TRIALS

Ma. Arnee V. Anico-Tondo, M.D., FPCP

CHAPTER 8: Principles of Cardiovascular Genetics

CHAPTER 11: The History and Physical Examination: An Evidence-Based Approach

CHAPTER 24: Diagnosis and Management of Acute Heart Failure

 First large, randomized, double-blind trial to prospectively compare diuretic

strategies in AHF
 308 patients were randomly assigned to treatment with intravenous furosemide
DOSE TRIAL using either twice-daily bolus dosing or a continuous infusion and to either a low-
dose (equivalent to the numerical value of the oral outpatient dose given IV) or
high-dose (2.5 times the oral dose given IV) strategy
 No differences were found in results between the continuous infusion and
intermittent bolus
suggesting that whichever approach is most likely to reliably produce the desired
diuresis in the particular local clinical practice should be used

CHAPTER 25: Management of Patients with Heart Failure with Reduced Ejection Fraction

ARIC (Atherosclerosis Risk in Co
mmunities) study
MESA (Multi-Ethnic Study of
Atherosclerosis) study
FAIR-HF trial
(Ferinject Assessment in Patients
with Iron Deficiency and Chronic
Heart Failure)
RED-HF trial
(Reduction of Events with
Darbepoetin Alfa in Heart Failure)
1 arnee anico-tondo2018  “ad miorem dei gloriam”
 Age-adjusted incidence of HF was greatest in black men, followed by black women,
white men, and white women
 Higher incidence of HF in blacks was attributed to the greater levels of
atherosclerosis risk factors in this population
 Blacks had the highest risk for development of HF, followed by Hispanic, white, and
Chinese Americans
 Correction of iron deficiency in patients with NYHA class II or III HF using
intravenous iron (ferric carboxymaltose) improved self reported patient global
assessment and NYHA functional class (as well as 6-minute walk distance and health-
related quality of life)
 Treatment of patients with HF who have mild to moderate anemia (hemoglobin
levels 9.0 to 12.0 g/dL) with the erythropoietin analog darbepoetin alfa was
evaluated
 No significant difference in the primary outcome variable of death from any cause or
hospitalization for worsening HF in the darbepoetin alfa group or in the secondary

