICD discharges. Avoid other antiarrhythmic drugs. Antiarrhythmics are not recommended to prevent
sudden cardiac death because they do not reduce mortality. It should be emphasized that a strategy of maintaining sinus
rhythm in patients with HF is not superior to ventricular rate control in patients with a history of atrial fibrillation.32

HMG CoA Reductase Inhibitors (Statins)

Although the benefit of statins in the primary and secondary prevention of coronary artery disease is well established, 2
recent trials have suggested that the benefits of statins in patients with HF may be more limited, even if they have coronary
artery disease.33 , 34 Nevertheless, patients included in these trials were relatively old (mean age at baseline of 69 and 73
years) and presented with a baseline LDL cholesterol of only 3.2 mmol/L and 3.5 mmol/L, respectively. Consequently, it
appears reasonable to continue treating younger patients and/or patients who are at high risk of cardiovascular events
(recent myocardial infarction, diabetes and known vascular disease). Moreover, because these trials did not study the impact
of statin discontinuation, it also appears reasonable to continue the use of these agents in patients who are receiving them.

Heart Failure with Preserved Systolic Function

Treatment of HF with PSF has been studied to a limited extent. Control risk factors (hypertension, diabetes mellitus,
ventricular rate in patients with supraventricular arrhythmias) and volume status and decrease heart rate to optimize filling
time.1 , 4 Recent trials have suggested that the chronic use of renin-angiotensin system modulators does not significantly
reduce the risk of mortality in patients with HF with PSF.35 , 36 , 37 Nevertheless, these agents should be used to treat
hypertension, particularly in patients with diabetes, left ventricular hypertrophy, nephropathy or coronary artery disease
because of their established efficacy and end-organ protection in these patient populations. Beta-blockers are
recommended in most patients,1 particularly those with CAD, prior MI, hypertension or atrial fibrillation (Figure 3 -
Management of Heart Failure with Preserved Systolic Function).4 Diuretics should be used to optimize volume status.1 Use
of verapamil or diltiazem may be considered to control the ventricular rate in patients with supraventricular arrhythmias1 ,
4 or angina, in those who cannot tolerate a beta-blocker,4 and may be particularly useful in patients with hypertrophic

cardiomyopathy. Calcium channel blockers may also be considered in patients with hypertension.4

Decompensated Heart Failure

Few large, randomized trials have been performed in patients with decompensated or acute HF. Intravenous loop diuretics
are recommended in patients with signs and symptoms of fluid retention (e.g., furosemide 40–200 mg 2 or 3 times daily
based on renal function or the patient’s usual dose of furosemide).1 , 4 , 16

Combinations of diuretics, or the addition of a vasodilator such as nitroglycerin, nesiritide or nitroprusside should be
given to hospitalized patients who do not respond to intravenous furosemide.1 , 4 Intravenous vasodilators with a loop

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Therapeutic Choice
diuretic can be used initially in patients with moderate to severe symptoms of pulmonary congestion or those with severe
hypertension.1 , 4 Sublingual nitroglycerin can be given before intravenous nitroglycerin. Invasive monitoring is
recommended when administering nitroprusside.4 Great care should be taken to prevent cyanide and thiocyanide toxicity with
nitroprusside; avoid in patients with hepatic or renal failure.3

In patients with low cardiac output, milrinone or dobutamine should be given if the systolic blood pressure is > 90 mm
Hg,1 and dobutamine if the systolic blood pressure is < 90 mm Hg.1 The use of vasopressors (dopamine or
norepinephrine) should be limited to patients with significant hypotension.1 Dosages of these agents are based on vital
signs, clinical status, comorbidities and the treatment regimen of the patient. In select patients, invasive monitoring of
hemodynamic parameters may be used to adjust the dose.

Therapeutic Tips

The choice of whether to start an ACE inhibitor or a beta-blocker first in a given patient is based on the vital signs, blood
pressure and comorbidities. Most clinicians will start both agents simultaneously at low doses.
If introduced sequentially, it is not necessary to reach the target doses of one agent before starting the other.
The doses of ACE inhibitors and beta-blockers should generally not be increased simultaneously.
Hypotension or worsening renal function when initiating or increasing the dose of an ACE inhibitor usually indicates the
need to reduce the dose of a diuretic.
The formulation of metoprolol available in Canada (metoprolol tartrate) has not been shown to reduce mortality in a
randomized trial of patients with HF, is not available in a commercial dosage form that is suitable for initial treatment of
HF and is not included in Canadian guidelines. Mortality and hospital admissions were significantly more frequent in
patients treated with metoprolol tartrate (target dose 50 mg BID) than with carvedilol (25 mg BID) in a large randomized
trial.38 The target dose of metoprolol tartrate used in this trial was lower than the target dose of controlled-release
metoprolol succinate that has been shown to significantly decrease mortality in a large placebo-controlled trial.12
In patients with hypotension, consider administering the blood pressure-lowering drugs at different times during the
day.
Cough is a symptom of HF decompensation. Careful evaluation is necessary when evaluating a cough in a patient
receiving an ACE inhibitor.
Electrolyte abnormalities are common in patients with HF. Patients need to be closely monitored, especially when taking
combinations that have additive effects, for example, increased serum potassium due to the combination of an ACE
inhibitor or ARB plus spironolactone.

Figure 1- Evaluation of Patients with Heart Failure

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a. Echocardiography (two dimensional or transthoracic) is used to determine LVEF, chamber size, wall thickness, valve function and
presence of pericardial disease. Consider other diagnostic investigations if inconclusive (e.g., magnetic resonance imaging or cardiac
catheterization).

Abbreviations: HF = heart failure; LV = left ventricular; LVEF = LV ejection fraction

Figure 2- Management of Systolic Heart Failure

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Therapeutic Choice

a. Identify and manage risk factors, educate all patients about their disease and implement nonpharmacologic treatment. Consider ICD and
resynchronization therapy in select patients.
b. Use an ARB in patients with ACEI-induced cough that is intolerable or angioedema (although there is a low risk of angioedema with
ARBs). Alternatively, substitute hydralazine/isosorbide dinitrate combination therapy for ACEI and/or ARB-induced hyperkalemia, renal
dysfunction or angioedema.
c. Consider using ACEI/ARB combination therapy to prevent disease progression in patients with minimal to moderate symptoms (i.e.,
NYHA II) who cannot tolerate a beta-blocker.
d. Use diuretics to minimize fluid retention. Consider combination diuretic therapy in patients with severe symptoms.
e. Avoid the combination of an ACEI plus an ARB and spironolactone because of the risk of hyperkalemia.

Abbreviations: ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker; LVEF = left
ventricular ejection fraction; NYHA = New York Heart Association

Figure 3- Management of Heart Failure with Preserved Systolic Function

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Therapeutic Choice

a. There is no strong consensus on the definition of HF with PSF or its treatment.


b. Diuretics should be used with care because excessive diuresis may decrease cardiac output and compromise renal function in HF with
PSF.
c. CCBs may improve symptoms by decreasing heart rate and increasing diastolic filling time.

Abbreviations: ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor antagonist;
CCB = calcium channel blocker; HF with PSF = heart failure with preserved systolic function

Table 4: Outcomes Associated with Drugs Used for Systolic Heart Failure

Number needed to
Relative risk Absolute risk treat to prevent one
Outcome Intervention Comparator reduction (%) reduction (%) outcome

Death prevented ACE inhibitor8 Placebo 16 4.5 23

Beta-blocker13 Placebo 32 5.5 29

Aldosterone antagonist22 Placebo 30 11 10

Hydralazine/isosorbide Placebo 39 4 25
dinitrate27

Hospitalizations ACE inhibitor8 Placebo 30 10.8 9


avoided
Beta-blocker13 Placebo 33 6 17

Digoxin23 Placebo 28 7.9 13

Table 5: Drugs Used for Heart Failure

Drug Costa
Class Drug Dose Adverse Effects Interactions Comments

ACE captopril Initial: Hypotension, Diuretics: Monitor $$$


Inhibitorsb Capoten, generics TID hyperkalemia, dry hypotension serum
Target: 50 mg TID cough, renal (monitor BP). creatinine
insufficiency, Potassium-sparing and
angioedema (rare), diuretics, potassium
skin rashes, taste potassium after
disturbance, supplements, initiation of
proteinuria, ARBs: therapy.

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Therapeutic Choice

Drug Costa
Class Drug Dose Adverse Effects Interactions Comments

neutropenia (rare), hyperkalemia Some


headache, dizziness. (monitor K+). experienced
clinicians
NSAIDs: ↓ use doses
hypotensive effect higher than
(monitor BP), fluid usual target
retention, renal doses.
failure.

Lithium: lithium
toxicity (monitor
lithium levels).

ACE enalapril Initial: Hypotension, Diuretics: Monitor $$$


Inhibitorsb Vasotec, generics 1.25–2.5 mg BID hyperkalemia, dry hypotension serum
Target: 10 mg BID cough, renal (monitor BP). creatinine
insufficiency, Potassium-sparing and
angioedema (rare), diuretics, potassium
skin rashes, taste potassium after
disturbance, supplements, initiation of
proteinuria, ARBs: therapy.
neutropenia (rare), hyperkalemia Some
headache, dizziness. (monitor K+). experienced
clinicians
NSAIDs: ↓ use doses
hypotensive effect higher than
(monitor BP), fluid usual target
retention, renal doses.
failure.

Lithium: lithium
toxicity (monitor
lithium levels).

ACE lisinopril Initial: Hypotension, Diuretics: Monitor $$


Inhibitorsb Prinivil, Zestril, 2.5–5 mg once daily hyperkalemia, dry hypotension serum
generics Target: 20–35 mg cough, renal (monitor BP). creatinine
once daily insufficiency, Potassium-sparing and
angioedema (rare), diuretics, potassium
skin rashes, taste potassium after
disturbance, supplements, initiation of
proteinuria, ARBs: therapy.
neutropenia (rare), hyperkalemia Some
headache, dizziness. (monitor K+). experienced
clinicians
NSAIDs: ↓ use doses
hypotensive effect higher than
(monitor BP), fluid usual target
retention, renal doses.
failure.

Lithium: lithium
toxicity (monitor
lithium levels).

ACE ramipril Initial: Hypotension, Diuretics: Monitor $$


Inhibitorsb Altace, generics 1.25–2.5 mg BID hyperkalemia, dry hypotension serum
Target: 5 mg BID cough, renal (monitor BP). creatinine
insufficiency, Potassium-sparing and
angioedema (rare), diuretics, potassium
skin rashes, taste potassium after
disturbance, supplements, initiation of

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Therapeutic Choice

Drug Costa
Class Drug Dose Adverse Effects Interactions Comments

proteinuria, ARBs: therapy.


neutropenia (rare), hyperkalemia Some
headache, dizziness. (monitor K+). experienced
clinicians
NSAIDs: ↓ use doses
hypotensive effect higher than
(monitor BP), fluid usual target
retention, renal doses.
failure.

Lithium: lithium
toxicity (monitor
lithium levels).

ACE trandolapril Initial: Hypotension, Diuretics: Monitor $$


Inhibitorsb Mavik 1 mg once daily hyperkalemia, dry hypotension serum
Target: 4 mg once cough, renal (monitor BP). creatinine
daily insufficiency, Potassium-sparing and
angioedema (rare), diuretics, potassium
skin rashes, taste potassium after
disturbance, supplements, initiation of
proteinuria, ARBs: therapy.
neutropenia (rare), hyperkalemia Some
headache, dizziness. (monitor K+). experienced
clinicians
NSAIDs: ↓ use doses
hypotensive effect higher than
(monitor BP), fluid usual target
retention, renal doses.
failure.

Lithium: lithium
toxicity (monitor
lithium levels).

Angiotensin candesartan Initial: 4 mg once Hypotension, Diuretics: $$


Receptor Atacand daily hyperkalemia, renal hypotension
Blockers Target: 32 mg once insufficiency, (monitor BP).
daily angioedema (rare, Potassium-sparing
less frequent than diuretics and ACE
with ACE inhibitors), inhibitors:
headache, dizziness. hyperkalemia
(monitor K+).

Potassium:
hyperkalemia
(monitor K+).

NSAIDs: ↓
hypotensive effect
(monitor BP), fluid
retention, renal
failure.

Lithium: lithium
toxicity (monitor
lithium levels).

Angiotensin valsartan Initial: 40 mg BID Hypotension, Diuretics: $$$


Receptor Diovan Target: 160 mg BID hyperkalemia, renal hypotension
Blockers insufficiency, (monitor BP).
angioedema (rare, Potassium-sparing

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Therapeutic Choice

Drug Costa
Class Drug Dose Adverse Effects Interactions Comments

less frequent than diuretics and ACE


with ACE inhibitors), inhibitors:
headache, dizziness. hyperkalemia
(monitor K+).

Potassium:
hyperkalemia
(monitor K+).

NSAIDs: ↓
hypotensive effect
(monitor BP), fluid
retention, renal
failure.

Lithium: lithium
toxicity (monitor
lithium levels).

Thiazides chlorthalidone Dehydration, Lithium: lithium Use in $


and Related generics 50–100 mg once hypokalemia, toxicity (monitor patients
Diuretics daily nausea, lithium levels). with mild
Max: 200 mg/day hypotension, Digoxin: digoxin HF or with a
(use lower doses azotemia, toxicity if K+ loop
when used in hypomagnesemia, depleted (monitor diuretic.
combination with a hypercalcemia, K+).
loop diuretic) hyponatremia,
hyperglycemia Corticosteroids:
(more with hypokalemia
thiazides),
(monitor K+).
hyperuricemia, rash,
↑ total cholesterol.
NSAIDs: ↓ diuretic
effect; increased
renal toxicity
(monitor).
Loop diuretics:
hypokalemia,
hypomagnesemia,
dehydration, renal
dysfunction
(monitor).

Thiazides hydrochlorothiazide 25–100 mg/day Dehydration, Lithium: lithium Use in $


and Related given in 1 or 2 hypokalemia, toxicity (monitor patients
Diuretics Apo-Hydro, other divided doses nausea, lithium levels). with mild
generics Max: 200 mg/day hypotension, Digoxin: digoxin HF or with a
(use lower doses in azotemia, toxicity if K+ loop
combination with a hypomagnesemia, depleted (monitor diuretic.
loop diuretic) hypercalcemia, K+).
hyponatremia,
hyperglycemia Corticosteroids:
(more with hypokalemia
thiazides),
(monitor K+).
hyperuricemia, rash,
↑ total cholesterol.
NSAIDs: ↓ diuretic
effect; increased
renal toxicity
(monitor).
Loop diuretics:
hypokalemia,
hypomagnesemia,
dehydration, renal
dysfunction

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Therapeutic Choice

Drug Costa
Class Drug Dose Adverse Effects Interactions Comments

(monitor).

Thiazides metolazone Dehydration, Lithium: lithium Use in $


and Related Zaroxolyn 2.5–10 mg once daily hypokalemia, toxicity (monitor patients
Diuretics (use lower doses in nausea, lithium levels). with mild
combination with a hypotension, Digoxin: digoxin HF or with a
loop diuretic) azotemia, toxicity if K+ loop diuretic
hypomagnesemia, depleted (monitor in those
hypercalcemia, K+). with
hyponatremia, refractory
hyperglycemia Corticosteroids: HF.
(more with hypokalemia
thiazides),
(monitor K+).
hyperuricemia, rash,
↑ total cholesterol.
NSAIDs: ↓ diuretic
effect; increased
renal toxicity
(monitor).
Loop diuretics:
hypokalemia,
hypomagnesemia,
dehydration, renal
dysfunction
(monitor).

Loop bumetanide Dehydration, Lithium: lithium 1 mg = 40 $$$


Diuretics Burinex 1–4 mg/day hypokalemia, toxicity (monitor mg
hypocalcemia, lithium levels). furosemide.
nausea, Digoxin: digoxin
hypotension, toxicity if K+
azotemia, depleted (monitor
hypomagnesemia, K+).
anorexia,
hyperglycemia (less Corticosteroids:
than with thiazides), hypokalemia
hyperuricemia,
(monitor K+).
weakness, fatigue,
rash, ↑ total
NSAIDs: ↓ diuretic
cholesterol,
effect; ↑ renal
ototoxicity with high
toxicity (monitor).
doses.
Thiazide diuretics:
hypokalemia,
hypomagnesemia,
dehydration, renal
dysfunction
(monitor).

Loop furosemide Dehydration, Lithium: lithium $


Diuretics Lasix, generics 20–500 mg/day hypokalemia, toxicity (monitor
given daily to BID hypocalcemia, lithium levels).
For decompensated nausea, Digoxin: digoxin
HF: may be given hypotension, toxicity if K+
BID or TID azotemia, depleted (monitor
hypomagnesemia, K+).
anorexia,
hyperglycemia (less Corticosteroids:
than with thiazides), hypokalemia
hyperuricemia,
(monitor K+).
weakness, fatigue,
rash, ↑ total
NSAIDs: ↓ diuretic
cholesterol,
effect; ↑ renal
ototoxicity with high

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Therapeutic Choice

Drug Costa
Class Drug Dose Adverse Effects Interactions Comments

doses. toxicity (monitor).


Thiazide diuretics:
hypokalemia,
hypomagnesemia,
dehydration, renal
dysfunction
(monitor).

Loop ethacrynic acid 50–200 mg daily or Dehydration, Lithium: lithium An $$$$$


Diuretics Edecrin divided BID hypokalemia, toxicity (monitor alternative
hypocalcemia, lithium levels). diuretic in
nausea, Digoxin: digoxin patients
hypotension, toxicity if K+ with
azotemia, depleted (monitor allergies to
hypomagnesemia, K+). loop
anorexia, diuretics.
hyperglycemia (less Corticosteroids: Higher risk
than with thiazides), hypokalemia of
hyperuricemia, ototoxicity
(monitor K+).
weakness, fatigue, than
rash, ↑ total furosemide.
NSAIDs: ↓ diuretic
cholesterol,
effect; ↑ renal
ototoxicity with high
toxicity (monitor).
doses.
Thiazide diuretics:
hypokalemia,
hypomagnesemia,
dehydration, renal
dysfunction
(monitor).

Aldosterone eplerenone Initial: 25 mg daily Hyperkalemia, ACE inhibitors, Monitor $$$$


Antagonists Inspra or every 2 days dehydration, ARBs, potassium serum
Target: 50 mg daily dizziness, diarrhea, supplements: creatinine
nausea. hyperkalemia. and
NSAIDs: ↓ diuretic potassium 3
effect, worsening days and 1
renal function, week after
hyperkalemia. initiating or
titrating the
Strong dose.
inhibitors/inducers Repeat
of CYP 3A4. every 1–3
mo once
stable.

Aldosterone spironolactone Initial: 12.5 mg daily Hyperkalemia, ACE inhibitors, Monitor $


Antagonists Aldactone, generics or every 2 days dehydration, nausea, ARBs, potassium serum
Target (for mortality gynecomastia supplements: creatinine
benefit): 25–50 (usually reversible hyperkalemia. and
mg/day upon NSAIDs: ↓ diuretic potassium 3
discontinuation). effect, worsening days and 1
Higher doses can be renal function, week after
used for stronger hyperkalemia. initiating or
diuretic effects, but titrating the
rarely dose.
used/appropriate, Repeat
unless patient has every 1–3
severe right HF mo once
stable.
eplerenone.

Beta1- bisoprolol Initial: 1.25 mg po Orthostatic Digoxin, Selective $


adrenergic generics daily hypotension, fluid amiodarone, beta-
Target: 10 mg daily retention, diltiazem, blocker.

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Therapeutic Choice

Drug Costa
Class Drug Dose Adverse Effects Interactions Comments

Antagonists bronchospasm (less verapamil: ↑


with beta1- bradycardia.
selective), dyspnea, Nondihydropyridine
bradycardia, calcium channel
malaise, fatigue, blockers: additive
asthenia, erectile cardiodepressant
dysfunction, may effect.
mask hypoglycemia.

Beta1- carvedilol Initial: 3.125 mg po Orthostatic Digoxin, Nonselective $$


adrenergic Apo-Carvedilol, BID hypotension, fluid amiodarone, beta-blocker
Antagonists other generics Target: 25 mg BID retention, diltiazem, with alpha-
bronchospasm (less verapamil: ↑ blocking
with beta1- bradycardia. activity. Has
selective), dyspnea, Nondihydropyridine some
bradycardia, calcium channel vasodilating
malaise, fatigue, blockers: additive effects.
asthenia, erectile cardiodepressant
dysfunction, may effect.
mask hypoglycemia.
More likely to cause CYP 2D6 inhibitors.
orthostatic
hypotension than
bisoprolol.