HF-ACTION
(A Controlled Trial Investigating
Outcomes of Exercise Training) trial
RALES trial
Randomized Aldactone Evaluation
Study
EMPHASIS-HF trial
Eplerenone in Mild Patients
Hospitalization and Survival Study in
Heart Failure
DOSE study
(Diuretic Optimal Strategy
Evaluation in Acute Heart Failure)
Relief for Acutely Fluid-Overloaded
Patients With Decompensated
Congestive Heart Failure (RAPID-
CHF) trial
Ultrafiltration versus IV Diuretics for
Patients Hospitalized for Acute
Decompensated Congestive Heart
Failure (UNLOAD)
CARRESS trial
(Cardiorenal
Rescue Study in Acute
Decompensated HF)
Studies on Left Ventricular
Dysfunction
(SOLVD) prevention study
Survival and Ventricular Enlargement
(SAVE)
2 arnee anico-tondo2018  “ad miorem dei gloriam”
outcome
 Lack of effect of darbepoetin alfa was consistent across all prespecified subgroups
 Hemoglobin level, like other HF surrogate endpoints, may be a prognostic marker,
with decreased levels correlated with poor prognosis, rather than an HF therapeutic
target
 Failed to show a significant improvement in all-cause mortality or all-cause
hospitalization in patients who received a 12-week (three times a week) exercise
training program followed by 25- to 30-minute home-based, self monitored exercise
workouts, 5 days/week, on a treadmill or stationary bicycle
 Trend toward decreased cardiovascular mortality or HF related hospitalizations was
observed, however, and quality of life was significantly improved in the exercise
group
 Adding the mineralocorticoid-receptor antagonist spironolactone to recommended
therapy in patients with systolic heart failure (EF <35%) and moderate-to-severe
symptoms (i.e.,[NYHA] functional class III or IV symptoms) decreased the rate of
death from any cause and the risk of hospitalization for cardiovascular reasons
 2737 patients with New York Heart Association class II heart failure and an ejection
fraction of no more than 35% to receive eplerenone (up to 50 mg daily) or placebo,
in addition to recommended therapy
 Eplerenone, as compared with placebo, reduced both the risk of death and the risk
of hospitalization among patients with systolic heart failure and mild symptoms
 Showed no significant difference in symptoms or renal function when patients with
acute decompensated HF were treated with an intravenous bolus of furosemide
compared with an intravenous infusion of furosemide
 Suggesting that whichever approach is most likely to reliably produce the desired
dieresis should be used
 First randomized controlled trial of ultrafiltration for acute decompensated HF
 Enrolled 40 patients, randomly assigned to receive either usual care (diuretic) or a
single 8-hour ultrafiltration procedure in addition to usual care
 Primary endpoint was weight loss 24 hours after enrolment
 Fluid removal after 24hours was approximately twice that for the ultrafiltration
group
 Long-term safety and efficacy of ultrafiltration therapy compared with intravenous
diuretics in a multicenter trial involving 200 patients, who were assessed at entry
and at intervals out to 90 days
 Primary endpoint was total weight loss during the first 48 hours of random
assignment and the change in dyspnea score during the first 48 hours of
randomization
 Although the two treatments were similar in their ability to relieve dyspnea,
ultrafiltration was associated with significantly greater fluid loss over 48 hours and
a lower rate of rehospitalization during the next 90 days
 Use of ultrafiltration in high-risk patients who are developing the cardiorenal
syndrome was explored
 Showed that ultrafiltration resulted in similar weight loss but resulted in an
increase in creatinine levels, compared to standard care, and was associated with
more serious adverse events and intravenous catheter-related complications
 Shown that asymptomatic patients with LV dysfunction are less likely to develop
symptomatic HF and to require hospitalizations for HF when treated with an ACE
inhibitor
 Trandolapril Cardiac Evaluation
(TRACE)
Vasodilator in Heart Failure II (V-
HeFT-II) trial
Candesartan Heart Failure:
Assessment
of Reduction in Mortality and
Morbidity trial
(CHARM-Alternative Trial)
CHARM-Added trial
Valsartan Heart
Failure Trial
(Val-Heft)
Losartan Heart Failure Survival Study
(ELITE-II)
Valsartan in Acute
Myocardial Infarction Trial (VALIANT)
Heart Failure Endpoint Evaluation of
Angiotensin II
Antagonist Losartan
(HEAAL)
Metoprolol in Dilated
Cardiomyopathy
(MDC) trial
Metoprolol CR/XL Randomized
Intervention Trial in Congestive
Heart
Cardiac Insufficiency Bisoprolol
Study I
(CIBIS-I) trial
CIBIS-II bisoprolol
CIBIS-III trial
3 arnee anico-tondo2018  “ad miorem dei gloriam”
 ACE inhibitors improve the natural history of HF through mechanisms other than
vasodilation
 Subjects treated with enalapril had significantly lower mortality than subjects treated
with the vasodilatory combination of hydralazine plus isosorbide dinitrate
 Candesartan significantly reduced all-cause mortality, cardiovascular death or
hospital admission for CHF
 When given in addition to ACE inhibitors in general cohorts of patients with
symptomatic HF, the effects of ARBs were shown to have a modest beneficial effect
 Addition of valsartan to ACE inhibitors had no beneficial effect on mortality,
although combined endpoint mortality and morbidity was significantly (13.2%)
lower with valsartan than with placebo because of a reduction in the number of
patients hospitalized for HF
 Direct comparison of ACE inhibitor and ARBs was assessed
 Losartan was not associated with improved survival in elderly patients with HF
when compared with captopril but was significantly better tolerated
 Valsartan was shown to be noninferior to captopril on all-cause mortality
 Combination of captopril and valsartan produced no further reduction in mortality
although the number of adverse events increased
 Question of high-dose versus low dose angiotensin receptor antagonism in clinical
outcomes was evaluated
 High-dose losartan was not associated with a significant reduction in the primary
endpoint of all-cause death or hospital admission for HF when compared with low-
dose losartan but was associated with a significant reduction in HF admissions
 Used the shorter-acting tartrate at a target dose of 50 mg three times a day in
patients with symptomatic HF with idiopathic dilated cardiomyopathy
 Benefit was due entirely to a reduction by metoprolol in the morbidity component of
the primary endpoint, with no favorable trends in the mortality component of the
primary endpoint
 Risk reduction of 34% reduction in mortality in subjects with mild to moderate HF
and moderate to severe systolic dysfunction when compared with the placebo group
reduced mortality from both sudden death and progressive pump failure
 Mortality was reduced across most demographic groups, including older versus
younger subjects, non-ischemic versus ischemic etiology, and lower versus higher EF
 Examined the effects of bisoprolol on mortality in subjects with symptomatic
ischemic or non-ischemic cardiomyopathy
 Showed a non significant 20% risk reduction for mortality at 2-year follow-up
evaluation