Vasodilators hydralazine Initial: 10–25 mg po Hypotension, Used in $$


Apo-Hydralazine, TID gastrointestinal combination
other generics complaints, lupus- with
Target: 75 mg TID like syndrome. isosorbide
dinitrate in
black
patients.

Vasodilators isosorbide dinitrate Initial: 10–20 mg po Headache, Sildenafil, Use in $


generics TID hypotension. vardenafil and combination
Target: 40 mg TID tadalafil: severe with
hypotension. hydralazine
in black
patients.

Vasodilators nesiritide 2 μg/kg iv bolus Hypotension, ↑ ↑ hypotensive For hospital $$$$$


Natrecor followed by 0.01 serum creatinine effects with ACE use only.
μg/kg/min infusion. inhibitors; possible There is
May ↑ dose at ≥ 3- additive limited
hour intervals by hypotension with experience
giving a 1 μg/kg other vasodilators with doses
bolus over 1 min > 0.01
then ↑ infusion rate µg/kg/min
by 0.005 μg/kg/min
Max: 0.03 μg/kg/min

Vasodilators nitroglycerin 5–200 µg/min iv Hypotension, Sildenafil, $$$$$


generics headache, vardenafil and
tachycardia, tadalafil: severe
bradycardia. hypotension.

Vasodilators nitroprusside 0.1–5 µg/kg/min iv Hypotension, $$$$$


generics cyanide toxicity,
thiocyanate toxicity,
methemoglobinemia,
coronary artery
steal, tachycardia, ↑
intracranial

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Therapeutic Choice

Drug Costa
Class Drug Dose Adverse Effects Interactions Comments

pressure.

Calcium amlodipine 2.5–10 mg daily Hypotension, $$-


Channel Norvasc, generics constipation, $$$
Blockers peripheral edema,
gingival hyperplasia,
headache, dizziness.

Calcium felodipine 2.5–10 mg daily Hypotension, $


Channel Plendil, Renedil, constipation,
Blockers generics peripheral edema,
gingival hyperplasia,
headache, dizziness.

Inotropic digoxin 0.0625–0.25 mg Anorexia, nausea, Amiodarone, Adjust dose $


Agents Lanoxin, Toloxin daily (lower doses vomiting, visual clarithromycin, based on
may be appropriate disturbances, cyclosporine, patient’s
in select patients) fatigue, dizziness, erythromycin, age, weight,
confusion, delirium. itraconazole, renal
Cardiac arrhythmia. propafenone, function and
Noncardiovascular quinidine, concomitant
adverse effects do ritonavir, drugs.
not always precede tetracycline and
potentially fatal verapamil ↑ digoxin
arrhythmias. serum levels.

Antacids,
cholestyramine,
colestipol,
neomycin,
rifampin, St. John’s
wort and
sulfasalazine ↓
digoxin serum
levels.

Amiodarone, beta-
blockers, diltiazem
and verapamil ↑
risk of bradycardia.

Inotropic milrinone 0.1–0.75 µg/kg/min Tachyarrhythmias, $$$$$


Agents Apo-Milrinone, other hypotension,
generics myocardial
ischemia,
thrombocytopenia.

Inotropic dobutamine 2–20 µg/kg/min Tachyarrhythmias, Beta-blockers $$$$$


Agents generics hypokalemia, reduce positive
myocardial inotropic effects of
ischemia. dobutamine.

a. Cost of 30-day supply for target doses; includes drug cost only. For ACE inhibitors, cost was calculated for the targeted dose.
b. Only captopril, enalapril, ramipril and trandolapril have been shown to reduce morbidity and prolong survival in heart failure or in
patients with LV dysfunction post-MI.

Dosage adjustment may be required in renal impairment; see Appendices: Dosage Adjustment in Renal Impairment

Legend: $ < $25 $$ $25–50 $$–$$$ $25–75 $$$ $50–75 $$$$ $75–100 $$$$$ > $100

Suggested Readings

Arnold JM, Liu P, Demers C et al. Canadian Cardiovascular Society consensus conference recommendations on heart failure

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Therapeutic Choice
2006: diagnosis and management. Can J Cardiol 2006;22(1):23-45.

Dickstein K, Cohen-Solal A, Filippatos G et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart
failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European
Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the
European Society of Intensive Care Medicine (ESICM). Eur Heart J 2008;29(19):2388-442.

Heart Failure Society Of America. HFSA 2006 comprehensive heart failure practice guideline. J Card Fail 2006;12(1):e1-122.

Howlett JG, McKelvie RS, Arnold JM et al. Canadian Cardiovascular Society Consensus Conference guidelines on heart failure,
update 2009: diagnosis and management of right-sided heart failure, myocarditis, device therapy and recent important
clinical trials. Can J Cardiol 2009;25(2):85-105.

Hunt SA. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of
the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to
Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2005;46(6):e1-82.

Jessup M, Brozena S. Heart failure. N Engl J Med 2003;348(20):2007-18.

References

1. Arnold JM, Liu P, Demers C et al. Canadian Cardiovascular Society consensus conference recommendations on heart
failure 2006: diagnosis and management. Can J Cardiol 2006;22(1):23-45.
2. Jessup M, Brozena S. Heart failure. N Engl J Med 2003;348(20):2007-18.
3. Dickstein K, Cohen-Solal A, Filippatos G et al. ESC Guidelines for the diagnosis and treatment of acute and chronic
heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the
European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and
endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J 2008;29(19):2388-442.
4. Heart Failure Society Of America. HFSA 2006 comprehensive heart failure practice guideline. J Card Fail 2006;12(1):e1-
122.
5. Hunt SA, Abraham WT, Chin MH et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the
Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the
International Society for Heart and Lung Transplantation. Circulation 2009;119(14):e391-479.
6. Ross H, Hendry P, Dipchand A et al. 2001 Canadian Cardiovascular Society Consensus Conference on cardiac
transplantation. Can J Cardiol 2003;19(6):620-54.
7. [No authors listed]. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North
Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med 1987;316
(23):1429-35.
8. [No authors listed]. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and
congestive heart failure. The SOLVD Investigators. N Engl J Med 1991;325(5):293-302.
9. [No authors listed]. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with
reduced left ventricular ejection fractions. The SOLVD Investigators. N Engl J Med 1992;327(10):685-91.
10. Packer M, Poole-Wilson PA, Armstrong PW et al. Comparative effects of low and high doses of the angiotensin-
converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group.
Circulation 1999;100(23):2312-8.
11. de Denus S, Tardif JC, White M et al. Quantification of the risk and predictors of hyperkalemia in patients with left
ventricular dysfunction: a retrospective analysis of the Studies of Left Ventricular Dysfunction (SOLVD) trials. Am Heart
J 2006;152(4):705-12.
12. [No authors listed]. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention
Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353(9169):2001-7.
13. [No authors listed]. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353
(9146):9-13.
14. Packer M, Bristow MR, Cohn JN et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart
failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996;334(21):1349-55.
15. Packer M, Coats AJ, Fowler MB et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med
2001;344(22):1651-8.
16. Brater DC. Diuretic therapy. N Engl J Med 1998;339(6):387-95.
17. Granger CB, McMurray JJ, Yusuf S et al. Effects of candesartan in patients with chronic heart failure and reduced left-
ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet
2003;362(9386):772-6.

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Therapeutic Choice
18. Pfeffer MA, McMurray JJ, Velazquez EJ et al. Valsartan, captopril, or both in myocardial infarction complicated by heart
failure, left ventricular dysfunction, or both. N Engl J Med 2003;349(20):1893-906.
19. McMurray JJ, Ostergren J, Swedberg K et al. Effects of candesartan in patients with chronic heart failure and reduced
left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet
2003;362(9386):767-71.
20. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J
Med 2001;345(23):1667-75.
21. Pitt B, Remme W, Zannad F et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular
dysfunction after myocardial infarction. N Engl J Med 2003;348(14):1309-21.
22. Pitt B, Zannad F, Remme WJ et al. The effect of spironolactone on morbidity and mortality in patients with severe heart
failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341(10):709-17.
23. [No authors listed]. The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis
Investigation Group. N Engl J Med 1997;336(8):525-33.
24. Gheorghiade M, van Veldhuisen DJ, Colucci WS. Contemporary use of digoxin in the management of cardiovascular
disorders. Circulation 2006;113(21):2556-64.
25. Rathore SS, Curtis JP, Wang Y et al. Association of serum digoxin concentration and outcomes in patients with heart
failure. JAMA 2003;289(7):871-8.
26. Adams KF, Gheorghiade M, Uretsky BF et al. Clinical benefits of low serum digoxin concentrations in heart failure. J Am
Coll Cardiol 2002;39(6):946-53.
27. Taylor AL, Ziesche S, Yancy C et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N
Engl J Med 2004;351(20):2049-57.
28. Tavazzi L, Maggioni AP, Marchioli R et al. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure
(the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372(9645):1223-30.
29. Howlett JG, McKelvie RS, Arnold JM et al. Canadian Cardiovascular Society Consensus Conference guidelines on heart
failure, update 2009: diagnosis and management of right-sided heart failure, myocarditis, device therapy and recent
important clinical trials. Can J Cardiol 2009;25(2):85-105.
30. Cohn JN, Ziesche S, Smith R et al. Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in
patients with chronic heart failure treated with enalapril: V-HeFT III. Vasodilator-Heart Failure Trial (V-HeFT) Study
Group. Circulation 1997;96(3):856-63.
31. Packer M, O'Connor CM, Ghali JK et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure.
Prospective Randomized Amlodipine Survival Evaluation Study Group. N Engl J Med 1996;335(15):1107-14.
32. Roy D, Talajic M, Nattel S et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med
2008;358(25):2667-77.
33. Gissi-HF Investigators, Tavazzi L, Maggioni AP et al. Effect of rosuvastatin in patients with chronic heart failure (the
GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372(9645):1231-9.
34. Kjekshus J, Apatrei E, Barrios V et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357
(22):2248-61.
35. Yusuf S, Pfeffer MA, Swedberg K et al. Effects of candesartan in patients with chronic heart failure and preserved left-
ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 2003;362(9386):777-81.
36. Massie BM, Carson PE, McMurray JJ et al. Irbesartan in patients with heart failure and preserved ejection fraction. N
Engl J Med 2008;359(23):2456-67.
37. Cleland JG, Tendera M, Adamus J et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study.
Eur Heart J 2006;27(19):2338-45.
38. Poole-Wilson PA, Swedberg K, Cleland JG et al. Comparison of carvedilol and metoprolol on clinical outcomes in
patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial.
Lancet 2003;362(9377):7-13.

Pharmacoeconomic Considerations: Heart Failure


Date of preparation: 2007-06-30
Blair Jarvis, MSc, BSP

Epidemiology

Country (Year) Prevalence

Canada (2000-2001)1 85 679 people spent a total of 1.4 million days in hospital for heart failure
Median length of stay: 7 days

Cost of Illness Data

Country and Year of Estimate Direct Costsa

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United States (2000)2 Direct costs over a 5-year period for:


• patients with left ventricular ejection fraction < 50%: US $33 023
• patients with preserved left ventricular ejection fraction: US $32 580

Commentary

Heart failure is the most common cause of hospitalization in the elderly, and 80% of hospitalizations for heart failure and
90% of deaths due to heart failure occur in those older than 65 years.3 In Canada, the mean age of a person hospitalized
for heart failure in 2000-2001 was 76 years and the in-hospital mortality rate was 15.5%.1 There were more than 100 000
hospital discharges for heart failure in that year, approximately one-third of which were after re-admissions. The burden of
heart failure in Canada is projected to increase as the population ages.4 Measures that stabilize the disease and reduce the
rate of hospitalization are likely to be highly cost-effective.
Drug therapy for heart failure reduces symptoms, improves health-related quality of life, retards disease progression,
prevents hospitalizations and prolongs life. The most extensive evidence of benefit pertains to the use of ACE inhibitors
and beta blockers.
There is evidence of substantial care gaps where the benefits of heart failure therapies are not being realized in routine
clinical practice.5 The difference in impact of interventions in clinical trials and clinical practice has been likened to a
“diffusion gradient.” Removing this diffusion gradient and increasing adherence with treatment guidelines is likely to be
cost-effective. For example, increasing use of ACE inhibitors, beta-blockers, digoxin and spironolactone by 10% would be
expected to reduce the rate of hospitalization for heart failure and save as much as $6.6 million in one year based on
Alberta data.6 This would result in a net savings of $2.3 million.6 Canadian treatment guidelines provide target doses for
each medication, so clinicians should be sure not only to prescribe appropriate drugs, but to titrate the dose to a level
shown to produce benefits in clinical trials. Programs of follow-up by nurses or pharmacists with patients released from
hospital have been shown to reduce re-admissions and hospital costs within six months.7
Most pharmacoeconomic studies are conducted from the societal rather than an individual perspective. The relative cost of
individual medications for heart failure is inexpensive because of the availability of generic products; however, because
patients must take a number of drugs to achieve optimal outcomes, the total cost for an individual may be substantial.
Patients who perceive the medical costs of heart failure to be a burden have worse health status than those without a
perceived economic burden.8 Thus, inquiring about financial constraints and involving other members of the health care
team (e.g., nurses, social workers, pharmacists) may be helpful in addressing the needs of patients with diminished health
status.

a. Direct costs include those associated with physician services, nursing care, diagnostic procedures, drugs and hospitalization.

1. Tsuyuki RT, Shibata MC, Nilsson C et al. Contemporary burden of illness of congestive heart failure in Canada. Can J
Cardiol 2003;19(4):436-8.
2. Liao L, Jollis JG, Anstrom KJ et al. Costs for heart failure with normal vs reduced ejection fraction. Arch Intern Med
2006;166(1):112-8.
3. Haldeman GA, Croft JB, Giles WH et al. Hospitalization of patients with heart failure: National Hospital Discharge
Survey, 1985 to 1995. Am Heart J 1999;137(2):352-60.
4. Johansen H, Strauss B, Arnold JM et al. On the rise: the current and projected future burden of congestive heart
failure hospitalization in Canada. Can J Cardiol 2003;19(4):430-5.
5. Kosiborod M, Lichtman JH, Heidenreich PA et al. National trends in outcomes among elderly patients with heart failure.
Am J Med 2006;119(7):616.e1-7.
6. Shibata MC, Nilsson C, Hervas-Malo M et al. Economic implications of treatment guidelines for congestive heart
failure. Can J Cardiol 2005;21(14):1301-6.
7. Tsuyuki RT, Fradette M, Johnson JA et al. A multicentre disease management program for hospitalized patients with
heart failure. J Card Fail 2004;10(6):473-80.
8. Conard MW, Heidenreich P, Rumsfeld JS et al. Patient-reported economic burden and the health status of heart failure
patients. J Card Fail 2006;12(5):369-74.

Therapeutic Choices. © Canadian Pharmacists Association, 2011. All rights reserved.

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Print Close

Cardiovascular Disorders: Hypertension

Date Prepared: November 2010

Norm R.C. Campbell, MD, FRCPC

Paul Gibson, MD, FRCPC

Ross T. Tsuyuki, PharmD, MSc, FCSHP, FACC

Goals of Therapy

Reduce the risk of premature cardiac, cerebrovascular and renal morbidity and mortality
Achieve blood pressure targets in treated patients. The targets presented in Table 1 are maximums; thus, the desired systolic
blood pressure (SBP) and diastolic blood pressure (DBP) values are below these thresholds.

Table 1: Blood Pressure Targets in Treated Patients1

Setting Target SBP/DBP (mm Hg)

Homea <135/85

Office

General patient population <140/90

Isolated systolic hypertension SBP <140

Diabetes mellitus <130/80

Chronic kidney disease <130/80

a. Measured by a validated home blood pressure monitor.

Adapted with permission from Canadian Hypertension Education Program.

Abbreviations: DBP=diastolic blood pressure; SBP=systolic blood pressure

Investigations

History:
duration of hypertension, usual level of blood pressure and any sudden change in severity of hypertension
history of antihypertensive drug use, reason for changing therapy, effectiveness, side effects and intolerance
drugs that may cause hypertension (Table 2)
drugs that may interact with antihypertensive drugs (those that induce or inhibit metabolism)
adherence with lifestyle recommendations and drug therapy
family history of hypertension, cardiovascular risk factors and premature cardiovascular disease
personal history of cigarette and alcohol use, usual physical activity, usual diet and sodium intake, current weight and
recent weight change, waist circumference, diabetes and dyslipidemia
cerebrovascular, cardiac and peripheral vascular symptoms to assess for target organ damage
symptoms of secondary hypertension, which include, for example, pheochromocytoma (hyperadrenergic symptoms), hyper-
and hypothyroidism, Cushing’s syndrome, renal/urinary symptoms or a past history of renal disease

Table 2: Drugs and Other Exogenous Factors That Can Induce or Aggravate Hypertension

Drugs/Substances Alcohol (excessive use)

Calcineurin inhibitors, e.g., cyclosporine, tacrolimus

Corticosteroids and anabolic steroids

Erythropoietin and analogues

Licorice root

Midodrine

Monoamine oxidase inhibitors

NSAIDs including “coxibs” (celecoxib)

Oral contraceptive and sex hormones

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Stimulants, including cocaine

Vasoconstricting, sympathomimetic decongestants

Venlafaxine (dose ≥300 mg/day)

Other Factors High salt (sodium) intake

Sleep apnea

Adapted with permission from Canadian Hypertension Education Program. 2010 Hypertension
Recommendations for the Management of Hypertension.

Diagnosis:1
the diagnosis of hypertension is immediate in the case of hypertensive emergencies and urgencies. This includes patients
with hypertension that is compromising vital organ function (encephalopathy, cardiac, or rapidly decreasing renal function),
hypertension and a major artery dissection, or those with DBP ≥130 mm Hg
hypertension may be diagnosed in 2 office visits if the blood pressure averages ≥180/110, or ≥140/90 mm Hg in the
presence of diabetes, renal disease, atherosclerotic cardiovascular disease or cerebrovascular disease
the diagnosis may be arrived at after 2 visits if home pressure measurement or ambulatory blood pressure measurement is
used
the diagnosis may require 3 visits if the blood pressure averages ≥160/100 mm Hg. However, 5 or more visits may be
required to establish the diagnosis if the initial blood pressure average is <160/100 mm Hg and there is no target organ
dysfunction. Attention to the details of measuring blood pressure is essential to making a correct diagnosis.1 Automated
blood pressure measurements (using an approved monitor) in the office is recommended.
home measurement of blood pressure can aid in the diagnosis of hypertension, identify white coat and masked
hypertension, improve blood pressure control and improve medication adherence in poorly adherent patients

Table 3: Hypertensive Patients Requiring Additional Laboratory Testing1

If these characteristics are present: Check for:

• High serum creatinine (high normal in the elderly) Renal disease

• Urinary albumin Diabetes, renal


disease

Two or more of: Renovascular disease


• Sudden onset or worsening of hypertension in patients aged >55 or <30 y
• Abdominal bruit
• Uncontrolled hypertension despite use of ≥3 drugs
• Decreased renal function associated with use of an ACE inhibitor or ARB
• Overt atherosclerotic vascular disease
• Recurrent episodes of hypertension and flash pulmonary edema

• Paroxysmal and/or severe sustained hypertension refractory to usual antihypertensive therapy Pheochromocytoma
• Hypertension and symptoms suggestive of catecholamine excess (2 or more of headaches,
palpitations, sweating, etc.)
• Hypertension triggered by beta-blockers, monoamine oxidase inhibitors, micturition or changes in
abdominal pressure
• Incidentally discovered adrenal adenoma
• MEN 2A or 2B; von Recklinghausen’s neurofibromatosis or von Hippel-Lindau disease

• Spontaneous hypokalemia Hyperaldosteronism


• Profound diuretic-induced hypokalemia (K+ <3 mmol/L)
• Hypertension refractory to treatment with ≥3 drugs
• Incidental adrenal adenoma

Abbreviations: ARB=angiotensin receptor blocker; MEN=multiple endocrine neoplasia

Physical exam:
fundi for hypertensive retinopathy
bruits and peripheral pulses for vascular disease and renovascular hypertension
edema and lung fields for signs of heart failure
heart sounds (4th heart sound), sustained and displaced apex for left ventricular hypertrophy
abdominal mass for polycystic kidneys and aortic aneurysm
neurologic exam for cerebrovascular disease
Initial laboratory testing:
serum potassium, sodium and creatinine
urinalysis
fasting glucose, total cholesterol, HDL-C, LDL-C, triglycerides
standard 12-lead ECG

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select patients should have additional testing (Table 3)

Therapeutic Choices

Nonpharmacologic Choices

All individuals should be advised about a healthy lifestyle to prevent or control hypertension and cardiovascular disease (Table 4).

Table 4: Effect of Lifestyle Changes on Blood Pressure in Adults with Hypertension

Intervention Change in Blood Pressure (systolic/diastolic) mm Hg

Reduction in sodium intake ↓ by 1800 mg (78 mmol) per day −5.8/−2.5

Weight loss 4.5 kg −7.2/−5.9

Reduction in alcohol intake ↓ by 2.7 drinks/day −4.6/−2.3

Exercise 3 times/week −10.3/−7.5

Dietary recommendations DASH dieta −11.4/−5.5

a. Available from: www.nhlbi.nih.gov/health/public/heart/hbp/dash/new_dash.pdf .

Adapted with permission from Campbell N. Canadian Hypertension Education


Program. Brief overview of 2004 recommendations. Can Fam Physician 2004;50:1411-5.

Weight loss of 4 kg or more if overweight (target body mass index: 18.5 to 24.9 kg/m2; waist circumference <102 cm in men
and <88 cm in women).
Healthy diet—high in fresh fruits, vegetables, soluble fibre and low-fat dairy products, low in saturated fats and sodium, e.g.,
DASH diet available at www.nhlbi.nih.gov/health/public/heart/hbp/dash/new_dash.pdf.
Sodium intake of 1500 mg (65 mmol) per day for those aged 19–50 years, 1300 mg (56 mmol) per day for those aged 51–70
years and 1200 mg (52 mmol) per day in those 71 years and older.
Regular, moderate intensity cardiorespiratory physical activity for 30–60 minutes on most days.
Low risk alcohol consumption (0 to 2 drinks/day, < 9 drinks/week for women and < 14 drinks/week for men).
Smoke-free environment.

Pharmacologic Choices1 (Table 6)

If the average SBP/DBP is 140–159/90–99 mm Hg, treatment is recommended in the presence of either:
hypertensive target organ damage or
other independent risk factors for cardiovascular disease, e.g., cigarette smoking, dyslipidemia, strong family history of
premature cardiovascular disease, truncal obesity, sedentary lifestyle, males older than 55 years, females older than 60 years.
More than 90% of patients with hypertension have other cardiovascular risks or overt cardiovascular disease so pharmacologic
therapy is almost always recommended.2

If the average SBP/DBP is 140–159/90– 99 mm Hg and the individual does not have additional risk factors, the short-term benefits
of pharmacotherapy are small; discuss the risks and benefits of therapy with the patient. Monitor blood pressure and other risk
factors regardless of whether such a patient chooses to begin drug therapy as generally the risks accumulate and blood pressure
increases over time.

Consider low-dose ASA in patients over age 50 once blood pressure is controlled. Consider therapy for dyslipidemia if the patient
meets the current Canadian criteria (see Cardiovascular Disorders: Dyslipidemias).

In general, the reduction in cardiovascular risk depends more on the extent of the reduction in blood pressure than on the specific
blood pressure medication. Pharmacologic therapy should usually be started with a low dose of the initial drug. Consider concurrent
risk factors and disease states when selecting initial therapy (Table 5). Dose titration to achieve goal blood pressure should be done
every 4–8 weeks for all but those with severe hypertension or target organ damage or high cardiovascular risk, for whom closer
follow-up and more frequent dosage titration is required. Lack of control over blood pressure is in most cases due to a failure to up-
titrate therapy (adding drugs and/or increasing doses) in response to high office readings. Greater confidence in office readings can
result from supplementing with home blood pressure measurements or ambulatory 24-hour monitors. Generally, high office readings
should trigger a dosage increase, addition of another medication, investigations to identify the cause of the high readings or a
follow-up appointment within 2–8 weeks to reassess blood pressure.

Diuretics

Diuretics are first-line therapy for uncomplicated hypertension. They are inexpensive and well tolerated, and extensive evidence
supports their efficacy. Therefore, low-dose thiazide or related diuretics (e.g., indapamide) should generally be selected first, unless
there are specific indications for other drugs (see Table 5). Diuretics have proven antihypertensive effectiveness in patients with
isolated systolic hypertension, the elderly and black patients.

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Diuretics can cause hypokalemia that may be associated with adverse cardiovascular outcomes. Consider alternative first-line agents
in those with or strongly predisposed to a serious arrhythmia, for example, prolonged QT syndrome. Consider using a combination
product to minimize the risk of hypokalemia (hydrochlorothiazide plus a potassium-sparing diuretic—spironolactone, amiloride or
triamterene). Reserve the use of high doses (e.g., >25 mg/day of hydrochlorothiazide) for patients with resistant hypertension
unresponsive to treatment with multiple drugs or secondary to renal impairment. Consider using a loop diuretic in patients with
renal impairment. Diuretics may worsen dysglycemia, although cardiovascular outcomes in patients with diabetes who are treated
with diuretics are similar to those treated with ACE inhibitors.3

Beta-blockers

Beta-blockers are first-line therapy in patients who are younger than 60 years, or who have stable angina, heart failure or a history
of myocardial infarction. Beta-blockers are also useful in patients who have migraine headaches, tachycardia or essential tremor.
However, beta-blockers are not as effective as angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs) or diuretics
as initial therapy for primary prevention of cardiovascular events in patients over the age of 60 years. In addition, they may be
ineffective in preventing cardiovascular events in people who smoke.4

Drugs that Act via the Renin Angiotensin Aldosterone System (RAAS)

The renin angiotensin aldosterone system (RAAS) plays a crucial role in modulating blood pressure, kidney function, electrolyte
balance and vascular and cardiac structure. Drugs that act directly on this system include angiotensin converting enzyme (ACE)
inhibitors, angiotensin receptor antagonists, direct renin inhibitors and spironolactone. Antihypertensive drugs that stimulate the
RAAS axis (e.g., diuretics) are as effective as those that block this system in preventing cardiovascular events in patients with
hypertension. However, some inhibitors of the RAAS do provide additional benefits in certain patients, including those with heart
failure, diabetes and/or chronic kidney disease. ACE inhibitors, ARBs and direct renin inhibitors are contraindicated in pregnant
women.5 , 6 , 7 Thus drugs from these classes should not be prescribed in women of child-bearing potential unless the risks are
carefully weighed and adequate measures are taken to prevent pregnancy (see Choices during Pregnancy and Breastfeeding).

Angiotensin Converting Enzyme Inhibitors

Angiotensin converting enzyme (ACE) inhibitors are first-line agents for non-black patients with uncomplicated hypertension and for
patients with diabetes, ischemic heart disease, recent myocardial infarction, heart failure or chronic kidney disease.

Angiotensin II Receptor Blockers

ARBs are first-line agents for patients with uncomplicated hypertension, for patients with diabetes or ischemic heart disease. They
are good alternatives to ACE inhibitors when the latter are specifically indicated but not tolerated.

Direct Renin Inhibitors

Aliskiren, the first direct renin inhibitor, prevents renin from converting angiotensinogen to angiotensin I. The drug has a long
duration of action and lowers blood pressure to the same extent as drugs from other antihypertensive classes. Until data become
available on the effect of aliskiren on cardiovascular events the drug should be used only when first-line therapies cannot be used.

Long-acting Calcium Channel Blockers

Long-acting dihydropyridine CCBs can be used as first-line agents but in practice they are generally used in combination therapy.
Short-acting formulations of these agents have caused an increase in cardiovascular events in randomized controlled trials and should
not be used. Elderly patients with isolated systolic hypertension and black patients are particularly responsive to CCBs.

Other Antihypertensive Drugs

In general, other classes of antihypertensive drugs should not be prescribed unless there are specific indications (Table 5),
contraindications or intolerance to first-line therapy, or a requirement for additional blood pressure lowering in combination with
first-line antihypertensive drugs.

Combination Therapy

About 50% of patients will require more than one antihypertensive agent to achieve blood pressure targets. If the goal blood
pressure is not achieved with moderate doses of a suitable first-line drug, add, rather than substitute, a second drug. Combining
drugs has a 5-fold better blood pressure lowering efficacy than a dose increase.8 In high-risk patients (hypertension with diabetes
or known cardiovascular disease) an ACE inhibitor (benazapril) with amlodipine was superior to an ACE inhibitor with a diuretic at
preventing cardiovascular events. The Canadian Hypertension Education Program (CHEP) recommends consideration of the ACE
inhibitor with amlodipine in high-risk patients whose blood pressure requires 2 or more medications for control.9 CHEP recommends
initiating therapy with a combination of 2 first-line agents if a patient's SBP is ≥20 or DBP is ≥10 mm Hg above the recommended
target.10 Use of a diuretic is desirable in combination with all other drug classes. In contrast, any combination of a beta-blocker,
ACE inhibitor and/or an ARB has less than additive antihypertensive effects when combined in a 2-drug regimen. These

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combinations should be avoided unless there is a specific indication, for example, use of an ACE inhibitor and a beta-blocker in
post-myocardial infarction patients or in those with heart failure (Table 5). All possible combinations of first-line agents are
rational choices to lower blood pressure when 3 or 4 drugs are required, with the exception of the simultaneous
prescription of ACE inhibitors and ARBs. A combination of ACE inhibitor plus ARB may further lower blood pressure
but is associated with more adverse effects (e.g., hyperkalemia, renal impairment) and no clear benefit in terms of
cardiovascular events.11 This combination is generally not recommended for the treatment of hypertension, though it
may be appropriate in some medical circumstances such as refractory heart failure. Useful Info?

Adherence

Medication adherence should be assessed at each visit. Poor adherence to therapy is a major cause of poor blood pressure control
and is indicated by:

Admitting poor adherence when questioned in a nonthreatening manner


Failure to keep scheduled appointments
Poor blood pressure control
Lack of secondary physiologic effects, e.g., decreased heart rate on beta-blocker
Failure to renew prescriptions on time
Lack of awareness of usual pill-taking routine and prescriptions
Poor adherence can be prevented. Routine care should include the following:

Ensure patients are well informed about hypertension and its treatment, preferably verbally and with patient information
pamphlets (available at www.hypertension.ca in the General Public section)
Include family or social support in lifestyle modification
Use a simplified regimen of long-acting, once-daily drugs, and use tablets that contain 2 drugs in combination when appropriate
Ensure the patient can afford the prescribed drugs
Advise the patient to establish a daily routine for pill-taking, e.g., putting their pills by their toothbrush and taking them every
morning prior to brushing
Treat poor adherence:

Determine the reason for poor adherence and tailor advice or interventions to the cause
Increase the frequency of office visits
Advise use of adherence-enhancing medication dispensers, e.g., Dosette
Advise self-measurement of blood pressure
Consider assessing adherence with an electronic pill dispenser
Advise home-monitoring of adherence with pill counts and marking on a calendar when the prescription needs renewing
Consider regular telephone contact with the patient if feasible

Resistant Hypertension

Many patients with hypertension require multiple drugs for blood pressure control. In those with resistant hypertension, investigate
for a white coat effect, secondary hypertension, renal dysfunction, poor adherence, and in those with a poor response to an
adequate combination of medications, consider the possibility of an “interfering lifestyle.” Refer (to a hypertension specialist,
nephrologist or internist) those who do not achieve blood pressure targets with medication regimens you feel comfortable
prescribing.

Hypertensive Emergencies

It is uncommon for elevated blood pressure alone, without new or progressive target organ damage, to require emergency therapy.
Refer true hypertensive emergencies to experienced centres with facilities to continuously monitor blood pressure. In stabilizing
patients for transfer, the use of intermediate-acting drugs (e.g., felodipine) with close blood pressure monitoring is generally safer
than using short-acting drugs that can rapidly produce hypotension with complications.

Choices during Pregnancy and Breastfeeding

Inform women with pre-existing hypertension who are of child-bearing potential, particularly those who are considering pregnancy,
that they are at an increased risk for adverse pregnancy outcomes including: intrauterine growth restriction; placental abruption;
preterm delivery and the attendant neonatal risks of prematurity; and particularly a heightened risk of preeclampsia, with a crude
risk of about 10% (varying with the severity and duration of the pre-existing hypertension). Enhanced surveillance is required
during pregnancy to monitor for these complications. Prior to conception, or immediately upon recognition of an unplanned
pregnancy, review the choice of antihypertensive medication for these women.

While there remains a dearth of high quality data on the effects of many common antihypertensive medications on the developing
fetus, international guidelines 12 , 13 , 14 have reached some consensus regarding a list of “preferred” medications for use in
pregnancy, as well as a few “avoid” and “must avoid” drugs. Medications widely considered “first-line” for the management of
hypertension in pregnancy include: methyldopa (250 mg BID to 1000 mg TID), labetalol (100 mg BID to 800 mg TID) and
nifedipine XL (30 mg OD to 60 mg BID). These medications are preferred as they have evidence and/or a strong clinical record of
safe and effective use in pregnancy,15 , 16 as well as an absence of demonstrated adverse effects on subsequent neonatal and
childhood development. Other antihypertensive medications considered appropriate for use in pregnancy include clonidine,
hydralazine and other beta-blockers (oxprenolol, pindolol, propranolol, metoprolol). The data regarding the use of
nondihydropyridine calcium channel blockers 17 , 18 and alpha-blockers in pregnancy is very limited, so these agents are

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typically deferred or exchanged for other preferred agents.

Avoid atenolol, as its use for the treatment of hypertension in pregnancy has been associated with fetal intrauterine growth
restriction (IUGR).19 The other beta-blockers, in contrast, are only weakly associated with IUGR and have been used widely in
pregnancy for various indications. Thiazides and loop diuretics are other classes of medications which most experts caution to
avoid during pregnancy. These medications may prevent the physiologic volume expansion seen in normal pregnancy, and thereby
impair uteroplacental perfusion and fetal growth.18 Available data do not support an adverse effect on perinatal outcome,13
however, and these medications may therefore be considered or continued in women felt to have volume-dependent hypertension
(renal impairment). They should be avoided in settings in which uteroplacental perfusion is already reduced (preeclampsia or IUGR).
Spironolactone should not be used at all in pregnancy, due to its anti-androgenic effects.20

ACE inhibitors have been clearly shown to be fetotoxic when taken during the second and third trimesters,21 leading to
oligohydramnios, IUGR, fetal/neonatal renal failure and other growth effects. First trimester exposure has also been shown to lead
to teratogenic effects, mainly to the fetal cardiovascular and central nervous system.22 Discontinue these drugs prior to conception,
or immediately upon discovery of an unplanned pregnancy. The data regarding the risk of fetal harm from ARBs 23 and direct
renin inhibitors 24 are less robust (mainly animal data), but they appear to have similar harmful effects and should be avoided just
as strictly as ACE inhibitors during pregnancy.

Following the completion of a pregnancy, many women require ongoing antihypertensive therapy. The choice of antihypertensive
agent may be influenced by whether or not the woman is breastfeeding her newborn child, as all oral medications appear in breast
milk to some degree.25 Breastfeeding women may safely continue treatment with any “pregnancy-preferred” drug. Most other
antihypertensive medications may also be safely utilized, but a few choices to avoid in these women include diuretics (which may
suppress lactation), atenolol and other beta-blockers with low serum protein-binding (which concentrate in breast milk), as well as
long-acting ACE inhibitors and those for which there is little or no lactation data (ramipril, lisinopril, cilazapril and perindopril).

Most women with pre-existing hypertension, particularly those with longstanding, difficult-to-control hypertension or end-organ
damage, should be followed throughout pregnancy by a specialist in obstetrics and gynecology. These clinicians are skilled at
ongoing maternal management as well as appropriate monitoring of fetal growth and well being. Women with difficult-to-control
hypertension or other medical issues benefit from assessment and follow-up with a hypertension specialist or obstetric medicine
physician during their pregnancy.

A discussion of general principles on the use of medications in these special populations can be found in Appendix: Drug Use During
Pregnancy and Appendix: Drug Use During Breastfeeding. Other specialized reference sources are also provided in these appendices.

Therapeutic Tips

Prescribe a lower starting dose of antihypertensive drugs in elderly patients.


Recent onset of hypertension or change in blood pressure control suggests an identifiable or secondary cause, such as drugs
known to exacerbate hypertension or new onset of significant renal artery stenosis.
Many drugs ineffective as monotherapy for hypertension are effective components in a rational combination regimen.
Consider concurrent cardiovascular risk factors and disease states when prescribing therapy (Table 5)
Cardiovascular risk can vary 10-fold in persons with the same blood pressure. Assess global cardiovascular risk in all
hypertensive patients using a risk form, chart or computer program (see Cardiovascular Disorders: Dyslipidemias, Figure 2 as
an example).
Blood pressure measurements taken at home correlate better with cardiovascular outcomes than office-based measurements.26 ,
27 Recommend monitors approved by the Canadian Hypertension Society and train patients to use the proper technique. To allay
anxiety, caution patients that some variation throughout the day is normal. Patient instructions for selecting and using home
blood pressure monitors can be found in the General Public section of www.hypertension.ca.
Pharmacists and nurses can play an important role in hypertension screening, medication selection, patient education, follow-up
and adherence monitoring. Dietitians can assist patients in managing their sodium and caloric intake.
A team approach to hypertension management is more effective than usual care. In patients with hypertension and diabetes,
joint care by a family physician, community pharmacist and nurse resulted in an approximate 6 mm Hg greater reduction in SBP
over 6 months, compared with usual physician-based care.28

Table 5: Individualization of Antihypertensive Therapy1

Risk Factor/
Disease Initial Therapy Second-line Therapy Notes/Cautions

Hypertension Without Other Compelling Indications (Target SBP/DBP <140/90 mm Hg)

Diastolic +/- Thiazide diuretic, beta-blocker, Combinations of first-line drugs Beta-blockers are not
systolic ACE inhibitor, ARB or long- recommended as initial therapy in
hypertension acting CCB. patients over 60 years of age.
Consider ASA and statins in Avoid hypokalemia in those who
select patients. are prescribed diuretics as
Consider initiating therapy with monotherapy by using K+-sparing
a combination of first-line agents.
drugs if SBP is ≥20 mm Hg or ACE inhibitors are not
DBP is ≥10 mm Hg above recommended as initial therapy in
target black patients.
ACE inhibitors, ARBs and direct
renin inhibitors are teratogenic.

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Therapeutic Choice

Risk Factor/
Disease Initial Therapy Second-line Therapy Notes/Cautions

Marked caution is required if


prescribing to women of child-
bearing potential.
Combination of an ACE inhibitor
with an ARB is not recommended.

Isolated systolic Thiazide diuretic, ARB or long- Combinations of first-line drugs See diastolic +/- systolic
hypertension acting dihydropyridine CCB. hypertension above.
without other
compelling
indications

Diabetes Mellitus (Target SBP/DBP <130/80 mm Hg)

Diabetes mellitus ACE inhibitor or ARB Add a thiazide diuretic, cardioselective If the SCr is >150 µmol/L, use a
with albuminuria beta-blocker, long-acting CCB loop diuretic rather than a low-
dose thiazide if volume control is
required.

Diabetes mellitus ACE inhibitor, ARB, long-acting Combine first-line drugs Albuminuria is defined as an
without albuminuria dihydropyridine CCB or If first-line agents are not tolerated albumin to creatinine ratio (ACR)
thiazide diuretic add a cardioselective beta-blocker >2 mg/mmol in men and >2.8
and/or a long-acting mg/mmol in women.
nondihydropyridine CCB

Cardiovascular and Cerebrovascular Disease (Target SBP/DBP <140/90 mm Hg)

Coronary Artery ACE inhibitor or ARB (except in Long-acting CCB. When combination Avoid short-acting nifedipine.
Disease low-risk patients); beta- therapy is being used for high-risk Combination of an ACE inhibitor
blocker for patients with stable patients, an ACE with an ARB is specifically not
angina inhibitor/dihydropyridine CCB is recommended.
preferred

Prior myocardial Beta-blocker and ACE inhibitor Long-acting CCB Combination of an ACE inhibitor
infarction (ARB if ACE inhibitor not with an ARB is specifically not
tolerated) recommended.

Heart failure ACE inhibitor (ARB if ACE ARB added to ACE inhibitor or Avoid nondihydropyridine CCB
inhibitor not tolerated) and hydralazine/isosorbide dinitrate (diltiazem, verapamil).
beta-blocker Thiazide or loop diuretic as additive Titrate doses of ACE inhibitors and
Spironolactone in patients with therapy ARBs to those used in clinical
NYHA class III or IV symptoms trials. Monitor serum K+ and SCr
with the combination of ACE
inhibitor and ARB.

Left ventricular Does not affect initial Combination of additional agents Hydralazine and minoxidil can
hypertrophy treatment recommendations increase left ventricular
hypertrophy.

Past stroke or TIA ACE inhibitor/diuretic Combination of additional agents Does not apply to patients with
combination acute stroke.
Blood pressure reduction reduces
recurrent cerebrovascular events in
patients with stable past
cerebrovascular disease.
Combination of an ACE inhibitor
with an ARB is specifically not
recommended.