 Reduced all-cause mortality by 32% , sudden cardiac death by 45%, HF
hospitalizations by 30%, and all-cause hospitalizations by 15%

 Whether an initial treatment strategy using the beta blocker bisoprolol noninferior to
a treatment strategy of using an ACE inhibitor (enalapril) first
 Primary endpoint analysis of death or rehospitalization did not meet the pre-
specified criteria for non-inferiority
 Intent-to-treat analysis showed that bisoprolol was noninferior to enalapril

Current guidelines continue to recommend starting with an ACE inhibitor first, with the subsequent addition of a beta blocker
Australia-
New Zealand Heart Failure Research
Collaborative Group Carvedilol
Trial (ANZ-Carvedilol)
Carvedilol
Prospective Randomized Cumulative
Survival (COPERNICUS) study
Carvedilol Post-Infarct Survival
Controlled Evaluation (CAPRICORN)
trial
Carvedilol or Metoprolol European
Trial (COMET)
On the basis of the results of the COMET study, short-acting metoprolol tartrate is not recommended for use in the treatment
Beta-Blocker Evaluation of Survival
Trial
(BEST)
Study of Effects of Nebivolol
Intervention on Outcomes
and Rehospitalization in Seniors
with Heart Failure (SENIORS)
Randomized Aldactone
Evaluation Study
(RALES) trial
Eplerenone in
Mild Patients Hospitalization and
Survival Study in Heart Failure
(EMPHASIS-HF) trial
4 arnee anico-tondo2018  “ad miorem dei gloriam”
 Did not provide clear-cut evidence to justify starting with a beta blocker first
 Showed a significant improvement in LVEF and a significant reduction in LV end-
diastolic volume index in the carvedilol-treated group at 12 months, as well a
significant relative risk reduction of 26% in the clinical composite of death and
hospitalization for the carvedilol group at 19 months
 Rates of hospitalization also were significantly lower for patients treated with
carvedilol (48%) compared with placebo (58%)
 Patients with advanced HF symptoms had to be clinically euvolemic and have an LV
EF less than 25%
 When compared with placebo, carvedilol reduced the mortality risk at 12 months by
38% and the relative risk of death or HF hospitalization by 31%
 Designed to test the long-term effectiveness of carvedilol for reducing morbidity
and mortality in patients with LV dysfunction after MI already treated with ACE
inhibitors
 Although carvedilol did not reduce the prespecified primary endpoint of mortality
plus cardiovascular hospitalization, it did significantly reduce total mortality by
23%), cardiovascular mortality by 25%, and nonfatal MI by 41%
 Carvedilol (target dose 25 mg twice daily) was compared with immediate-release
metoprolol tartrate (target dose 50 mg twice daily) with respect to the primary
endpoint of all-cause mortality associated with a significant 33% reduction in all-
cause mortality when compared with metoprolol tartrate (33.9% versus 39.5%)
of HF
 Evaluated the third-generation beta-adrenergic blocking agent bucindolol, which is a
completely non-selective beta1 and beta2 blocker with some alpha1 receptor
blockade properties
 A nonsignificant 10% reduction in total mortality was noted in the bucindolol
treated group, whereas a statistically significant 19% reduction in mortality was
observed in white patients
 Differential response to bucindolol has been suggested to be secondary to a
polymorphism (arginine 389) in the beta1-adrenergic receptor that is more prevalent
among whites
 Nebivolol significantly reduced the composite outcome of death and cardiovascular
hospitalizations, which was the primary endpoint of the trial, but did not reduce
mortality
 Evaluated spironolactone (25 mg/day initially, titrated to 50 mg/day for signs of
worsening HF) versus placebo in NYHA class III or IV HF patients with an LVEF below
35%, who were being treated with an ACE inhibitor, a loop diuretic, and in most
cases digoxin
 Administration of spironolactone led to a 30% reduction in total mortality when
compared with placebo
 Frequency of hospitalization for worsening HF also was 35% lower in the
spironolactone group than in the placebo group
 Gynecomastia was reported in 10% of men who were treated with spironolactone,
as compared with 1% of men in the placebo group
 Performed in patients with NYHA class II HF with an EF below 30% (or 35% if the
QRS width was more than 130 milliseconds)
 Demonstrated that eplerenone (titrated to 50 mg/day) led to a significant 27%
decrease in cardiovascular death or HF hospitalization
 Significant decreases also were observed in all-cause death (24%), cardiovascular