Nondiabetic Chronic Kidney Disease (Target SBP/DBP <130/80 mm Hg)

Nondiabetic chronic ACE inhibitor (ARB if ACE Combinations of additional agents Avoid ACE inhibitors or ARBs in
kidney disease with inhibitor not tolerated) patients with bilateral renal artery
proteinuria diuretics as additive therapy stenosis or unilateral disease with
a solitary kidney.
Carefully monitor serum K+ and
SCr in patients on an ACE inhibitor
or an ARB.
Combination of an ACE inhibitor
with an ARB is specifically not
recommended in patients with
chronic kidney disease without

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Therapeutic Choice

Risk Factor/
Disease Initial Therapy Second-line Therapy Notes/Cautions

proteinuria.

Renovascular Does not affect initial Combinations of additional agents Avoid ACE inhibitors or ARBs in
disease treatment recommendations patients with bilateral renal artery
stenosis or unilateral disease with
a solitary kidney.

Other Conditions (Target SBP/DBP <140/90 mm Hg)

Peripheral arterial Does not affect initial Combinations of additional agents Avoid beta-blockers in patients
disease treatment recommendations with severe disease.

Dyslipidemia Does not affect initial Combinations of additional agents


treatment recommendations

Overall vascular Statin therapy for patients with


protection hypertension and 3 or more
cardiovascular risk factors or
with atherosclerotic disease

Low-dose ASA in patients over Exercise caution if blood pressure


50 y with controlled blood is not controlled.
pressure

Adapted with permission from Canadian Hypertension Education Program.

Abbreviations: ACE=angiotensin converting enzyme; ARB=angiotensin II receptor blocker; CCB=calcium channel blocker; NYHA =New York
Heart Association; SCr=serum creatinine; TIA=transient ischemic attack

Table 6: Drugs for Hypertension

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

Diuretics hydrochlorothiazide Initial: Hypotension, ↓ Li + excretion Particularly $


12.5 mg/day weakness, (monitor Li + levels, effective in ISH,
Apo-Hydro, other Usual: muscle cramps, adjust dose). the elderly and
generics 25 mg/day impotence. NSAIDs ↓ black patients.
Once daily po Hypokalemia, hypotensive efficacy. Monitor SCr and
hyponatremia, K+.
hyperuricemia, Diuretic-induced
hyperglycemia, hypokalemia ↑ the Consider
hyperlipidemia. alternatives in
risk of digoxin
Rare: azotemia, patients with or
toxicity.
blood predisposed to
dyscrasias, arrhythmias.
↓ efficacy of
allergic
antihyperglycemic
reactions Can exacerbate
agents.
(potential cross gout and diabetes
sensitivity with (biochemical
other abnormalities are
sulfonamide less frequent at
derivatives), 12.5–25 mg/day).
photosensitivity,
fatigue. Ineffective in
patients with ClCr
<30 to 40 mL/min.

Diuretics chlorthalidone Initial: 12.5 Hypotension, ↓ Li + excretion Lowest available $


generics mg/day weakness, (monitor Li + levels, tablet strength is
Usual: 12.5–25 muscle cramps, adjust dose). 50 mg. Tablet (or
mg/day impotence. NSAIDs ↓ “pill”) splitters,
Hypokalemia, hypotensive efficacy. widely available in
Once daily po hyponatremia, pharmacies, can be
hyperuricemia, Diuretic-induced used to derive a
hyperglycemia, hypokalemia ↑ the dose of 12.5 mg
hyperlipidemia. (¼ tablet) with
risk of digoxin
Rare: azotemia, reasonable
toxicity.
blood accuracy.

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

dyscrasias, Particularly
allergic ↓ efficacy of effective in ISH,
reactions antihyperglycemic the elderly and
(potential cross agents. black patients.
sensitivity with Monitor SCr and
other K+.
sulfonamide
derivatives), Consider
photosensitivity, alternatives in
fatigue. patients with or
predisposed to
arrhythmias.

Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).

Ineffective in
patients with ClCr
<30 to 40 mL/min.

Diuretics indapamide Initial: Hypotension, ↓ Li + excretion Particularly $


Lozide, generics 1.25 mg/day weakness, (monitor Li + levels, effective in ISH,
Usual: muscle cramps, adjust dose). the elderly and
2.5 mg/day impotence. NSAIDs ↓ black patients.
Once daily po Hypokalemia, hypotensive efficacy. Monitor SCr and
hyponatremia, K+.
hyperuricemia, Diuretic-induced
hyperglycemia, hypokalemia ↑ the Consider
hyperlipidemia. alternatives in
risk of digoxin
Rare: azotemia, patients with or
toxicity.
blood predisposed to
dyscrasias, arrhythmias.
↓ efficacy of
allergic
antihyperglycemic
reactions Can exacerbate
agents.
(potential cross gout and diabetes
sensitivity with (biochemical
other abnormalities are
sulfonamide less frequent at
derivatives), 12.5–25 mg/day).
photosensitivity,
fatigue. Ineffective in
patients with ClCr
<30 to 40 mL/min.

Diuretics metolazone Initial: Hypotension, ↓ Li + excretion Particularly $


Zaroxolyn 2.5 mg/day weakness, (monitor Li + levels, effective in ISH,
Usual: muscle cramps, adjust dose). the elderly and
5 mg/day impotence. NSAIDs ↓ black patients.
Maximum: Hypokalemia, hypotensive efficacy. Monitor SCr and
10 mg/day hyponatremia, K+.
Once daily po hyperuricemia, Diuretic-induced
hyperglycemia, hypokalemia ↑ the Consider
hyperlipidemia. alternatives in
risk of digoxin
Rare: azotemia, patients with or
toxicity.
blood predisposed to
dyscrasias, arrhythmias.
↓ efficacy of
allergic
antihyperglycemic
reactions Can exacerbate
agents.
(potential cross gout and diabetes
sensitivity with (biochemical
other abnormalities are
sulfonamide less frequent at
derivatives), 12.5–25 mg/day).

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

photosensitivity,
fatigue. Ineffective in
patients with ClCr
<30 to 40 mL/min.

Metolazone is
effective in patients
with moderate to
severe renal
dysfunction.

Diuretic hydrochlorothiazide/ ½ tab/day Hypotension, ↓ Li + excretion Particularly $


Combinations amiloride (50/5) Once daily po weakness, (monitor Li + levels, effective in ISH,
generics muscle cramps, adjust dose). the elderly and
impotence. NSAIDs ↓ black patients.
Hypokalemia, hypotensive efficacy. Monitor SCr and
hyponatremia, K+.
hyperuricemia, Diuretic-induced
hyperglycemia, hypokalemia ↑ the Consider
hyperlipidemia. alternatives in
risk of digoxin
Rare: azotemia, patients with or
toxicity.
blood predisposed to
dyscrasias, arrhythmias.
↓ efficacy of
allergic
antihyperglycemic
reactions Can exacerbate
agents.
(potential cross gout and diabetes
sensitivity with (biochemical
May exacerbate ACE
other abnormalities are
inhibitor-induced
sulfonamide less frequent at
hyperkalemia.
derivatives), 12.5–25 mg/day).
photosensitivity,
fatigue. Ineffective in
patients with ClCr
<30 to 40 mL/min.

Lower incidence of
hypokalemia than
with
hydrochlorothiazide
alone.

Diuretic hydrochlorothiazide/ Initial: Hypotension, ↓ Li + excretion Particularly $


Combinations triamterene ½ tab/day weakness, (monitor Li + levels, effective in ISH,
(25/50) Usual: 1 tab/day muscle cramps, adjust dose). the elderly and
generics Once daily po impotence. NSAIDs ↓ black patients.
Hypokalemia, hypotensive efficacy. Monitor SCr and
hyponatremia, K+.
hyperuricemia, Diuretic-induced
hyperglycemia, hypokalemia ↑ the Consider
hyperlipidemia. alternatives in
risk of digoxin
Rare: azotemia, patients with or
toxicity.
blood predisposed to
dyscrasias, arrhythmias.
↓ efficacy of
allergic
antihyperglycemic
reactions Can exacerbate
agents.
(potential cross gout and diabetes
sensitivity with (biochemical
May exacerbate ACE
other abnormalities are
inhibitor-induced
sulfonamide less frequent at
hyperkalemia.
derivatives), 12.5–25 mg/day).
photosensitivity,
fatigue. Ineffective in
patients with ClCr
<30 to 40 mL/min.

Lower incidence of
hypokalemia than
with

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

hydrochlorothiazide
alone.

Diuretic hydrochlorothiazide/ Initial: ½ Hypotension, ↓ Li + excretion Particularly $


Combinations spironolactone tab/day weakness, (monitor Li + levels, effective in ISH,
(25/25) Usual: 1 tab/day muscle cramps, adjust dose). the elderly and
Aldactazide, Once daily po impotence. NSAIDs ↓ black patients.
generics Hypokalemia, hypotensive efficacy. Monitor SCr and
hyponatremia, K+.
hyperuricemia, Diuretic-induced
hyperglycemia, hypokalemia ↑ the Consider
hyperlipidemia. alternatives in
risk of digoxin
Rare: azotemia, patients with or
toxicity.
blood predisposed to
dyscrasias, arrhythmias.
↓ efficacy of
allergic
antihyperglycemic
reactions Can exacerbate
agents.
(potential cross gout and diabetes
sensitivity with (biochemical
May exacerbate ACE
other abnormalities are
inhibitor-induced
sulfonamide less frequent at
hyperkalemia.
derivatives), 12.5–25 mg/day).
photosensitivity,
fatigue. Ineffective in
patients with ClCr
Gynecomastia in <30 to 40 mL/min.
men and breast
tenderness in Lower incidence of
women. hypokalemia than
with
hydrochlorothiazide
alone.

Beta1-adrenergic nadolol Initial: Fatigue, Bradycardia with Beta-blockers $


Antagonists, generics 20 mg/day bradycardia, digoxin or should not be used
nonselective Usual: decreased nondihydropyridine as initial therapy in
160 mg/day exercise CCBs. patients aged >60
Maximum: capacity, Cardiodepressant y unless
320 mg/day headache, effects with specifically
Once daily po impotence, vivid nondihydropyridine indicated.
dreams. CCBs and Avoid in patients
Less common: amiodarone. with asthma.29
hyperglycemia,
depression, Avoid abrupt
heart failure, withdrawal (may
heart block. precipitate
ischemia). Taper
the dose before
discontinuation.

Avoid in patients
with severe PAD.

Contraindicated in
patients with 2nd or
3rd degree heart
block in the
absence of a
pacemaker.

Beta1-adrenergic propranolol, Initial: Fatigue, Bradycardia with Beta-blockers $$$$


Antagonists, controlled release 80 mg/day bradycardia, digoxin or should not be used
nonselective Usual: decreased nondihydropyridine as initial therapy in
Inderal-LA
320 mg/day exercise CCBs. patients aged >60
Maximum: capacity, Cardiodepressant y unless
480 mg/day headache, effects with specifically

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

SR (once daily impotence, vivid nondihydropyridine indicated.


po) formulation dreams. CCBs and Avoid in patients
recommended Less common: amiodarone. with asthma.29
hyperglycemia,
depression, CYP2D6 inhibitors ↑ Avoid abrupt
heart failure, levels of propranolol withdrawal (may
heart block. and metoprolol. precipitate
ischemia). Taper
Propranolol ↑ serum the dose before
levels of rizatriptan. discontinuation.

Avoid in patients
with severe PAD.

Contraindicated in
patients with 2nd or
3rd degree heart
block in the
absence of a
pacemaker.

Propranolol is more
likely to cause CNS
side effects
(insomnia,
depression, vivid
dreams) than other
agents because of
greater lipid
solubility.

Beta1-adrenergic timolol Initial: Fatigue, Bradycardia with Beta-blockers $$


Antagonists, Apo-Timol, other 5 mg BID bradycardia, digoxin or should not be used
nonselective generics Usual: decreased nondihydropyridine as initial therapy in
20 mg BID exercise CCBs. patients aged >60
Maximum: capacity, Cardiodepressant y unless
30 mg BID po headache, effects with specifically
impotence, vivid nondihydropyridine indicated.
dreams. CCBs and Avoid in patients
Less common: amiodarone. with asthma.29
hyperglycemia,
depression, Avoid abrupt
heart failure, withdrawal (may
heart block. precipitate
ischemia). Taper
the dose before
discontinuation.

Avoid in patients
with severe PAD.

Contraindicated in
patients with 2nd or
3rd degree heart
block in the
absence of a
pacemaker.

Beta1-adrenergic atenolol Initial: Fatigue, Bradycardia with Beta-blockers $


Antagonists, β1- Tenormin, generics 25 mg/day bradycardia, digoxin or should not be used
Usual: decreased nondihydropyridine as initial therapy in
selective
50 mg/day exercise CCBs. patients aged >60
Maximum: capacity, Cardiodepressant y unless
100 mg/day headache, effects with specifically
impotence, vivid nondihydropyridine indicated.
Once daily or dreams. CCBs and Avoid in patients
BID po Less common: amiodarone. with asthma.29
hyperglycemia,

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

depression, Avoid abrupt


heart failure, withdrawal (may
heart block. precipitate
ischemia). Taper
Fewer non- the dose before
cardiac effects discontinuation.
due to
cardioselectivity. Avoid in patients
with severe PAD.

Contraindicated in
patients with 2nd or
3rd degree heart
block in the
absence of a
pacemaker.

Beta1-adrenergic bisoprolol Initial: Fatigue, Bradycardia with Beta-blockers $


Antagonists, β1- generics 5 mg/day bradycardia, digoxin or should not be used
Usual: decreased nondihydropyridine as initial therapy in
selective
10 mg/day exercise CCBs. patients aged >60
Maximum: capacity, Cardiodepressant y unless
20 mg/day headache, effects with specifically
Once daily po impotence, vivid nondihydropyridine indicated.
dreams. CCBs and Avoid in patients
Less common: amiodarone. with asthma.29
hyperglycemia,
depression, Avoid abrupt
heart failure, withdrawal (may
heart block. precipitate
ischemia). Taper
Fewer non- the dose before
cardiac effects discontinuation.
due to
cardioselectivity. Avoid in patients
with severe PAD.

Contraindicated in
patients with 2nd or
3rd degree heart
block in the
absence of a
pacemaker.

Beta1-adrenergic metoprolol Initial: Fatigue, Bradycardia with Beta-blockers $


Antagonists, β1- Betaloc, Lopresor, 50 mg/day bradycardia, digoxin or should not be used
generics Usual: decreased nondihydropyridine as initial therapy in
selective
100–200 mg/day exercise CCBs. patients aged >60
capacity, Cardiodepressant y unless
Maximum: headache, effects with specifically
400 mg/day impotence, vivid nondihydropyridine indicated.
Give regular dreams. CCBs and Avoid in patients
formulations BID Less common: amiodarone. with asthma.29
po; SR hyperglycemia,
formulations depression, CYP2D6 inhibitors ↑ Avoid abrupt
once daily po heart failure, levels of propranolol withdrawal (may
heart block. and metoprolol. precipitate
ischemia). Taper
Fewer non- the dose before
cardiac effects discontinuation.
due to
cardioselectivity. Avoid in patients
with severe PAD.

Contraindicated in
patients with 2nd or
3rd degree heart

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

block in the
absence of a
pacemaker.

Beta1-adrenergic pindolol Initial: Fatigue, Bradycardia with Beta-blockers $$


Antagonists, Visken, generics 5 mg BID po bradycardia, digoxin or should not be used
nonselective with Usual: decreased nondihydropyridine as initial therapy in
intrinsic 15 mg BID po exercise CCBs. patients aged >60
sympathomimetic Maximum: capacity, Cardiodepressant y unless
activity (ISA) 60 mg/day headache, effects with specifically
impotence, vivid nondihydropyridine indicated.
dreams. CCBs and Avoid in patients
Less common: amiodarone. with asthma.29
hyperglycemia,
depression, Avoid abrupt
heart failure, withdrawal (may
heart block. precipitate
ischemia). Taper
the dose before
discontinuation.

Avoid in patients
with severe PAD.

Contraindicated in
patients with 2nd or
3rd degree heart
block in the
absence of a
pacemaker.

Agents with ISA


have less effect on
resting heart rate
than those without
ISA.

Beta1-adrenergic acebutolol Initial: Fatigue, Bradycardia with Beta-blockers $


Antagonists, β1- Apo-Acebutolol, 100 mg/day bradycardia, digoxin or should not be used
Rhotral, Sectral, Usual: decreased nondihydropyridine as initial therapy in
selective with ISA
other generics 400 mg/day exercise CCBs. patients aged >60
Maximum: capacity, Cardiodepressant y unless
800 mg/day headache, effects with specifically
Once daily or impotence, vivid nondihydropyridine indicated.
BID po dreams. CCBs and Avoid in patients
Less common: amiodarone. with asthma.29
hyperglycemia,
depression, Avoid abrupt
heart failure, withdrawal (may
heart block. precipitate
ischemia). Taper
Fewer non- the dose before
cardiac effects discontinuation.
due to
cardioselectivity. Avoid in patients
with severe PAD.

Contraindicated in
patients with 2nd or
3rd degree heart
block in the
absence of a
pacemaker.

Agents with ISA


have less effect on
resting heart rate
than those without
ISA.

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

Beta1-adrenergic labetalol Initial: Fatigue, Bradycardia with Beta-blockers $$


Antagonists with Trandate, generics 50 mg BID po bradycardia, digoxin or should not be used
alpha1-blocking Usual: decreased nondihydropyridine as initial therapy in
200 mg BID po exercise CCBs. patients aged >60
activity
Maximum: capacity, Cardiodepressant y unless
1200 mg/day headache, effects with specifically
impotence, vivid nondihydropyridine indicated.
dreams. CCBs and Avoid in patients
Less common: amiodarone. with asthma.29
hyperglycemia,
depression, Avoid abrupt
heart failure, withdrawal (may
heart block. precipitate
ischemia). Taper
Edema, the dose before
dizziness and discontinuation.
nasal congestion
and postural Avoid in patients
hypotension due with severe PAD.
to alpha1
antagonism. Contraindicated in
patients with 2nd or
3rd degree heart
block in the
absence of a
pacemaker.

ACE Inhibitors benazepril Initial: Dry cough, Marked ↑ in serum Contraindicated $$


Lotensin, generics 10 mg/day hyperkalemia. K+ in patients in pregnancy—
Usual: Unusual: receiving K+ caution when
20 mg/day angioedema. supplements and/or prescribing to
Maximum: Can precipitate women of child-
K+-sparing diuretics.
40 mg/day renal failure in bearing
↓ hypotensive effect
Once daily or renovascular
with NSAIDs and ↑ potential. 5 , 6
BID po disease, volume Use lower (50%)
risk of renal
depletion or initial doses if on
those receiving dysfunction.
diuretics (↑ risk of
NSAIDs. hypotension with
Elevated Li + levels
hypovolemia).
(potential toxicity).
Hyperkalemia
usually occurs only
in those on K+
supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.

ACE Inhibitors captopril Initial: Dry cough, Marked ↑ in serum Contraindicated $$


Capoten, generics 25 mg/day hyperkalemia. K+ in patients in pregnancy—
Usual: Unusual: receiving K+ caution when
75 mg/day angioedema. supplements and/or prescribing to
Maximum: Can precipitate women of child-
K+-sparing diuretics.
150 mg/day renal failure in bearing
↓ hypotensive effect
Divide BID or renovascular
with NSAIDs and ↑ potential. 5 , 6
TID po disease, volume Use lower (50%)
depletion or risk of renal
initial doses if on
dysfunction.
those receiving diuretics (↑ risk of
NSAIDs. hypotension with
Elevated Li + levels
hypovolemia).
(potential toxicity).
Hyperkalemia

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

usually occurs only


in those on K+
supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.

ACE Inhibitors cilazapril Initial: Dry cough, Marked ↑ in serum Contraindicated $$


Inhibace, generics 2.5 mg/day hyperkalemia. K+ in patients in pregnancy—
Usual: Unusual: receiving K+ caution when
2.5–5 mg/day angioedema. supplements and/or prescribing to
Maximum: Can precipitate women of child-
K+-sparing diuretics.
10 mg/day renal failure in bearing
↓ hypotensive effect
Once daily or renovascular
with NSAIDs and ↑ potential. 5 , 6
BID po disease, volume Use lower (50%)
risk of renal
depletion or initial doses if on
those receiving dysfunction.
diuretics (↑ risk of
NSAIDs. hypotension with
Elevated Li + levels
hypovolemia).
(potential toxicity).
Hyperkalemia
usually occurs only
in those on K+
supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.

ACE Inhibitors enalapril Initial: Dry cough, Marked ↑ in serum Contraindicated $$-
Vasotec, generics 5 mg/day hyperkalemia. K+ in patients in pregnancy— $$$
Usual: Unusual: receiving K+ caution when
10–40 mg/day angioedema. supplements and/or prescribing to
Maximum: Can precipitate women of child-
K+-sparing diuretics.
40 mg/day renal failure in bearing
↓ hypotensive effect
Once daily or renovascular
with NSAIDs and ↑ potential. 5 , 6
BID po disease, volume Use lower (50%)
depletion or risk of renal
initial doses if on
dysfunction.
those receiving diuretics (↑ risk of
NSAIDs. hypotension with
Elevated Li + levels
hypovolemia).
(potential toxicity).
Hyperkalemia
usually occurs only
in those on K+
supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

ACE Inhibitors fosinopril Initial: Dry cough, Marked ↑ in serum Contraindicated $


Monopril, generics 10 mg/day hyperkalemia. K+ in patients in pregnancy—
Usual: Unusual: receiving K+ caution when
20 mg/day angioedema. supplements and/or prescribing to
Maximum: Can precipitate women of child-
K+-sparing diuretics.
40 mg/day Once renal failure in bearing
↓ hypotensive effect
daily or BID po renovascular
with NSAIDs and ↑ potential. 5 , 6
disease, volume Use lower (50%)
depletion or risk of renal
initial doses if on
those receiving dysfunction.
diuretics (↑ risk of
NSAIDs. hypotension with
Elevated Li + levels
hypovolemia).
(potential toxicity).
Hyperkalemia
usually occurs only
in those on K+
supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.

ACE Inhibitors lisinopril Initial: Dry cough, Marked ↑ in serum Contraindicated $


Prinivil, Zestril, 10 mg/day hyperkalemia. K+ in patients in pregnancy—
generics Usual: Unusual: receiving K+ caution when
20 mg/day angioedema. supplements and/or prescribing to
Maximum: Can precipitate women of child-
K+-sparing diuretics.
40 mg/day renal failure in bearing
↓ hypotensive effect
Once daily po renovascular
with NSAIDs and ↑ potential. 5 , 6
disease, volume Use lower (50%)
depletion or risk of renal
initial doses if on
those receiving dysfunction.
diuretics (↑ risk of
NSAIDs. hypotension with
Elevated Li + levels
hypovolemia).
(potential toxicity).
Hyperkalemia
usually occurs only
in those on K+
supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.

ACE Inhibitors perindopril Initial: Dry cough, Marked ↑ in serum Contraindicated $$-
Coversyl, generics 4 mg/day hyperkalemia. K+ in patients in pregnancy— $$$
Maximum: Unusual: receiving K+ caution when
8 mg/day angioedema. supplements and/or prescribing to
Once daily or Can precipitate women of child-
K+-sparing diuretics.
BID po renal failure in bearing
↓ hypotensive effect
renovascular
with NSAIDs and ↑ potential. 5 , 6
disease, volume Use lower (50%)
depletion or risk of renal
initial doses if on
dysfunction.
those receiving diuretics (↑ risk of
NSAIDs. hypotension with
Elevated Li + levels
hypovolemia).
(potential toxicity).
Hyperkalemia
usually occurs only
in those on K+

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.

ACE Inhibitors quinapril Initial: Dry cough, Marked ↑ in serum Contraindicated $$


Accupril 10 mg/day hyperkalemia. K+ in patients in pregnancy—
Maximum: Unusual: receiving K+ caution when
40 mg/day angioedema. supplements and/or prescribing to
Once daily or Can precipitate women of child-
K+-sparing diuretics.
BID po renal failure in bearing
↓ hypotensive effect
renovascular
with NSAIDs and ↑ potential. 5 , 6
disease, volume Use lower (50%)
risk of renal
depletion or initial doses if on
those receiving dysfunction.
diuretics (↑ risk of
NSAIDs. hypotension with
Elevated Li + levels
hypovolemia).
(potential toxicity).
Hyperkalemia
usually occurs only
in those on K+
supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.

ACE Inhibitors ramipril Initial: Dry cough, Marked ↑ in serum Contraindicated $


Altace, generics 2.5 mg/day hyperkalemia. K+ in patients in pregnancy—
Usual: Unusual: receiving K+ caution when
10 mg/day angioedema. supplements and/or prescribing to
Maximum: Can precipitate women of child-
K+-sparing diuretics.
20 mg/day renal failure in bearing
↓ hypotensive effect
Once daily or renovascular
with NSAIDs and ↑ potential. 5 , 6
BID po disease, volume Use lower (50%)
depletion or risk of renal
initial doses if on
dysfunction.
those receiving diuretics (↑ risk of
NSAIDs. hypotension with
Elevated Li + levels
hypovolemia).
(potential toxicity).
Hyperkalemia
usually occurs only
in those on K+
supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.

ACE Inhibitors trandolapril Initial: Dry cough, Marked ↑ in serum Contraindicated $$


Mavik 1 mg/day hyperkalemia. K+ in patients in pregnancy—

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

Maximum: Unusual: receiving K+ caution when


4 mg/day angioedema. supplements and/or prescribing to
Once daily po Can precipitate K+-sparing diuretics. women of child-
renal failure in ↓ hypotensive effect bearing
renovascular with NSAIDs and ↑ potential. 5 , 6
disease, volume risk of renal Use lower (50%)
depletion or dysfunction. initial doses if on
those receiving diuretics (↑ risk of
NSAIDs. hypotension with
Elevated Li + levels
(potential toxicity). hypovolemia).
Hyperkalemia
usually occurs only
in those on K+
supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.

Angiotensin candesartan Initial: Hyperkalemia. Marked ↑ in serum Contraindicated $$


Receptor Blockers Atacand 8 mg/day Can precipitate K+ in patients in pregnancy—
(ARB) Usual: renal failure in receiving K+ caution when
8–16 mg/day susceptible supplements and/or prescribing to
Once daily po patients women of child-
K+-sparing diuretics.
(bilateral bearing
May elevate Li +
renovascular potential. 7
disease, those levels (monitor Li + Use lower initial
with volume levels, adjust dose). doses in patients
depletion or who are volume
with concurrent depleted or on
NSAID use). diuretics (↑ risk of
hypotension in
Angioedema has hypovolemia).
been reported,
but a causal Hyperkalemia
association has usually occurs only
not been in those on K+
established. supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.

Angiotensin eprosartan Initial: Hyperkalemia. Marked ↑ in serum Contraindicated $$


Receptor Blockers Teveten 600 mg/day Can precipitate K+ in patients in pregnancy—
(ARB) Maximum: renal failure in receiving K+ caution when
800 mg/day susceptible supplements and/or prescribing to
Once daily or patients women of child-
K+-sparing diuretics.
BID po (bilateral bearing
May elevate Li +
renovascular potential. 7
disease, those levels (monitor Li + Use lower initial
with volume levels, adjust dose). doses in patients
depletion or who are volume
with concurrent depleted or on
NSAID use). diuretics (↑ risk of
hypotension in
Angioedema has hypovolemia).

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

been reported,
but a causal Hyperkalemia
association has usually occurs only
not been in those on K+
established. supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.

Angiotensin irbesartan Initial: Hyperkalemia. Marked ↑ in serum Contraindicated $$


Receptor Blockers Avapro 150 mg/day Can precipitate K+ in patients in pregnancy—
(ARB) Usual: renal failure in receiving K+ caution when
150–300 mg/day susceptible supplements and/or prescribing to
Once daily po patients women of child-
K+-sparing diuretics.
(bilateral bearing
May elevate Li +
renovascular potential. 7
disease, those levels (monitor Li + Use lower initial
with volume levels, adjust dose). doses in patients
depletion or who are volume
with concurrent depleted or on
NSAID use). diuretics (↑ risk of
hypotension in
Angioedema has hypovolemia).
been reported,
but a causal Hyperkalemia
association has usually occurs only
not been in those on K+
established. supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.

Angiotensin losartan Initial: Hyperkalemia. Marked ↑ in serum Contraindicated $$


Receptor Blockers Cozaar 50 mg/day Can precipitate K+ in patients in pregnancy—
(ARB) Usual: renal failure in receiving K+ caution when
25–100 mg/day susceptible supplements and/or prescribing to
Maximum: patients women of child-
K+-sparing diuretics.
100 mg/day (bilateral bearing
May elevate Li +
Once daily or renovascular potential. 7
BID po disease, those levels (monitor Li + Use lower initial
with volume levels, adjust dose). doses in patients
depletion or who are volume
with concurrent depleted or on
NSAID use). diuretics (↑ risk of
hypotension in
Angioedema has hypovolemia).
been reported,
but a causal Hyperkalemia
association has usually occurs only
not been in those on K+
established. supplements or
drugs that cause
K+ retention, those
with renal
impairment or

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

diabetics with high


serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.

Angiotensin olmesartan Initial: Hyperkalemia. Marked ↑ in serum Contraindicated $$


Receptor Blockers Olmetec 20 mg/day Can precipitate K+ in patients in pregnancy—
(ARB) Maximum: renal failure in receiving K+ caution when
40 mg/day susceptible supplements and/or prescribing to
Once daily po patients women of child-
K+-sparing diuretics.
(bilateral bearing
May elevate Li +
renovascular potential. 7
disease, those levels (monitor Li + Use lower initial
with volume levels, adjust dose). doses in patients
depletion or who are volume
with concurrent depleted or on
NSAID use). diuretics (↑ risk of
hypotension in
Angioedema has hypovolemia).
been reported,
but a causal Hyperkalemia
association has usually occurs only
not been in those on K+
established. supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.

Angiotensin telmisartan Initial: Hyperkalemia. Marked ↑ in serum Contraindicated $$


Receptor Blockers Micardis 80 mg/day Can precipitate K+ in patients in pregnancy—
(ARB) Usual: renal failure in receiving K+ caution when
80 mg/day susceptible supplements and/or prescribing to
Once daily po patients women of child-
K+-sparing diuretics.
(bilateral bearing
May elevate Li +
renovascular potential. 7
disease, those levels (monitor Li + Use lower initial
with volume levels, adjust dose). doses in patients
depletion or who are volume
with concurrent depleted or on
NSAID use). diuretics (↑ risk of
hypotension in
Angioedema has hypovolemia).
been reported,
but a causal Hyperkalemia
association has usually occurs only
not been in those on K+
established. supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.

Angiotensin valsartan Initial: Hyperkalemia. Marked ↑ in serum Contraindicated $$

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

Receptor Blockers Diovan 80 mg/day Can precipitate K+ in patients in pregnancy—


(ARB) Usual: renal failure in receiving K+ caution when
80–320 mg/day susceptible supplements and/or prescribing to
Once daily po patients women of child-
K+-sparing diuretics.
(bilateral bearing
May elevate Li +
renovascular potential. 7
disease, those levels (monitor Li + Use lower initial
with volume levels, adjust dose). doses in patients
depletion or who are volume
with concurrent depleted or on
NSAID use). diuretics (↑ risk of
hypotension in
Angioedema has hypovolemia).
been reported,
but a causal Hyperkalemia
association has usually occurs only
not been in those on K+
established. supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.

Direct Renin aliskiren Initial: Diarrhea. The Low potential for May take 4 wk to $$
Inhibitors Rasilez 150 mg/day incidence of dry drug interactions. realize maximum
Maximum: cough and antihypertensive
300 mg/day hyperkalemia is effect.
Once daily po low compared Effect on
with ACE cardiovascular
inhibitors. outcomes not yet
established.

Limited data in
patients with
greater than
moderate renal
dysfunction.

Avoid use in
pregnancy.

Calcium Channel amlodipine Initial: Ankle edema, CYP3A4 substrate $$


Blockers, Norvasc, generics 2.5 mg/day flushing, (many potential
dihydropyridine Maximum: headache and interactions).
10 mg/day palpitations. Strong inhibitors
Once daily po include azole
antifungals, protease
inhibitors,
macrolides and
quinidine.

Grapefruit juice may


↑ serum
concentrations.

Calcium Channel felodipine Initial: Ankle edema, CYP3A4 substrate Grapefruit juice $$
Blockers, Plendil, Renedil, 2.5 mg/day flushing, (many potential causes marked
dihydropyridine generics Usual: headache and interactions). elevations in
10 mg/day palpitations. Strong inhibitors felodipine serum
Maximum: include azole levels and adverse
20 mg/day antifungals, protease events.

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

Once daily po inhibitors,


macrolides and
quinidine.

Grapefruit juice may


↑ serum
concentrations.

Calcium Channel nifedipine XL Initial: Ankle edema, CYP3A4 substrate Do not use short- $$
Blockers, Adalat XL, generics 30 mg/day flushing, (many potential acting nifedipine
dihydropyridine Usual: headache and interactions). formulations for
60 mg/day palpitations. Strong inhibitors treatment of
Maximum: include azole essential
120 mg/day antifungals, protease hypertension.
Once daily po inhibitors,
macrolides and
quinidine.

Grapefruit juice may


↑ serum
concentrations.

Calcium Channel diltiazem Initial: Headache, CYP3A4 substrate Caution in patients $$


Blockers, Cardizem CD, Tiazac, 120 mg/day dizziness, (many potential with heart failure,
nondihydropyridine
Tiazac XC, generics
Usual: bradycardia, interactions). or 2nd or 3rd
240–360 mg/day heart block, new Strong inhibitors degree heart block
onset or include azole without a
Maximum: worsening of antifungals, protease functioning
360 mg/day heart failure. inhibitors, pacemaker.
Give CD or XC macrolides and
formulation once quinidine.
daily po, SR
formulation BID Grapefruit juice may
po ↑ serum
concentrations.

Nondihydropyridines
inhibit the
metabolism of
carbamazepine,
cyclosporine,
lovastatin,
simvastatin.
Rifampin induces
metabolism of
nondihydropyridines.
Additive negative
inotropic effects with
amiodarone, beta-
blockers and
digoxin.

Calcium Channel verapamil Initial: Headache, CYP3A4 substrate Caution in patients $$-
Blockers, Isoptin SR, generics 80 mg TID po dizziness, (many potential with heart failure, $$$
nondihydropyridine Maximum: bradycardia, interactions). or 2nd or 3rd
160 mg TID po heart block, new Strong inhibitors degree heart block
onset or include azole without a
worsening of antifungals, protease functioning
SR (once daily heart failure. inhibitors, pacemaker.
or BID po): Constipation. macrolides and
Initial: 180 quinidine.
mg/day; Usual:
180–480 Grapefruit juice may
mg/day; ↑ serum
Maximum: 480 concentrations.
mg/day

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

Nondihydropyridines
inhibit the
metabolism of
carbamazepine,
cyclosporine,
lovastatin,
simvastatin.
Rifampin induces
metabolism of
nondihydropyridines.
Additive negative
inotropic effects with
amiodarone, beta-
blockers and
digoxin.

Verapamil ↑ digoxin
levels by 50–75%
within 1 wk (monitor
levels).

Centrally Acting methyldopa Initial: Drowsiness, dry Iron salts ↓ Positive Coombs’ $$
Antihypertensive generics 500 mg/day mouth, nasal absorption (separate test is common,
Agents Usual: congestion, administration). but usually
2000 mg/day depression, Additive hypotension unimportant;
Maximum: orthostatic with levodopa. hemolytic anemia
3000 mg/day hypotension, is rare.
Divide BID or palpitations, May exacerbate Li + Drug fever with or
TID po sexual adverse events without an
dysfunction, without increasing influenza-like
sodium and Li + levels. illness; hepatic
water retention. disorders have
occurred.

Alpha1-adrenergic doxazosin Initial: Orthostatic Caution when adding Not for initial $
Antagonists Cardura, generics 1 mg/day hypotension, other hypotensive therapy.
Usual: headache, drugs, may cause
1–8 mg/day drowsiness, syncope.
Maximum: palpitations,
16 mg/day nasal
Once daily po congestion.
Syncope usually
occurs at the
start of therapy,
with rapid dose
titration or on
addition of other
agents. Titrate
slowly. If
interrupted for
several days
restart at initial
dose.

Alpha1-adrenergic prazosin Initial: Orthostatic Caution when adding Not for initial $-$$
Antagonists Apo-Prazo, other 0.5 mg with hypotension, other hypotensive therapy.
generics p.m. meal headache, drugs, may cause
(day 1), then drowsiness, syncope.
0.5 mg BID-TID palpitations,
po × 3 days nasal
Maximum: congestion.
20 mg/day Syncope usually
occurs at the
start of therapy,
with rapid dose
titration or on
addition of other
agents. Titrate

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

slowly. If
interrupted for
several days
restart at initial
dose.

Alpha1-adrenergic terazosin Initial: Orthostatic Caution when adding Not for initial $
Antagonists Hytrin, generics 1 mg QHS po hypotension, other hypotensive therapy.
Usual: headache, drugs, may cause
1–5 mg/day drowsiness, syncope.
Maximum: palpitations, Verapamil ↑ serum
20 mg/day nasal concentrations of
Once daily or congestion. terazosin.
BID po Syncope usually
occurs at the
start of therapy,
with rapid dose
titration or on
addition of other
agents. Titrate
slowly. If
interrupted for
several days
restart at initial
dose.

Beta1-adrenergic atenolol/ 50/25 mg, or Fatigue, Bradycardia with Beta-blockers $


Antagonist/ chlorthalidone 100/25 mg once bradycardia, digoxin or should not be used
Diuretic Tenoretic, generics daily pob decreased nondihydropyridine as initial therapy in
Combinations exercise CCBs. patients aged >60
capacity, Cardiodepressant y unless
headache, effects with specifically
impotence, vivid nondihydropyridine indicated.
dreams. CCBs and Avoid in patients
Less common: amiodarone. with asthma.29
hyperglycemia,
depression, ↓ Li + excretion Avoid abrupt
heart failure, (monitor Li + levels, withdrawal (may
heart block. adjust dose). precipitate
NSAIDs ↓ ischemia). Taper
Hypotension, hypotensive efficacy. the dose before
weakness, discontinuation.
muscle cramps, Diuretic-induced
impotence. hypokalemia ↑ the Avoid in patients
Hypokalemia, risk of digoxin with severe PAD.
hyponatremia, toxicity.
hyperuricemia, Contraindicated in
hyperglycemia, ↓ efficacy of patients with 2nd or
hyperlipidemia.
antihyperglycemic 3rd degree heart
Rare: azotemia,
agents. block in the
blood
absence of a
dyscrasias,
pacemaker.
allergic
reactions
Particularly
(potential cross
effective in ISH,
sensitivity with
the elderly and
other
black patients.
sulfonamide
Monitor SCr and
derivatives),
photosensitivity, K+.
fatigue.
Consider
alternatives in
patients with or
predisposed to
arrhythmias.

Can exacerbate
gout and diabetes

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).

Ineffective in
patients with ClCr
<30 to 40 mL/min.

The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
agents if a patient's
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.

Beta1-adrenergic pindolol/ 10/25 mg or Fatigue, Bradycardia with Beta-blockers $$


Antagonist/ hydrochlorothiazide 10/50 mg once bradycardia, digoxin or should not be used
Diuretic daily pob decreased nondihydropyridine as initial therapy in
Combinations Viskazide exercise CCBs. patients aged >60
capacity, Cardiodepressant y unless
headache, effects with specifically
impotence, vivid nondihydropyridine indicated.
dreams. CCBs and Avoid in patients
Less common: amiodarone. with asthma.29
hyperglycemia,
depression, ↓ Li + excretion Avoid abrupt
heart failure, (monitor Li + levels, withdrawal (may
heart block. adjust dose). precipitate
NSAIDs ↓ ischemia). Taper
Hypotension, hypotensive efficacy. the dose before
weakness, discontinuation.
muscle cramps, Diuretic-induced
impotence. hypokalemia ↑ the Avoid in patients
Hypokalemia, risk of digoxin with severe PAD.
hyponatremia, toxicity.
hyperuricemia, Contraindicated in
hyperglycemia, ↓ efficacy of patients with 2nd or
hyperlipidemia.
antihyperglycemic 3rd degree heart
Rare: azotemia,
agents. block in the
blood
absence of a
dyscrasias,
pacemaker.
allergic
reactions
Particularly
(potential cross
effective in ISH,
sensitivity with
the elderly and
other
black patients.
sulfonamide
Monitor SCr and
derivatives),
photosensitivity, K+.
fatigue.
Consider
alternatives in
patients with or
predisposed to
arrhythmias.

Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).

Ineffective in

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

patients with ClCr


<30 to 40 mL/min.

The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
agents if a patient's
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.