Eplerenone Post-Acute Myocardial
Infarction Heart Failure Efficacy
and Survival
(EPHESUS) study
On the basis of the results of the RALES and EMPHASIS-HF trials, aldosterone antagonists currently are recommended for all
patients with persistent NYHA class II to IV symptoms and an EF less than 35%, despite treatment with an ACE inhibitor (or an
ARB if an ACE inhibitor is not tolerated) and a beta blocker
Systolic Heart
Failure Treatment with the If
Inhibitor Ivabradine Trial (SHIFT)
(BEAUTIFUL) trial
Aliskiren Trial
on Acute Heart Failure Outcomes
(ASTRONAUT)
ATMOSPHERE study
(Efficacy and Safety of Aliskiren
and Aliskiren/Enalapril Combination
on Morbi-mortality in Patients
with Chronic Heart Failure)
Randomized Assessment of
Digoxin and Inhibitors of
Angiotensin-Converting Enzyme
(RADIANCE)
Prospective Randomized Study of
Ventricular Function
and Efficacy of Digoxin (PROVED)
Digoxin Investigator
Group (DIG) trial
GISSI-HF (Gruppo Italiano
5 arnee anico-tondo2018  “ad miorem dei gloriam”
death (24%), all-cause hospitalization (23%), and HF hospitalizations (43%)
 Background therapy for EMPHASIS-HF included ACE inhibitors or ARBs and beta
blockers
 Evaluated the effect of eplerenone (titrated to a maximum of 50 mg/day) on
morbidity and mortality among patients with acute MI complicated by LV
dysfunction and HF
 Treatment with eplerenone led to a 15% decrease in all-cause death
 Enrolled symptomatic patients with an LVEF of 35% or less who were in sinus
rhythm with heart rate of 70 beats/min or higher and on standard medical therapy
for HF (including beta blockers)
 Ivabradine (uptitrated to a maximal dosage of 7.5 mg twice daily) reduced the
primary composite outcome of cardiovascular death and HF hospitalization
 More than 10,000 patients with coronary heart disease and an EF below 40% were
randomly assigned to treatment with ivabradine 7.5 mg twice daily or placebo
 Although this trial did not meet its primary endpoint of reducing cardiovascular
death, MI, or HF hospitalization, the drug was well tolerated in this patient
population
 Patients with an LVEF of 40% or less and elevated natriuretic peptide (BNP) of 400
pg/mL or higher or NT-proBNP of 1600 pg/mL or greater) who were being discharged
from the hospital after admission for an acute decompensated HF
 Primary endpoint was cardiovascular death or HF rehospitalization at 6 months
 No significant difference in the primary endpoint was observed in the aliskiren
treated group compared with patients treated with standard medical therapy for HF
at 6 months or at 12 months
 In patients with chronic heart failure, the addition of aliskiren to enalapril led to more
adverse events without an increase in benefit
 Non-inferiority was not shown for aliskerin as compared with enlapril
 Provided strong support for clinical benefit of digoxin
 In these studies, worsening HF and increased HF hospitalizations were more
common among patients who were withdrawn from digoxin than among those who
were maintained on digoxin (page 534)
 Digoxin had a neutral effect on the primary endpoint of mortality, reduced
hospitalizations (including 30-day readmissions for HF) and favorably affected the
combined endpoints of death and hospitalization for worsening HF
 Mortality was directly related to the digoxin serum level
 In men, trough levels between 0.6 and 0.8 ng/mL were associated with decreased
mortality, suggesting that trough levels of digitalis should be maintained between 0.5
and 1.0 ng/mL
 There is also evidence that digoxin may be potentially harmful in women
 In a post hoc multivariable analysis of the DIG trial, digoxin was associated with a
significantly higher risk (23%) of death from any cause among women, but
not men, possibly because of the relatively lower body weights in women
 Long-term administration of 1 g/day of omega n-3 PUFAs resulted in a significant
 per lo Studio della Sopravvivenza
nell’Insufficienza Cardiaca Heart
Failure)
In view of the small treatment effect of n-3 PUFAs, they are not endorsed by current practice guidelines
STICH (Surgical Treatment for
Ischemic Heart
Failure) trial
WARCEF (Warfarin Versus Aspirin in
Reduced Cardiac Ejection Fraction)
trial
AF-CHF (Atrial Fibrillation and
Congestive
Heart Failure) study
ANDROMEDA trial
(European Trial of Dronedarone in
Moderate to Severe Congestive
Heart Failure)
CHAPTER 34: Diagnosis of Cardiac Arrhythmias
CAST
(Cardiac Arrhythmia Suppression
Trial)
CHAPTER 42: Risk Markers and the Primary Prevention of Cardiovascular Disease
Trial of Preventing Hypertension
(TROPHY)
Hypertension in the Very Elderly
Trial (HYVET)
ACCORD
6 arnee anico-tondo2018  “ad miorem dei gloriam”
reduction in both all-cause mortality and all-cause mortality and cardiovascular
admissions
 Showed that CABG did not reduce all-cause death which was the primary endpoint
of the trial but did reduce a composite endpoint of cardiovascular death, death from
any cause, and hospitalization for cardiovascular causes
 Results of STICH suggest that CABG is beneficial in patients with HF of ischemic
etiology who are otherwise suitable candidates for surgery
 Whether patients with HF who are in sinus rhythm should be treated with
anticoagulants to reduce stroke was addressed in this study
 Based on the results, there is no compelling reason to use warfarin rather than
aspirin in patients with HFrEF who are in sinus rhythm
 Did not show a difference in a composite of clinical outcomes when a strategy of
strict rate control (<80 beats/ min at rest and <110 beats/min during a 6-minute
walk) was compared with lenient rate control
 With the recognition that sustained tachycardia can lead to a cardiomyopathy,
atrioventricular node ablation and cardiac resynchronization therapy (CRT) have
been suggested for control of ventricular rate in extreme cases of a rapid
ventricular response with atrial fibrillation
 Had to be terminated prematurely because of a twofold increase in mortality in the
dronedarone-treated patients with HF
 Excess mortality was predominantly related to worsening of HF
 As a result of this study, dronedarone is contraindicated in patients with NYHA class
IV HF, or those with NYHA class II or III HF who have had a recent episode of HF-
related decompensation
(Patients after MI) PVCs identified patients at increased risk for sudden death but that
successful suppression of PVCs with flecainide, encainide, or moricizine was associated
with increased mortality in comparison to placebo
Support the feasibility of drug treatment of pre hypertension to prevent progression to
hypertension
Treatment of this growing patient population (older than 80 years of age) with a
diuretic and an ACE inhibitor if needed was both safe and effective, reducing not only
the risk of heart failure and death from stroke but also that of death from any cause
 Evaluated the potential benefits of targeting a systolic blood pressure level below
120 mm Hg versus a level below 140 mm Hg in 4733 patients with type 2 diabetes.
 After a mean of 4.7 years, the annual rate of the primary outcome, a composite of
rates of nonfatal myocardial infarction, nonfatal stroke, and death from
(Action to Control CardiovascularRisk
in Diabetes) trial
cardiovascular causes did not differ significantly between groups.
 The intensive therapy group experienced fewer strokes but more frequent serious
adverse events attributable to blood pressure problems.
 The investigators concluded that the evidence did not justify a systolic blood
pressure target below 120 mm Hg in patients with type 2 diabetes