ACE Inhibitor/ trandolapril/ Trandolapril 1–4 Dry cough, Marked ↑ in serum Contraindicated $$$
Calcium Channel verapamil mg/day plus hyperkalemia. K+ in patients in pregnancy—
Blocker Tarka verapamil 180– Unusual: receiving K+ caution when
Combinations 480 mg/day. angioedema. supplements and/or prescribing to
Once daily or Can precipitate women of child-
K+-sparing diuretics.
BID po b renal failure in
↓ hypotensive effect
bearing
renovascular
with NSAIDs and ↑ potential. 5 , 6
disease, volume Use lower (50%)
risk of renal
depletion or initial doses if on
those receiving dysfunction.
diuretics (↑ risk of
NSAIDs. hypotension with
Elevated Li + levels
hypovolemia).
Headache, (potential toxicity).
Hyperkalemia
dizziness, usually occurs only
bradycardia, CYP3A4 substrate
(many potential in those on K+
heart block, new supplements or
onset or interactions).
Strong inhibitors drugs that cause
worsening of
include azole K+ retention, those
heart failure.
antifungals, protease with renal
inhibitors, impairment or
Constipation.
macrolides and diabetics with high
quinidine. serum K+ levels.
Assess SCr and K+
Grapefruit juice may after a few days,
↑ serum then regularly.
concentrations.
Caution in patients
with heart failure,
Inhibits metabolism or 2nd or 3rd
of carbamazepine, degree heart block
cyclosporine, without a
lovastatin, functioning
simvastatin. pacemaker.

Rifampin ↑ The Canadian


metabolism of Hypertension
verapamil. Education Program
recommends
Additive inotropic initiating therapy
effects with with a combination
amiodarone, beta- of two first-line
blockers, digoxin. agents if a patient's
SBP is ≥20 or DBP
Verapamil ↑ digoxin is ≥10 mm Hg
levels by 50–75% above the
within 1 wk (monitor recommended
levels). target.

ACE Inhibitor/ cilazapril/ 5/12.5 mg once Dry cough, Marked ↑ in serum Contraindicated $$
Diuretic hydrochlorothiazide daily pob hyperkalemia. K+ in patients in pregnancy—

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

Combinations Unusual: receiving K+ caution when


Inhibace Plus, angioedema. supplements and/or prescribing to
generics Can precipitate K+-sparing diuretics. women of child-
renal failure in ↓ hypotensive effect bearing
renovascular with NSAIDs and ↑ potential. 5 , 6
disease, volume risk of renal Use lower (50%)
depletion or dysfunction. initial doses if on
those receiving diuretics (↑ risk of
NSAIDs. + hypotension with
Elevated Li levels
(potential toxicity). hypovolemia).
Hypotension, Hyperkalemia
weakness, + usually occurs only
muscle cramps, ↓ Li excretion
+ in those on K+
impotence. (monitor Li levels,
supplements or
Hypokalemia, adjust dose).
drugs that cause
hyponatremia, NSAIDs ↓ +
hyperuricemia, hypotensive efficacy. K retention, those
with renal
hyperglycemia,
Diuretic-induced impairment or
hyperlipidemia.
hypokalemia ↑ the diabetics with high
Rare: azotemia,
blood risk of digoxin serum K+ levels.
dyscrasias, toxicity. Assess SCr and K+
allergic after a few days,
reactions ↓ efficacy of then regularly.
(potential cross antihyperglycemic
sensitivity with agents. Particularly
other effective in ISH,
sulfonamide the elderly and
derivatives), black patients.
photosensitivity, Monitor SCr and
fatigue. K+.

Consider
alternatives in
patients with or
predisposed to
arrhythmias.

Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).

Ineffective in
patients with ClCr
<30 to 40 mL/min.

The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
agents if a patient's
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.

ACE Inhibitor/ enalapril/ 5/12.5 mg or Dry cough, Marked ↑ in serum Contraindicated $$


Diuretic hydrochlorothiazide 10/25 mg once hyperkalemia. K+ in patients in pregnancy—
Combinations daily pob Unusual: receiving K+ caution when
Vaseretic angioedema. supplements and/or prescribing to
Can precipitate women of child-
K+-sparing diuretics.
renal failure in bearing
↓ hypotensive effect

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

renovascular with NSAIDs and ↑ potential. 5 , 6


disease, volume risk of renal Use lower (50%)
depletion or dysfunction. initial doses if on
those receiving diuretics (↑ risk of
NSAIDs. Elevated Li + levels hypotension with
(potential toxicity). hypovolemia).
Hypotension, Hyperkalemia
weakness, ↓ Li + excretion usually occurs only
muscle cramps, in those on K+
(monitor Li + levels,
impotence. supplements or
adjust dose).
Hypokalemia, drugs that cause
NSAIDs ↓
hyponatremia,
hypotensive efficacy. K+ retention, those
hyperuricemia,
with renal
hyperglycemia,
Diuretic-induced impairment or
hyperlipidemia.
hypokalemia ↑ the diabetics with high
Rare: azotemia,
blood risk of digoxin serum K+ levels.
dyscrasias, toxicity. Assess SCr and K+
allergic after a few days,
reactions ↓ efficacy of then regularly.
(potential cross antihyperglycemic
sensitivity with agents. Particularly
other effective in ISH,
sulfonamide the elderly and
derivatives), black patients.
photosensitivity, Monitor SCr and
fatigue. K+.

Consider
alternatives in
patients with or
predisposed to
arrhythmias.

Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).

Ineffective in
patients with ClCr
<30 to 40 mL/min.

The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
agents if a patient's
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.

ACE Inhibitor/ lisinopril/ 10/12.5 mg, Dry cough, Marked ↑ in serum Contraindicated $-$$
Diuretic hydrochlorothiazide 20/12.5 mg or hyperkalemia. K+ in patients in pregnancy—
Combinations 20/25 once daily Unusual: receiving K+ caution when
Prinzide, Zestoretic, po b angioedema. supplements and/or prescribing to
Can precipitate women of child-
generics K+-sparing diuretics.
renal failure in bearing
↓ hypotensive effect
renovascular
with NSAIDs and ↑ potential. 5 , 6
disease, volume Use lower (50%)
depletion or risk of renal
initial doses if on
dysfunction.
those receiving diuretics (↑ risk of

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

NSAIDs. Elevated Li + levels hypotension with


(potential toxicity). hypovolemia).
Hypotension, Hyperkalemia
weakness, ↓ Li + excretion usually occurs only
muscle cramps,
(monitor Li + levels, in those on K+
impotence. supplements or
adjust dose).
Hypokalemia, drugs that cause
NSAIDs ↓
hyponatremia, +
hypotensive efficacy. K retention, those
hyperuricemia, with renal
hyperglycemia, impairment or
Diuretic-induced
hyperlipidemia. diabetics with high
hypokalemia ↑ the
Rare: azotemia,
risk of digoxin serum K+ levels.
blood
dyscrasias,
toxicity. Assess SCr and K+
allergic after a few days,
↓ efficacy of then regularly.
reactions
(potential cross antihyperglycemic
sensitivity with agents. Particularly
other effective in ISH,
sulfonamide the elderly and
derivatives), black patients.
photosensitivity, Monitor SCr and
fatigue. K+.

Consider
alternatives in
patients with or
predisposed to
arrhythmias.

Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).

Ineffective in
patients with ClCr
<30 to 40 mL/min.

The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
agents if a patient's
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.

ACE Inhibitor/ perindopril/ 4/1.25 mg once Dry cough, Marked ↑ in serum Contraindicated $$
Diuretic indapamide daily pob hyperkalemia. K+ in patients in pregnancy—
Combinations Coversyl Plus, Unusual: receiving K+ caution when
Coversyl Plus LD angioedema. supplements and/or prescribing to
Can precipitate women of child-
K+-sparing diuretics.
renal failure in bearing
↓ hypotensive effect
renovascular
with NSAIDs and ↑ potential. 5 , 6
disease, volume Use lower (50%)
depletion or risk of renal
initial doses if on
dysfunction.
those receiving diuretics (↑ risk of
NSAIDs. hypotension with
Elevated Li + levels
hypovolemia).
Hypotension, (potential toxicity).
Hyperkalemia
weakness, usually occurs only
muscle cramps, ↓ Li + excretion

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

impotence. (monitor Li + levels, in those on K+


Hypokalemia, adjust dose). supplements or
hyponatremia, NSAIDs ↓ drugs that cause
hyperuricemia, hypotensive efficacy. K+ retention, those
hyperglycemia, with renal
hyperlipidemia. Diuretic-induced impairment or
Rare: azotemia, hypokalemia ↑ the diabetics with high
blood risk of digoxin serum K+ levels.
dyscrasias, toxicity.
allergic Assess SCr and K+
reactions after a few days,
↓ efficacy of then regularly.
(potential cross antihyperglycemic
sensitivity with agents.
other Particularly
sulfonamide effective in ISH,
derivatives), the elderly and
photosensitivity, black patients.
fatigue. Monitor SCr and
K+.

Consider
alternatives in
patients with or
predisposed to
arrhythmias.

Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).

Ineffective in
patients with ClCr
<30 to 40 mL/min.

The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
agents if a patient's
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.

ACE Inhibitor/ quinapril/ 10/12.5 mg, Dry cough, Marked ↑ in serum Contraindicated $$
Diuretic hydrochlorothiazide 20/12.5 mg or hyperkalemia. K+ in patients in pregnancy—
Combinations 20/25 mg once Unusual: receiving K+ caution when
Accuretic daily pob angioedema. supplements and/or prescribing to
Can precipitate women of child-
K+-sparing diuretics.
renal failure in bearing
↓ hypotensive effect
renovascular
with NSAIDs and ↑ potential. 5 , 6
disease, volume Use lower (50%)
depletion or risk of renal
initial doses if on
dysfunction.
those receiving diuretics (↑ risk of
NSAIDs. hypotension with
Elevated Li + levels
hypovolemia).
Hypotension, (potential toxicity).
Hyperkalemia
weakness, usually occurs only
muscle cramps, ↓ Li + excretion
in those on K+
impotence. (monitor Li + levels, supplements or
Hypokalemia, adjust dose). drugs that cause
hyponatremia, NSAIDs ↓
K+ retention, those
hyperuricemia, hypotensive efficacy.

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

hyperglycemia, with renal


hyperlipidemia. Diuretic-induced impairment or
Rare: azotemia, hypokalemia ↑ the diabetics with high
blood risk of digoxin serum K+ levels.
dyscrasias, toxicity. Assess SCr and K+
allergic after a few days,
reactions ↓ efficacy of then regularly.
(potential cross antihyperglycemic
sensitivity with agents. Particularly
other effective in ISH,
sulfonamide the elderly and
derivatives), black patients.
photosensitivity, Monitor SCr and
fatigue.
K+.

Consider
alternatives in
patients with or
predisposed to
arrhythmias.

Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).

Ineffective in
patients with ClCr
<30 to 40 mL/min.

The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
agents if a patient's
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.

ACE Inhibitor/ ramipril/ 2.5/12.5 mg, Dry cough, Marked ↑ in serum Contraindicated $
Diuretic hydrochlorothiazide 5/12.5 mg, hyperkalemia. K+ in patients in pregnancy—
Combinations 10/12.5 mg, Unusual: receiving K+ caution when
Altace HCT, generics 5/25, mg or angioedema. supplements and/or prescribing to
10/25 mg once Can precipitate women of child-
K+-sparing diuretics.
daily pob renal failure in
↓ hypotensive effect
bearing
renovascular
with NSAIDs and ↑ potential. 5 , 6
disease, volume Use lower (50%)
depletion or risk of renal
initial doses if on
dysfunction.
those receiving diuretics (↑ risk of
NSAIDs. hypotension with
+
Elevated Li levels
hypovolemia).
Hypotension, (potential toxicity).
Hyperkalemia
weakness, usually occurs only
+
↓ Li excretion
muscle cramps, in those on K+
impotence. (monitor Li + levels, supplements or
Hypokalemia, adjust dose). drugs that cause
hyponatremia, NSAIDs ↓
K+ retention, those
hyperuricemia, hypotensive efficacy.
with renal
hyperglycemia,
impairment or
hyperlipidemia. Diuretic-induced
diabetics with high
Rare: azotemia, hypokalemia ↑ the
blood serum K+ levels.
risk of digoxin

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

dyscrasias, toxicity. Assess SCr and K+


allergic after a few days,
reactions ↓ efficacy of then regularly.
(potential cross antihyperglycemic
sensitivity with agents. Particularly
other effective in ISH,
sulfonamide the elderly and
derivatives), black patients.
photosensitivity, Monitor SCr and
fatigue. K+.

Consider
alternatives in
patients with or
predisposed to
arrhythmias.

Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).

Ineffective in
patients with ClCr
<30 to 40 mL/min.

The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
agents if a patient's
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.

ARB/ candesartan/ 16/12.5 mg Hyperkalemia. Marked ↑ in serum Contraindicated $$


Diuretic hydrochlorothiazide once daily pob Can precipitate K+ in patients in pregnancy—
Combinations renal failure in receiving K+ caution when
Atacand Plus susceptible supplements and/or prescribing to
patients women of child-
K+-sparing diuretics.
(bilateral bearing
May elevate Li +
renovascular potential. 7
disease, those levels (monitor Li + Use lower initial
with volume levels, adjust dose). doses in patients
depletion or who are volume
with concurrent ↓ Li + excretion depleted or on
NSAID use). (monitor Li + levels, diuretics (↑ risk of
adjust dose). hypotension in
Angioedema has NSAIDs ↓ hypovolemia).
been reported, hypotensive efficacy.
but a causal Hyperkalemia
association has Diuretic-induced usually occurs only
not been hypokalemia ↑ the in those on K+
established. risk of digoxin supplements or
toxicity. drugs that cause
Hypotension,
K+ retention, those
weakness, ↓ efficacy of with renal
muscle cramps, antihyperglycemic impairment or
impotence. agents. diabetics with high
Hypokalemia,
hyponatremia, serum K+ levels.
hyperuricemia, Assess SCr and K+

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

hyperglycemia, after a few days,


hyperlipidemia. then regularly.
Rare: azotemia,
blood Particularly
dyscrasias, effective in ISH,
allergic the elderly and
reactions black patients.
(potential cross Monitor SCr and
sensitivity with K+.
other
sulfonamide Consider
derivatives), alternatives in
photosensitivity, patients with or
fatigue. predisposed to
arrhythmias.

Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).

Ineffective in
patients with ClCr
<30 to 40 mL/min.

The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
agents if a patient's
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.

ARB/ eprosartan/ 600/12.5 mg Hyperkalemia. Marked ↑ in serum Contraindicated $$


Diuretic hydrochlorothiazide once daily pob Can precipitate K+ in patients in pregnancy—
Combinations renal failure in receiving K+ caution when
Teveten Plus susceptible supplements and/or prescribing to
patients women of child-
K+-sparing diuretics.
(bilateral bearing
May elevate Li +
renovascular potential. 7
disease, those levels (monitor Li + Use lower initial
with volume levels, adjust dose). doses in patients
depletion or who are volume
with concurrent ↓ Li + excretion depleted or on
NSAID use). (monitor Li + levels, diuretics (↑ risk of
adjust dose). hypotension in
Angioedema has NSAIDs ↓ hypovolemia).
been reported, hypotensive efficacy.
but a causal Hyperkalemia
association has Diuretic-induced usually occurs only
not been hypokalemia ↑ the in those on K+
established. risk of digoxin supplements or
toxicity. drugs that cause
Hypotension,
K+ retention, those
weakness, ↓ efficacy of with renal
muscle cramps, antihyperglycemic impairment or
impotence. agents. diabetics with high
Hypokalemia,
hyponatremia, serum K+ levels.
hyperuricemia, Assess SCr and K+
hyperglycemia, after a few days,

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

hyperlipidemia. then regularly.


Rare: azotemia,
blood Particularly
dyscrasias, effective in ISH,
allergic the elderly and
reactions black patients.
(potential cross Monitor SCr and
sensitivity with K+.
other
sulfonamide Consider
derivatives), alternatives in
photosensitivity, patients with or
fatigue. predisposed to
arrhythmias.

Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).

Ineffective in
patients with ClCr
<30 to 40 mL/min.

The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
agents if a patient's
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.

ARB/ irbesartan/ 150/12.5, Hyperkalemia. Marked ↑ in serum Contraindicated $$


Diuretic hydrochlorothiazide 300/12.5 or Can precipitate K+ in patients in pregnancy—
Combinations 300/25 mg once renal failure in receiving K+ caution when
Avalide daily pob susceptible supplements and/or prescribing to
patients women of child-
K+-sparing diuretics.
(bilateral bearing
May elevate Li +
renovascular potential. 7
disease, those levels (monitor Li + Use lower initial
with volume levels, adjust dose). doses in patients
depletion or who are volume
with concurrent ↓ Li + excretion depleted or on
NSAID use). (monitor Li + levels, diuretics (↑ risk of
adjust dose). hypotension in
Angioedema has NSAIDs ↓ hypovolemia).
been reported, hypotensive efficacy.
but a causal Hyperkalemia
association has Diuretic-induced usually occurs only
not been hypokalemia ↑ the in those on K+
established. risk of digoxin supplements or
toxicity. drugs that cause
Hypotension,
K+ retention, those
weakness, ↓ efficacy of with renal
muscle cramps, antihyperglycemic impairment or
impotence. agents. diabetics with high
Hypokalemia,
hyponatremia, serum K+ levels.
hyperuricemia, Assess SCr and K+
hyperglycemia, after a few days,
hyperlipidemia. then regularly.

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

Rare: azotemia,
blood Particularly
dyscrasias, effective in ISH,
allergic the elderly and
reactions black patients.
(potential cross Monitor SCr and
sensitivity with K+.
other
sulfonamide Consider
derivatives), alternatives in
photosensitivity, patients with or
fatigue. predisposed to
arrhythmias.

Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).

Ineffective in
patients with ClCr
<30 to 40 mL/min.

The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
agents if a patient's
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.

ARB/ losartan/ 50/12.5 mg or Hyperkalemia. Marked ↑ in serum Contraindicated $$


Diuretic hydrochlorothiazide 100/25 mg once Can precipitate K+ in patients in pregnancy—
Combinations daily pob renal failure in receiving K+ caution when
Hyzaar, Hyzaar DS susceptible supplements and/or prescribing to
patients women of child-
K+-sparing diuretics.
(bilateral bearing
May elevate Li +
renovascular potential. 7
disease, those levels (monitor Li + Use lower initial
with volume levels, adjust dose). doses in patients
depletion or who are volume
with concurrent ↓ Li + excretion depleted or on
NSAID use). (monitor Li + levels, diuretics (↑ risk of
adjust dose). hypotension in
Angioedema has NSAIDs ↓ hypovolemia).
been reported, hypotensive efficacy.
but a causal Hyperkalemia
association has Diuretic-induced usually occurs only
not been hypokalemia ↑ the in those on K+
established. risk of digoxin supplements or
toxicity. drugs that cause
Hypotension,
K+ retention, those
weakness, ↓ efficacy of with renal
muscle cramps, antihyperglycemic impairment or
impotence. agents. diabetics with high
Hypokalemia,
hyponatremia, serum K+ levels.
hyperuricemia, Assess SCr and K+
hyperglycemia, after a few days,
hyperlipidemia. then regularly.
Rare: azotemia,

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

blood Particularly
dyscrasias, effective in ISH,
allergic the elderly and
reactions black patients.
(potential cross Monitor SCr and
sensitivity with K+.
other
sulfonamide Consider
derivatives), alternatives in
photosensitivity, patients with or
fatigue. predisposed to
arrhythmias.

Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).

Ineffective in
patients with ClCr
<30 to 40 mL/min.

The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
agents if a patient's
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.

ARB/ olmesartan/ 20/12.5 mg, Hyperkalemia. Marked ↑ in serum Contraindicated $$


Diuretic hydrochlorothiazide 40/12.5 mg or Can precipitate K+ in patients in pregnancy—
Combinations 40/25 mg once renal failure in receiving K+ caution when
Olmetec Plus daily pob susceptible supplements and/or prescribing to
patients women of child-
K+-sparing diuretics.
(bilateral bearing
May elevate Li +
renovascular potential. 7
disease, those levels (monitor Li + Use lower initial
with volume levels, adjust dose). doses in patients
depletion or who are volume
with concurrent ↓ Li + excretion depleted or on
NSAID use). (monitor Li + levels, diuretics (↑ risk of
adjust dose). hypotension in
Angioedema has NSAIDs ↓ hypovolemia).
been reported, hypotensive efficacy.
but a causal Hyperkalemia
association has Diuretic-induced usually occurs only
not been hypokalemia ↑ the in those on K+
established. risk of digoxin supplements or
toxicity. drugs that cause
Hypotension,
K+ retention, those
weakness, ↓ efficacy of with renal
muscle cramps, antihyperglycemic impairment or
impotence. agents. diabetics with high
Hypokalemia,
hyponatremia, serum K+ levels.
hyperuricemia, Assess SCr and K+
hyperglycemia, after a few days,
hyperlipidemia. then regularly.
Rare: azotemia,
blood Particularly

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

dyscrasias, effective in ISH,


allergic the elderly and
reactions black patients.
(potential cross Monitor SCr and
sensitivity with K+.
other
sulfonamide Consider
derivatives), alternatives in
photosensitivity, patients with or
fatigue. predisposed to
arrhythmias.

Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).

Ineffective in
patients with ClCr
<30 to 40 mL/min.

The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
agents if a patient's
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.

ARB/ telmisartan/ 80/12.5 mg Hyperkalemia. Marked ↑ in serum Contraindicated $$


Diuretic hydrochlorothiazide once daily pob Can precipitate K+ in patients in pregnancy—
Combinations renal failure in receiving K+ caution when
Micardis Plus susceptible supplements and/or prescribing to
patients women of child-
K+-sparing diuretics.
(bilateral bearing
May elevate Li +
renovascular potential. 7
disease, those levels (monitor Li + Use lower initial
with volume levels, adjust dose). doses in patients
depletion or who are volume
with concurrent ↓ Li + excretion depleted or on
NSAID use). (monitor Li + levels, diuretics (↑ risk of
adjust dose). hypotension in
Angioedema has NSAIDs ↓ hypovolemia).
been reported, hypotensive efficacy.
but a causal Hyperkalemia
association has Diuretic-induced usually occurs only
not been hypokalemia ↑ the in those on K+
established. risk of digoxin supplements or
toxicity. drugs that cause
Hypotension,
K+ retention, those
weakness, ↓ efficacy of with renal
muscle cramps, antihyperglycemic impairment or
impotence. agents. diabetics with high
Hypokalemia,
hyponatremia, serum K+ levels.
hyperuricemia, Assess SCr and K+
hyperglycemia, after a few days,
hyperlipidemia. then regularly.
Rare: azotemia,
blood Particularly
dyscrasias, effective in ISH,

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

allergic the elderly and


reactions black patients.
(potential cross Monitor SCr and
sensitivity with K+.
other
sulfonamide Consider
derivatives), alternatives in
photosensitivity, patients with or
fatigue. predisposed to
arrhythmias.

Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).

Ineffective in
patients with ClCr
<30 to 40 mL/min.

The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
agents if a patient's
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.

ARB/ valsartan/ 80/12.5 mg, Hyperkalemia. Marked ↑ in serum Contraindicated $$


Diuretic hydrochlorothiazide 160/12.5 mg or Can precipitate K+ in patients in pregnancy—
Combinations 160/25 mg once renal failure in receiving K+ caution when
Diovan-HCT daily pob susceptible supplements and/or prescribing to
patients women of child-
K+-sparing diuretics.
(bilateral bearing
May elevate Li +
renovascular potential. 7
disease, those levels (monitor Li + Use lower initial
with volume levels, adjust dose). doses in patients
depletion or who are volume
with concurrent ↓ Li + excretion depleted or on
NSAID use). (monitor Li + levels, diuretics (↑ risk of
adjust dose). hypotension in
Angioedema has NSAIDs ↓ hypovolemia).
been reported, hypotensive efficacy.
but a causal Hyperkalemia
association has Diuretic-induced usually occurs only
not been hypokalemia ↑ the in those on K+
established. risk of digoxin supplements or
toxicity. drugs that cause
Hypotension,
K+ retention, those
weakness, ↓ efficacy of with renal
muscle cramps, antihyperglycemic impairment or
impotence. agents. diabetics with high
Hypokalemia,
hyponatremia, serum K+ levels.
hyperuricemia, Assess SCr and K+
hyperglycemia, after a few days,
hyperlipidemia. then regularly.
Rare: azotemia,
blood Particularly
dyscrasias, effective in ISH,
allergic the elderly and

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

reactions black patients.


(potential cross Monitor SCr and
sensitivity with K+.
other
sulfonamide Consider
derivatives), alternatives in
photosensitivity, patients with or
fatigue. predisposed to
arrhythmias.

Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).

Ineffective in
patients with ClCr
<30 to 40 mL/min.

The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
agents if a patient's
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.

Calcium Channel amlodipine/ Amlodipine 5 or Ankle edema, CYP3A4 substrate For patients with $$$$
Blocker/ atorvastatin 10 mg plus flushing, (many potential hypertension and
HMG CoA Caduet atorvastatin 10, headache and interactions). an indication for an
Reductase Inhibitor 20, 40 or 80 mg palpitations. Strong inhibitors HMG-CoA inhibitor.
Combinations once daily pob Adverse effects include azole
of atorvastatin antifungals, protease
include inhibitors,
constipation, macrolides and
flatulence, quinidine.
dyspepsia,
abdominal pain Grapefruit juice may
and myalgia. ↑ serum
concentrations.

Amlodipine and
atorvastatin are both
substrates of
CYP3A4.

Direct Renin aliskiren/ 150/12.5 mg, Diarrhea. The Low potential for May take 4 wk to $$
Inhibitor/ hydrochlorothiazide 150/25 mg, incidence of dry drug interactions. realize maximum
Diuretic cough and ↓ Li + excretion antihypertensive
Combinations Rasilez HCT 300/12.5 mg hyperkalemia is (monitor Li + levels, effect.
or 300/25 mg low compared adjust dose). Effect on
with ACE NSAIDs ↓ cardiovascular
once daily pob inhibitors. hypotensive efficacy. outcomes not yet
Hypotension, established.
weakness, Diuretic-induced
muscle cramps, hypokalemia ↑ the Limited data in
impotence. risk of digoxin patients with
Hypokalemia, toxicity. greater than
hyponatremia, moderate renal

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Drug Interactions Comments

hyperuricemia, ↓ efficacy of dysfunction.


hyperglycemia, antihyperglycemic
hyperlipidemia. agents. Avoid use in
Rare: azotemia, pregnancy.
blood
dyscrasias, Particularly
allergic effective in ISH,
reactions the elderly and
(potential cross black patients.
sensitivity with Monitor SCr and
other K+.
sulfonamide
derivatives), Consider
photosensitivity, alternatives in
fatigue. patients with or
predisposed to
arrhythmias.

Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).

Ineffective in
patients with ClCr
<30 to 40 mL/min.

a. Cost of 30-day supply of usual dose of drug; includes drug cost only.
b. It is generally recommended that the dose of the each component is titrated before starting a combination product.

Dosage adjustment may be required in renal impairment; see Appendices: Dosage Adjustment in Renal Impairment.

Abbreviations: CV=cardiovascular; IR=immediate-release; ISA=intrinsic sympathomimetic activity; ISH=isolated systolic


hypertension; PAD=peripheral arterial disease; SR=slow-release; TCA=tricyclic antidepressant

Legend: $ <$20 $-$$ <$20–40 $$ $20–40 $$-$$$ $20–60 $$$ $40–60 $$$$ >$60

Suggested Readings

Adrogue HJ, Madias NE. Sodium and potassium in the pathogenesis of hypertension. N Engl J Med 2007;356(19):1966-78.

Canadian recommendations on the management of hypertension are updated annually. A summary of the important and new
recommendations can be found at www.hypertension.ca/ in the For General Public section and is also broadly published in
multidisciplinary journals annually.

Hackam DG, Khan NA, Hemmelgarn BR et al. The 2010 Canadian Hypertension Education Program recommendations for the
management of hypertension: part 2–therapy. Can J Cardiol 2010;26(5):249-58.

Quinn RR, Hemmelgarn BR, Padwal RS et al. The 2010 Canadian Hypertension Education Program recommendations for the
management of hypertension: part 1–blood pressure measurement, diagnosis and assessment of risk. Can J Cardiol 2010;26
(5):241-8.

References

1. Campbell NR, Kaczorowski J, Lewanczuk RZ et al. 2010 Canadian Hypertension Education Program (CHEP) recommendations:
the scientific summary—an update of the 2010 theme and the science behind new CHEP recommendations. Can J Cardiol
2010;26(5):236-40.
2. Khan N, Chockalingam A, Campbell NR. Lack of control of high blood pressure and treatment recommendations in Canada. Can
J Cardiol 2002;18(6):657-61.

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Therapeutic Choice
3. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-
converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288(23):2981-97.
4. MRC trial of treatment of mild hypertension: principal results. Medical Research Council Working Party. Br Med J (Clin Res Ed)
1985;291(6488):97-104.
5. Cooper WO, Hernandez-Diaz S, Arbogast PG et al. Major congenital malformations after first-trimester exposure to ACE
inhibitors. N Engl J Med 2006;354(23):2443-51.
6. Friedman JM. ACE inhibitors and congenital anomalies. N Engl J Med 2006;354(23):2498-500.
7. Alwan S, Polifka JE, Friedman JM. Angiotensin II receptor antagonist treatment during pregnancy. Birth Defects Res A Clin Mol
Teratol 2005;73(2):123-30.
8. Wald DS, Law M, Morris JK et al. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on
11,000 participants from 42 trials. Am J Med 2009;122(3):290-300.
9. Weber MA, Bakris GL, Dahlof B et al. Baseline characteristics in the Avoiding Cardiovascular events through Combination
therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial: a hypertensive population at high cardiovascular
risk. Blood Press 2007;16(1):13-9.
10. Hackam DG, Khan NA, Hemmelgarn BR et al. The 2010 Canadian Hypertension Education Program recommendations for the
management of hypertension: part 2–therapy. Can J Cardiol 2010;26(5):249-58.
11. Mann JF, Schmieder RE, McQueen M et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk
(the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372(9638):547-53.
12. Magee LA, Helewa M, Moutquin JM et al. Diagnosis, evaluation, and management of hypertensive disorders of pregnancy. J
Obstet Gynaecol Can 2008;30(3):S1-S48.
13. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J
Obstet Gynecol 2000;183(1):S1-22.
14. Lowe SA, Brown MA, Dekker GA et al. Guidelines for the management of hypertensive disorders of pregnancy 2008. Aust N Z J
Obstet Gynaecol 2009;49(3):242-6.
15. Podymow T, August P. Update on the use of antihypertensive drugs in pregnancy. Hypertension 2008;51(4):960-9.
16. Magee LA. Drugs in pregnancy. Antihypertensives. Best Pract Res Clin Obstet Gynaecol 2001;15(6):827-45.
17. Magee LA, Schick B, Donnenfeld AE et al. The safety of calcium channel blockers in human pregnancy: a prospective,
multicentre cohort study. Am J Obstet Gynecol 1996;174(3):823-8.
18. Papatsonis DN, Lok CA, Bos JM et al. Calcium channel blockers in the management of preterm labor and hypertension in
pregnancy.Eur J Obstet Gynecol Reprod Biol 2001;97(2):122-40.
19. Butters L, Kennedy S, Rubin PC. Atenolol in essential hypertension during pregnancy. BMJ 1990;301(6752):587-9.
20. Groves TD, Corenblum B. Spironolactone therapy during human pregnancy. Am J Obstet Gynecol 1995;172(5):1655-6.
21. Shotan A, Widerhorn J, Hurst A et al. Risks of angiotensin-converting enzyme inhibition during pregnancy: experimental and
clinical evidence, potential mechanisms, and recommendations for use. Am J Med 1994;96(5):451-6.
22. Cooper WO, Hernandez-Diaz S, Arbogast PG et al. Major congenital malformations after first trimester exposure to ACE
inhibitors. N Engl J Med 2006;354(23):2443-51.
23. Lambot MA, Vermeylen D, Noel JC. Angiotensin-II-receptor inhibitors in pregnancy. Lancet 2001;357(9268):1619-20.
24. Cheng JW. Aliskiren: renin inhibitor for hypertension management. Clin Ther 2008;30(1):31-47.
25. Beardmore KS, Morris JM, Gallery ED. Excretion of antihypertensive medication into human breast milk: a systematic review.
Hypertens Pregnancy 2002;21(1):85-95.
26. Ohkubo T, Imai Y, Tsuji I et al. Home blood pressure measurement has a stronger predictive power for mortality than does
screening blood pressure measurement: a population-based observation in Ohasama, Japan. J Hypertens 1998;16(7):971-5.
27. Ohkubo T, Asayam K, Kikuya M et al. How many times should blood pressure be measured at home for better prediction of
stroke risk? Ten-year follow-up results from the Ohasama study. J Hypertens 2004;22(6):1099-104.
28. McLean DL, McAlister FA, Johnson JA et al. A randomized trial of the effect of community pharmacist and nurse care on
improving blood pressure management in patients with diabetes mellitus: Study of Cardiovascular Risk Intervention by
Pharmacists-Hypertension (SCRIP-HTN). Arch Intern Med 2008;168(21):2355-61.
29. Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane
Database Syst Rev 2005;(4):CD003566.

Therapeutic Choices. © Canadian Pharmacists Association, 2011. All rights reserved.

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Therapeutic Choice

Print Close

Cardiovascular Disorders: Intermittent Claudication

Date Prepared: October 2010

Richard I. Ogilvie, MD, FRCPC, FACP

Goals of Therapy

Improve mobility and quality of life


Increase walking distance and time to claudication
Increase capacity for regular dynamic leg exercise
Prevent associated cardiovascular events

Investigations

History with special attention to cardiovascular disease risk factors and associated conditions:
hypertension
diabetes mellitus
smoking
dyslipidemia
angina pectoris/MI
TIA/stroke
Define walking time to claudication (severe <1/2 city block; moderate 1/2 to 1 block; mild >1 block)
Define duration of symptoms (6–12 months are required to develop collateral circulation)
Physical examination:
signs of hypertension, dyslipidemia, diabetes mellitus, atherosclerosis (aortic aneurysm, bruits), heart
failure
signs of peripheral artery obstruction as indicated by diminished pulses in the femoral, popliteal, posterior
tibial and/or dorsalis pedis arteries. Alternatively, the absence of a bruit or decreased pulse reduces the
likelihood of obstruction
evidence of acute peripheral artery occlusion (acute onset of continuous pain, pale and cool limb or mottled
discolouration, thickened, swollen, stiff muscles plus pain over the muscle)
resting pain, dependent rubor, cyanosis, muscle atrophy and/or trophic ulcers suggest severe obstruction
Laboratory tests:
fasting blood glucose, serum creatinine and lipid profile
hemoglobin (anemia may exacerbate symptoms), hematocrit, platelet count
increased levels of D-dimer and inflammatory markers (C-reactive protein, amyloid A) are associated with
higher short-term (within 1–2 years) risk of cardiovascular and all-cause mortality1
resting Doppler-derived or sphygmomanometric ankle/arm systolic pressure index (ankle-brachial index)
(Figure 1 - Treatment of Intermittent Claudication)2
consider invasive angiography for patients with signs of severe limb ischemia (resting pain, muscle
atrophy, cyanosis, nonhealing ischemic ulcers or gangrene) in preparation for possible angioplastic or
surgical revascularization

Therapeutic Choices (Figure 1 - Treatment of Intermittent Claudication)

Nonpharmacologic Choices

Discontinuation of smoking (active and passive) (see Psychiatric Disorders: Smoking Cessation).
Time (collateral flow develops over 6–12 months).
Nondrug treatment of obesity (see Endocrine and Metabolic Disorders: Obesity), lipid disorders (see
Cardiovascular Disorders: Dyslipidemias), hypertension (see Cardiovascular Disorders: Hypertension) and
associated conditions.
Regular dynamic leg exercise (5 times per week for 8 weeks initially).3 , 4 , 5 Dynamic leg exercise for 6–12
months after the onset of claudication allows collateral circulation to develop; continued exercise 3 or more
times a week over 24–36 months slows functional decline.3
For patients with chronic intermittent claudication, and without signs of severe arterial obstruction, the role of
angioplasty remains to be defined.
For patients with severe ischemia, bypass surgery or angioplasty have similar effects on amputation-free
survival and all-cause mortality over a 6-month period, although morbidity and costs are higher for patients
receiving surgery first rather than angioplasty.6 , 7 Amputation-free survival is higher and all-cause mortality is
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Therapeutic Choice
lower 2 and 3 years after surgery compared with angioplasty according to a post-hoc analysis of a large
randomized trial.6
Paresthesia and paralysis require immediate surgical revascularization (fibrinolysis may be considered where
symptoms present for <14 days).

Pharmacologic Choices (Table 1)

Pharmacologic options for improving mobility, walking distance and time to claudication are limited. Drug therapy is
most effective in reducing the risk of cardiovascular events.

Cardiovascular Risk Reduction

Intermittent claudication occurs as a symptom of atherosclerotic occlusion in peripheral arterial disease (PAD). In
this condition it is essential to optimize treatment of hypertension (see Cardiovascular Disorders: Hypertension),
dyslipidemia (see Cardiovascular Disorders: Dyslipidemias) and diabetes mellitus (see Endocrine and Metabolic
Disorders: Diabetes Mellitus).8

Antiplatelet agents reduce the relative risk of vascular death in high-risk patients by about 25% and are equally
effective in those with coronary artery disease (CAD) and PAD.9 Clopidogrel may be more effective than ASA in
patients with PAD10 but is usually reserved for those who cannot tolerate ASA or continue to have events while on
ASA. Clopidogrel plus ASA is not significantly better than ASA alone in patients with atherothrombosis, but
combination therapy increases the risk of bleeding,11 and is therefore not recommended.

The ACE inhibitor ramipril reduces the risk of ischemic events beyond that expected from lowering
blood pressure in patients with PAD.12 Ramipril demonstrated similar effects in patients with or
without PAD in the HOPE study. Ramipril also increases walking time and distance over a 6-month
period in patients with PAD, according to the results of a small randomized study.13 Useful Info?

Beta-blockers reduce the risk of MI and death in patients with atherosclerosis, but use of these agents in patients
with peripheral vascular disease, including PAD, was previously discouraged because they were thought to worsen
symptoms. Beta-blockers do not affect walking capacity in patients with PAD14; thus, it is reasonable to use them to
treat hypertension in this population,15 although they should be used cautiously in those with severe PAD.15 Beta-
blockers are not recommended for the treatment of hypertension in patients over 60 years of age unless there are
other compelling indications such as angina, recent MI or a supraventricular arrhythmia.

Lipid-lowering drugs reduce the risk of cardiovascular events in patients with atherosclerosis and may improve
symptoms and increase walking distance in patients with intermittent claudication.16 , 17

Specific Therapy for Intermittent Claudication

Pentoxifylline, a methylxanthine derivative, alters erythrocyte deformability and reduces blood viscosity, platelet
reactivity and plasma hypercoagulability.18 Pentoxifylline produces marginal but statistically significant improvement
in pain-free and maximal walking distance and thus is not indicated for mild claudication. Smoking cessation and
regular dynamic leg exercise are probably more beneficial than pentoxifylline for moderate claudication. If
pentoxifylline is used, a total of 24 weeks of therapy followed by an 8-week drug-free period (as exercise tolerance
increases) can decrease or eliminate the need for pentoxifylline.

Pentoxifylline may be beneficial adjunctive therapy for trophic ulcers in diabetic and nondiabetic patients.19 Assess
therapy at 4-week intervals. Cost of therapy is unlikely to be justified beyond 24 weeks of treatment.

Cilostazol inhibits platelet aggregation by selectively inhibiting phosphodiesterase III and is a vasodilator that
improves maximal treadmill walking distance.20 , 21 , 22 It is not available in Canada.

Other Therapies

The role of vasoactive agents, buflomedil,23 prostaglandin analogues,24 L-carnitine or arterial gene therapy25 has
not been defined by adequate clinical trials. Low molecular weight heparin, oral anticoagulants, vitamin E and
chelation therapy are not effective for PAD.

Figure 1-Treatment of Intermittent Claudication

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Therapeutic Choice

Table 1: Drug Treatment for Intermittent Claudication

Adverse Costa
Class Drug Dose Effects Comments Drug Interactions

Antiplatelet acetylsalicylic 80– GI ↑ bleeding risk with $


Agents acid (ASA) 325 intolerance, anticoagulants and
mg GI bleeding, clopidogrel.
Aspirin, Coated
daily nausea,
Aspirin, po heartburn.
generics

Antiplatelet clopidogrel 75 mg Skin rash, ↑ bleeding risk with $$$$


Agents Plavix daily diarrhea, ASA. PPI use may
po bleeding. reduce clopidogrel
efficacy.26

Rheologic pentoxifylline 400 Nausea, Clinical effectiveness is ↓ effect of adenosine; ↑ $$


Modifiers Trental, mg SR vomiting, marginal. Not effect of theophylline,
generics TID po dizziness, recommended in patients warfarin,

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Therapeutic Choice

Adverse Costa
Class Drug Dose Effects Comments Drug Interactions

headache, with marked hepatic or sympathomimetics,


flushing. renal dysfunction. antihypertensives,
Contraindications: acute hypoglycemics.
MI, hemorrhage, peptic
ulcer disease, xanthine
intolerance.

a.Cost of 30-day supply; includes drug cost only.