CHAPTER 43: Systemic Hypertension: Mechanisms and Diagnosis

 Randomized, double-blind, placebo-controlled study of carotid baroreceptor pacing

in patients with drug-resistant hypertension
 265 patients with resistant hypertension and baseline blood pressure averaging
169/101 mm Hg (despite treatment of most patients with five or more blood
pressure medications) underwent implantation of the Rheos device
 Subsequently random assignment (2:1) 1 month after implantation to immediate
initiation of bilateral carotid baroreceptor pacing (group A) or delayed initiation
until the 6-month visit (group B)
 All patients received open-label baroreceptor pacing for another 6 months
RHEOS PIVOTAL TRIAL  Results were largely negative, but mixed
 No group differences at 6 or 12 months in the co primary endpoints of percentage
of subjects in whom systolic blood pressure decreased by at least 10 mm Hg (54%
for group A and 46% for group B; P = NS); and 9% of patients developed transient
or permanent facial nerve injury
 Post-hoc analysis showed that 42% of group A patients and 24% of group B
patients achieved systolic blood pressure control (systolic blood pressure ≤ 140 mm
Hg) at 6 months (P = 0.005), with just over 50% of both groups achieving systolic
blood pressure control at 12 months (at which point group B had received
baroreceptor pacing for 6 months).
 The reduction in blood pressure associated with a small initial decrease in
estimated glomerular filtration rate (eGFR)
 106 non-U.S. patients with drug-resistant hypertension and baseline blood pressure
of 178/97 mm Hg despite treatment with an average of five or more blood pressure
medications randomly were assigned to undergo renal denervation while continuing
Symplicity HTN-2 trial previous drug therapy or to continue previous drug therapy alone
(Renal Denervation in Patients with  Primary endpoint was the change from baseline in seated office-based measurement
Uncontrolled Hypertension) of systolic blood pressure at 6 months
 Office-based blood pressure fell dramatically by 32/12 mm Hg in the active treatment
group, versus no change in the control group. The 24-hour ambulatory blood pressure,
measured in less than half of patients, fell less dramatically: by 11/7 mm Hg in the
active treatment group, versus no change in the control group
Symplicity HTN-1 trial  88 patients show impressive sustained reductions in office blood pressure averaging
−36/−14 mm Hg, but ambulatory blood pressure was not assessed

7 arnee anico-tondo2018  “ad miorem dei gloriam”

 CHAPTER 45: Lipoprotein Disorders and Cardiovascular Disease

CHAPTER 49: Coronary Blood Flow and Myocardial Ischemia

CHAPTER 52: STEMI Management

CAPTIM Reported a trend toward a lower mortality rate in patients with STEMI who received
(Comparison of primary Angioplasty prehospital fibrinolysis than in those who received primary PCI, especially if they were
and Pre-hospital fibrinolysis In acute treated within 2 hours of the onset of symptoms
Myocardial infarction) trial

CHAPTER 53:Non-ST Elevation Acute Coronary Syndromes

CHAPTER 54: Stable Ischemic Heart Disease

 Did not reveal an additional benefit of lowering systolic blood pressure below 120
ACCORD-BP study mm Hg in persons with type 2 diabetes mellitus as compared with lowering blood
pressure to less than 140 mm Hg
VA-HIT  Demonstrated the efficacy of gemfibrozil treatment in patients with low HDL
(Veterans cholesterol (≤40 mg/dL) without elevations in LDL cholesterol (≤140 mg/dL) or
Affairs High-Density Lipoprotein triglyceride levels (mean, 160 mg/dL) and who were not treated with a statin.
Cholesterol Intervention Trial)  Gemfibrozil resulted in a 6% increase in HDL cholesterol and a 31% decrease in
triglyceride levels, and these changes were associated with a 24% reduction in
death, nonfatal MI, and stroke
 Randomized trial of extended-release niacin versus placebo in 3414 patients with atherosclerotic vascular disease who had
low baseline levels of HDL (<40 mg/dL for men; <50 mg/dL for women) and well-controlled LDL cholesterol values (<70 mg/dL)
while taking a statin, with or without ezetimibe
- Found NO INCREMENTAL clinical benefit of the addition of niacin to statin therapy during a mean 3-year follow-up
Heart Protection Study 2  Secondary prevention trial involving 25,673 IHD patients
(Treatment of HDL to Reduce the  Reported no significant reduction in a composite of major vascular events during a
Incidence of Vascular Events) mean 4 years of treatment with simvastatin combined with extended-release
niacin and laropiprant, a prostaglandin D2 receptor-1 antagonist used to retard

8 arnee anico-tondo2018  “ad miorem dei gloriam”


CAPRIE trial
(Clopidogrel versus Aspirin in
Patients at Risk of Ischaemic Events)
CHARISMA
(Clopidogrel for High
Atherothrombotic Risk and Ischemic
Stabilization Management and
Avoidance) trial
cutaneous flushing during niacin therapy, as compared with statin based therapy
alone
 Randomized comparison between clopidogrel and aspirin in patients with
established atherosclerotic vascular disease
 Treatment with clopidogrel resulted in a modest 8.7% relative reduction in the risk
for vascular death, ischemic stroke, or MI (P = 0.043) over a period of 2 years
 Showed no overall benefit of the addition of clopidogrel to aspirin with
respect to the primary endpoint of cardiovascular death, MI, or stroke over a
median of 28 months in patients with clinically evident cardiovascular disease (n =
12,153) or in asymptomatic subjects with multiple risk factors

CHAPTER 57: Disease OF Aorta

CHAPTER 58: Peripheral Artery Disease

Two international registries have detected a high prevalence of concomitant CAD and cerebrovascular disease in patients
with PAD
REACH  62% of the patients had either or both coronary and cerebrovascular disease
(Reduction of  Approximately 25% of the patients with PAD had a history of MI, 30% had angina, 16%
Atherothrombosis for had a previous stroke, and 15% had a previous transient ischemic attack
Continued Health) registry
AGATHA  Approximately 50% of the patients with PAD had established CAD and 50% had previous
(A Global stroke, transient ischemic attack, or carotid artery revascularization
Atherothrombosis
Assessment) registry
ACCF/AHA PAD guidelines and the European Society of Cardiology (ESC) PAD guidelines recommend that patients with PAD
receive diet and drug therapy to achieve a target LDL cholesterol level of 100 mg/dL or less
Heart Protection Study Lipid-lowering therapy with simvastatin reduced the risk for adverse cardiovascular outcomes
by 25% in patients with atherosclerosis, including more than 6700 patients with PAD
TREADMILL TRIAL  Atorvastatin (80 mg) increased pain-free walking distance by more than 60% versus a
(Treatment of Peripheral 38% increase with placebo
Atherosclerotic Disease with
Moderate or Intensive Lipid
Lowering)
FIELD study Fenofibrate reduced the risk for minor amputation, primarily in patients who did not have
(Fenofibrate and Event known PAD
Lowering Intervention in
Diabetes)
ACCF/AHA PAD guidelines recommend that patients with PAD receive advice to stop smoking and comprehensive smoking
cessation instruction, including behavior modification and pharmacologic treatment
ACCORD STUDY  Intensive glucose control versus placebo did not reduce the primary composite
(Action to Control Cardiovascular endpoint of nonfatal MI, nonfatal stroke, or cardiovascular death but it did increase the
Risk in Diabetes) risk for death and decreased the risk for nonfatal MI, which were secondary outcome
measures