Dosage adjustment may be required in renal impairment; see Appendices: Dosage Adjustment in Renal Impairment

Abbreviations: SR=sustained release

Legend: $ <$20 $$ $20-40 $$$$ $60-80

Suggested Readings

Ankle Brachial Index Collaboration, Fowkes FG, Murray GD et al. Ankle brachial index combined with Framingham
Risk Score to predict cardiovascular events and mortality: a meta-analysis. JAMA 2008;300(2):197-208.

Gardner AW, Montgomery PS, Afaq A. Exercise performance in patients with peripheral arterial disease who have
different types of exertional leg pain. J Vasc Surg 2007;46(1):79-86.

Rowlands TE, Donnelly R. Medical therapy for intermittent claudication. Eur J Vasc Endovasc Surg 2007;34(3):314-
21.

Sutton-Tyrrell K, Venkitachalam L, Kanaya AM et al. Relationship of ankle blood pressures to cardiovascular events
in older adults. Stroke 2008;39(3):863-9.

White C. Clinical practice. Intermittent claudication. N Engl J Med 2007;356(12):1241-50.

References

1. Vidula H, Tian L, Liu K et al. Biomarkers of inflammation and thrombosis as predictors of near-term mortality
in patients with peripheral arterial disease: a cohort study. Ann Intern Med 2008;148(2):85-93.
2. Feringa HH, Bax JJ, Hoeks S et al. A prognostic risk index for long-term mortality in patients with peripheral
arterial disease. Arch Intern Med 2007;167(22):2482-9.
3. McDermott MM, Liu K, Ferrucci L et al. Physical performance in peripheral arterial disease: a slower rate of
decline in patients who walk more. Ann Intern Med 2006;144(1):10-20.
4. Kim DH. Exercise and peripheral arterial disease. Ann Intern Med 2006;144(9):699-700.
5. Wind J, Koelemay MJ. Exercise therapy and the additional effect of supervision on exercise therapy in patients
with intermittent claudication. Systematic review of randomised controlled trials. Eur J Vasc Endovasc Surg
2007;34(1):1-9.
6. Adam DJ, Beard JD, Cleveland T et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL):
multicentre, randomised controlled trial. Lancet 2005;366(9501):1925-34.
7. Goy JJ, Urban P. Life and limb: bypass versus angioplasty in the ischaemic limb. Lancet 2005;366
(9501):1905-6.
8. Hirsch AT, Haskal ZJ, Hertzer NR et al. ACC/AHA 2005 practice guidelines for the management of patients with
peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic). Circulation 2006;113
(11):e463-654.
9. Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial
infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists'
Collaboration. BMJ 1994;308(6921):81-106.

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Therapeutic Choice
10. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
CAPRIE Steering Committee. Lancet 1996;348(9038):1329-39.
11. Bhatt DL, Fox KA, Hacke W et al. Clopidogrel and aspirin versus aspirin alone for the prevention of
atherothrombotic events. N Engl J Med 2006;354(16):1706-17.
12. Yusuf S, Sleight P, Pogue J et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on
cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N
Engl J Med 2000;342(3):145-53.
13. Ahimastos AA, Lawler A, Reid CM et al. Brief communication: ramipril markedly improves walking ability in
patients with peripheral arterial disease: a randomized trial. Ann Intern Med 2006;144(9):660-4.
14. Radack K, Deck C. Beta-adrenergic blocker therapy does not worsen intermittent claudication in subjects with
peripheral arterial disease. A meta-analysis of randomized controlled trials. Arch Intern Med 1991;151
(9):1769-76.
15. Heintzen MP, Strauer BE. Peripheral vascular effects of beta-blockers. Eur Heart J 1994;15 (Suppl C):2-7.
16. Mohler ER, Hiatt WR, Creager MA. Cholesterol reduction with atorvastatin improves walking distance in
patients with peripheral arterial disease. Circulation 2003;108(12):1481-6.
17. Mondillo S, Ballo P, Barbati R et al. Effects of simvastatin on walking performance and symptoms of
intermittent claudication in hypercholesterolemic patients with peripheral vascular disease. Am J Med
2003;114(5):359-64.
18. Hood SC, Moher D, Barber GG. Management of intermittent claudication with pentoxifylline: meta-analysis of
randomized controlled trials. CMAJ 1996;155(8):1053-9.
19. Jull A, Waters J, Arroll B. Pentoxifylline for treatment of venous leg ulcers: a systematic review. Lancet
2002;359(9317):1550-4.
20. Dawson DL, Cutler BS, Hiatt WR et al. A comparison of cilostazol and pentoxifylline for treating intermittent
claudication. Am J Med 2000;109(7):523-30.
21. Money SR, Herd JA, Isaacsohn JL et al. Effect of cilostazol on walking distances in patients with intermittent
claudication caused by peripheral vascular disease. J Vasc Surg 1998;27(2):267-74.
22. Rowlands TE, Donnelly R. Medical therapy for intermittent claudication. Eur J Vasc Endovasc Surg 2007;34
(3):314-21.
23. de Backer TL, Bogaert M, Vander Stichele R. Buflomedil for intermittent claudication. Cochrane Database Syst
Rev 2008;(1):CD000988.
24. Milio G, Mina C, Cospite V et al. Efficacy of the treatment with prostaglandin E-1 in venous ulcers of the lower
limbs. J Vasc Surg 2005;42(2):304-8.
25. Lederman RJ, Mendelsohn FO, Anderson RD et al. Therapeutic angiogenesis with recombinant fibroblast
growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial. Lancet 2002;359
(9323):2053-8.
26. Lau WC, Gurbel PA. The drug-drug interaction between proton pump inhibitors and clopidogrel. CMAJ
2009;180(7):699-700.

Therapeutic Choices. © Canadian Pharmacists Association, 2011. All rights reserved.

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Therapeutic Choice

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Cardiovascular Disorders: Post-myocardial Infarction

Date Prepared: April 2007


Date Revised: January 2009

William L. Williams, MDCM, FRCPC

About 70% of patients presenting with myocardial infarction (MI) qualify for acute reperfusion by thrombolysis or
primary coronary angioplasty.1 The reperfused patient with an aborted MI presents a particular challenge with
respect to recurrent ischemic complications. Reperfusion therapy has reduced 30-day mortality from 10% to
between 3 and 4% and improved overall prognosis.2 The prognosis of the post-MI patient depends on the
interaction between residual left ventricular dysfunction, the potential for recurrent ischemia and the risk of
arrhythmia (Table 1).3 Older patients with comorbid conditions such as diabetes mellitus or renal failure have worse
outcomes. Patients who receive timely reperfusion therapy with thrombolysis or primary angioplasty enjoy a much
better prognosis than those treated conservatively.1

Table 1: Investigation and Therapy of the Post-Infarction Patient to Improve Prognosis

Factor
Affecting
Prognosis Investigation Therapy

Left Ventricular Ejection fraction: echocardiogram, gated nuclear or contrast Beta-blockers, ACE
Dysfunction ventriculogram inhibitors, ARBs, warfarin
for LV thrombus or atrial
fibrillation

Ischemia Low-risk outpatients post-thrombolysis: physiologic stress test Beta-blockers, statins, ACE
using exercise, dipyridamole or dobutamine with ECG; nuclear inhibitors, ARBs,
scintigraphy or echocardiographic wall motion assessment. Perform antiplatelet agents
coronary angiography if the result is abnormal
High-risk patients: coronary angiography

Arrhythmia Holter monitor, event recorder, implantable arrhythmia detector Beta-blockers, possibly
amiodarone or ICD

Abbreviations: ACE inhibitor = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker;
ICD = implantable cardioverter/defibrillator; LV = left ventricle.

Cardiovascular disease in women remains the leading cause of death and accounts for more than half of all deaths
among women over the age of 50 years. Sex differences are apparent with respect to prevalence, presentation,
treatment and outcome. Some risk factors, for example diabetes mellitus, appear to be more malignant in women
than in men. Mortality rates in men have been declining, while those in women have remained stable.4

Historically, women have been under-represented in clinical trials, perhaps due to exclusion with advanced age and
comorbidities. This has led to a knowledge gap whereby little is known about why cardiovascular disease affects
women differently from men.

Investigation and treatment of patients after myocardial infarction should be gender neutral as the vast majority of
post-MI interventions benefit patients of both sexes.4

Goals of Therapy

Establish a risk profile


Prevent death and prevent or delay recurrent events (MI, heart failure and angina)
Retard progression of coronary disease
Return patient to a meaningful quality of life
Target modifiable risk factors that are responsible for 90% of risk

Investigations

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Therapeutic Choice
A simple algorithm for evaluating post-infarction patients who have been treated with or without fibrinolysis is
presented in Figure 1 - Stratifying Post-MI Patients to Conservative or Invasive Therapy. The higher the risk, the
more likely the patient will benefit from an invasive strategy.5 Identifying patients at high risk begins with an
assessment of readily accessible clinical predictors.

Predictors of early recurrent events (i.e, one to six months post-MI) include:6
recurrent ischemia or angina with an ST-segment shift
bigger infarction as evidenced by: pulmonary congestion, hypotension, tachycardia, higher Killip class
(Table 2), azotemia

Table 2: The Killip Classification

Killip Class Patient Characteristics

I No clinical signs of heart failure

II Mild heart failure, rales, elevated jugular venous pulse (SBP ≥ 90 mm Hg)

III Frank pulmonary edema (SBP ≥ 90 mm Hg)

IV Cardiogenic shock (SBP < 90 mm Hg)

Predictors of late recurrent events (i.e., one to two years post-MI):6


residual left ventricular ejection fraction < 30%
older age and comorbidity (diabetes, renal failure, other vascular disease)
ventricular irritability, as evidenced by resuscitated VF or sustained or nonsustained VT, especially in
patients with low ejection fraction
An important determinant of prognosis after MI is left ventricular dysfunction, which is reflected by the left
ventricular ejection fraction (LVEF). LVEF can be measured by echocardiography or inferred from clinical signs
present at the time of infarction such as pulmonary congestion, resting tachycardia, hypotension, new bundle branch
block or recurrent arrhythmia. The extent of the current of injury pattern on ECG and the degree of enzyme release
also reflect infarct size. If a low LVEF is suspected (< 40%), refer the patient to a tertiary care centre for further
investigation. Otherwise, smaller centres without access to echocardiography can perform a modified treadmill test
prior to discharge.

Indications for post-infarction coronary arteriography sanctioned by current guidelines are listed in Table 3.
However, in many centres most patients treated with thrombolytics also visit the angiography suite before hospital
discharge,7 as the prognosis is improved among those with demonstrable ischemia.8

A decision algorithm for the unique situation presented by post-MI patients following primary angioplasty is
illustrated in Figure 2 - Management of MI Patients After Primary PCI.

Table 3: Evidence-based Indications for Post-infarction Coronary Angiography4

Spontaneous or provocable ischemia, especially when present after fibrinolysis

LV dysfunction/LVEF ≤ 40%

Hemodynamic instability

Prior repair of a mechanical complication

Malignant ventricular arrhythmia

Patients with non-ST-segment elevation MI

Abbreviations: LV = left ventricle; LVEF = LV ejection fraction.

Select patients may be investigated for arrhythmia (Holter monitor, event recorder, implantable arrhythmia
detector); however, this is not routinely recommended.4

Therapeutic Choices

Vascular inflammation contributes to the pathogenesis of plaque rupture. Thus agents with anti-inflammatory and
antithrombotic properties now have a well-established role in the management of the post-MI patient.

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Comprehensive management of the post-MI patient should include treatment of hypertension, dyslipidemia and
diabetes mellitus. Smoking cessation decreases the relative risk of death and re-infarction by 50% in patients with
MI.9 The rate of re-infarction and death decreased from 16 to 6% during two years of observation among men who
succeeded in stopping smoking.10 Weight loss and physical activity are also important components of secondary
prevention of MI.

Nonpharmacologic Choices

Essential elements of cardiac rehabilitation are provided in Figure 3 - Elements of Cardiac Rehabilitation.
Weight loss is indicated if the patient’s BMI is > 25 or the waist circumference is > 100 cm in men or > 90 cm
in women. The goal is a sustained 5 to 10% decrease in body weight.9 Nutritional counselling is beneficial for
patients attempting to lose weight.9
Regular exercise with an individual prescription that accounts for age, obesity, level of fitness and
biomechanical capability. Generally, the goal of burning off 1000 kcal/week can be attained by engaging in 30-
45 minutes of moderate aerobic activity three or four times per week.9
Revascularization is indicated in select patients (Figure 1 - Stratifying Post-MI Patients to Conservative or
Invasive Therapy and Figure 2 - Management of MI Patients After Primary PCI).
An implantable cardioverter/defibrillator may be indicated in select patients.

Pharmacologic Choices

Among high-risk patients, antiplatelet agents, beta-blockers, ACE inhibitors and lipid-lowering therapies
independently reduce the incidence of vascular events by approximately 25% (Table 4).11 An overview of individual
agents is provided in Table 6.

Table 4: Potential Cumulative Impact of Four Treatments for Secondary Prevention of Cardiovascular Events

2-year Event Rate


(death, MI or stroke)
Relative Risk Reduction

None — 8%

ASA 25% 6%

Beta-blocker 25% 4.5%

Lipid lowering (↓ LDL-C by 1.5 mmol/L) 30% 3%

ACE inhibitor 25% 2.3%

Cumulative relative risk reduction if all four drugs are used is about 75%

To calculate the cumulative risk reduction a multiplicative scale was used. For example, two interventions each
reducing the risk of an event by 30% would be expected to have about a 50% relative risk reduction (1–[0.7 ×
0.7]). No interactions in treatment effects are observed in trials, suggesting that the proportionate risk reduction
of a specific drug in the presence or absence of other effective interventions would be expected to be similar.
Smoking cessation lowers the risk of recurrent MI by about half after two years. In a smoker with vascular
disease, quitting smoking and the use of the four preventive strategies could theoretically have a large potential
benefit (approximately 80% relative risk reduction)

Reprinted from The Lancet. Volume 360(9326). Yusuf S. Two decades of progress in preventing vascular disease. Lancet pages
2-3. Copyright 2002. With permission from Elsevier.

Antiplatelet Agents12 , 13 , 14 , 15

Antiplatelet agents are effective in preventing vascular events, including nonfatal MI and death, in post-MI
patients.5 , 16 ASA is the antiplatelet agent of choice due to its effectiveness and low cost, and is recommended as
chronic therapy in all CAD patients without contraindications, including those who are post-MI. Low doses (80 to
325 mg daily) are usually well tolerated.

Clopidogrel is recommended in patients who have contraindications to or cannot tolerate ASA. Acute and long-term

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outcomes in patients treated conservatively or with thrombolysis are improved by clopidogrel.17 Clopidogrel is
essential therapy for those undergoing stent deployment. When used with ASA, clopidogrel has been effective in
improving coronary patency and reducing the risk of infarction or death among those with unstable angina, ST-
segment elevation MI treated with thrombolytics18 and after stent deployment. When drug-eluting stents are
used according to the approved indications, it is recommended that clopidogrel be continued for at
least one year after deployment; when these devices are used in more complex, off-label settings, it is
recommended that clopidogrel be continued indefinitely.19 Useful Info?

Beta-Blockers20 , 21 , 22

Beta-blockers reduce cardiovascular mortality and re-infarction rates, and increase the probability of long-term
survival by up to 40%.5 In the absence of contraindications, these drugs are recommended in all patients post-MI
including those with non-ST-segment elevation MI (NSTEMI) and those receiving thrombolytic therapy or primary
angioplasty (Figure 2 - Management of MI Patients After Primary PCI). They should be started within a few days of
MI, if not earlier, and therapy should be continued indefinitely.5 Beta-blockers should be avoided among patients
with hypotension, bradycardia and active heart failure.

Higher-risk patients with reduced LV function, especially when associated with heart failure, receive the greatest
benefit from beta-blockers provided they can be closely monitored. As a class, all beta-blockers that lower resting
heart rate improve outcome. Moreover, this benefit extends to those already on ACE inhibitors.

Beta-blockers are underused in the post-MI population,5 with less than half of patients receiving long-term therapy.
However, the benefit of therapy with these drugs outweighs the risk in patients with type 1 diabetes mellitus,
chronic obstructive pulmonary disease (COPD), severe peripheral vascular disease, a PR interval > 0.24 sec and
moderate or severe heart failure (Figure 2 - Management of MI Patients After Primary PCI).5 Low-dose beta-blockers
may be safely administered in some patients with a history of asthma. The appropriate use of beta-blockers after MI
is illustrated in Figure 4 - Beta-Blockers in the Chronic Post-MI Period.

ACE Inhibitors23 , 24 , 25

ACE inhibitors improve heart failure, reduce mortality and may reduce the likelihood of a recurrent MI.5 These
agents have greater relative and absolute benefits among high-risk patients with LV dysfunction or pulmonary
congestion. Start ACE inhibitors early in all patients without contraindications post-STEMI. Long term treatment with
ACE inhibitors is recommended for patients with STEMI, with the greatest benefit conferred among the higher-risk
subgroup with previous myocardial infarction, heart failure, depressed LVEF and tachycardia.5 Among patients with
evidence of atherosclerosis or multiple risk factors, chronic use of an ACE inhibitor reduces the risk of MI.25

Angiotensin Receptor Blockers

Angiotensin receptor blockers (ARBs) have similar benefits to ACE inhibitors. A large randomized trial demonstrated
equivalence between the ACE inhibitor captopril and the ARB valsartan in MI patients with heart failure and LV
dysfunction.26 There was no advantage of combined therapy with captopril and valsartan. ARBs may be used instead
of ACE inhibitors in patients who do not tolerate the latter due to cough or angioedema. Data are accumulating to
suggest that ARBs may be used in lieu of ACE inhibitors as primary therapy, especially among patients with heart
failure or an LVEF < 40%.5

HMG CoA Reductase Inhibitors (Statins)

There is a linear relationship between LDL-C levels and cardiovascular risk. Lipid-lowering therapy to achieve a 1
mmol/L decrease in LDL-C reduces the absolute risk by 1% and relative risk by 20% over five years.27 The
pleiotropic benefits of statin therapy may extend beyond mere lipid lowering.28 Aggressive lipid lowering not only
decreases the atherosclerotic burden, but may reduce coronary events by stabilizing fragile coronary plaques.29 , 30

Recommended targets for LDL-C have become progressively lower as the safety and efficacy of cholesterol-lowering
treatment have become established. Among high-risk patients, attainment of an LDL-C < 2 mmol/L provides optimal
benefits.31 Lipid-lowering therapy should be considered for most individuals with an LDL-C of 5 mmol/L or a total
cholesterol to high-density lipoprotein cholesterol ratio (TC:HDL-C) of 6.0.31 Attainment of more aggressive targets
may require more intensive treatment with, for example, atorvastatin 80 mg/day32 or rosuvastatin 40 mg/day.

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Only 1% of patients discontinue therapy due to muscle discomfort, and there is no increase in myopathy with more
aggressive therapy.31

A small minority of patients may require additional therapy with an agent that inhibits cholesterol absorption (i.e.,
ezetimibe or a bile acid sequestrant such as cholestyramine).

Recommendations from the Canadian Cardiovascular Society Guidelines are categorized by cardiovascular risk
(Table 5).31 Starting a statin prior to discharge after an acute MI improves both early and late outcomes. The benefit
is independent of the lipid level at the start of treatment.29 , 33

Table 5: Canadian Cardiovascular Society 2006 Guidelines for Lipid-lowering Treatment

Risk Level 10-year CAD Risk Recommendations

Primary treatment target:


LDL-C < 2.0 mmol/L
High ≥ 20% Secondary treatment target:
TC:HDL-C < 4.0

Initiate treatment when:


LDL-C ≥ 3.5 mmol/L
Moderate 10–19%
TC:HDL-C ≥ 5.0

Initiate treatment when:


LDL-C ≥ 5.0 mmol/L
Low < 10%
TC:HDL-C ≥ 6.0

Adapted from McPherson R et al. Can J Cardiol 2006;22(11):913-27.31

Abbreviations: HDL-C=high-density lipoprotein cholesterol; LDL-C =low-density lipoprotein cholesterol; TC=total cholesterol

Oral Anticoagulants

Oral anticoagulants are recommended for post-MI patients with persistent or paroxysmal atrial fibrillation,
demonstrable LV thrombus, or large infarcts with extensive dyskinetic segments or aneurysm.34 , 35

All post-MI patients seem to benefit modestly from warfarin therapy with a 20% risk reduction relative to ASA in the
combined end-point of death, re-infarction or embolic stroke (ARR 3%). Moderate to high intensity anticoagulation
with warfarin, administered alone or in combination with ASA, is superior to ASA alone in reducing composite
events but is associated with a higher risk of bleeding.36 The increased risk of bleeding and the demands of
adjusting the dose to maintain the INR pre