9 arnee anico-tondo2018  “ad miorem dei gloriam”

 ADVANCE STUDY  Intensive glucose control did not affect macrovascular events, including death
(Action in Diabetes and Vascular
Disease: Preterax and Diamicron
Modified Release Controlled
Evaluation)
VADT  Intensive glucose control did not affect the primary composite endpoint of MI, stroke,
(Veterans Affairs Diabetes cardiovascular death, congestive heart failure, revascularization, and amputation for
Trial) ischemic gangrene
PROactive study  Assessed the effect of pioglitazone versus placebo on a broad range of cardiovascular
(Prospective endpoints in patients with type 2 diabetes and established atherosclerosis, including
Pioglitazone Clinical Trial in CAD, cerebrovascular disease, and PAD, and found no significant benefit of pioglitazone
Macrovascular Events) on the primary outcome
 In patients with no PAD at baseline, composite primary and secondary event rates were
lower with pioglitazone than with placebo treatment.
 In the PAD patients, however, pioglitazone did not affect these cardiovascular events
UKPDS  Intensive treatment with sulfonylureas or insulin associated with a 15% reduction in MI
(United Kingdom Prospective but no decrease in the incidence of PAD
Diabetes Study) of patients with
type 2 diabetes mellitus
Current guidelines variably recommend that patients with PAD and diabetes be treated with glucose-lowering agents to
achieve a hemoglobin A1c level of either less than 6.5% or less than 7.0%
ACCORD study  Showed no difference in cardiovascular outcomes between intensive antihypertensive
of patients with diabetes at therapy to achieve a systolic blood pressure of less than 120 mm Hg and standard
high risk for cardiovascular therapy to a target systolic blood pressure of less than 140 mm Hg
events
ADVANCE trial  Treatment with perindopril and indapamide lowered blood pressure and reduced
macrovascular and microvascular events, including death from cardiovascular disease
 It is not known whether antihypertensive therapy limits the progression of PAD
HOPE study  Angiotensin-converting enzyme inhibitor ramipril decreased the risk for vascular
(Heart Outcomes death, MI, or stroke by 22%
Prevention Evaluation)  Forty-four percent of the patients enrolled in the HOPE trial had evidence of PAD, as
manifested by an ABI lower than 0.9
ONTARGET  Included patients with vascular disease or diabetes, the effect of telmisartan and
(Ongoing Telmisartan Alone and in ramipril on the composite endpoint of cardiovascular death, MI, stroke, or
Combination with hospitalization for heart failure was similar
Ramipril Global Endpoint Trial)  More than 13% of the patients in ONTARGET had PAD
 Current recommendations are that patients with PAD and hypertension receive blood pressure–lowering agents to achieve
a target blood pressure of 140/90 mm Hg or lower
POPADAD trial  Aspirin did not decrease the risk for a composite primary endpoint that included
(Prevention death from coronary heart disease or stroke, nonfatal MI or stroke,
of Progression of Arterial Disease or amputation above the ankle for critical limb ischemia
and Diabetes)
of asymptomatic PAD
(the Aspirin for Asymptomatic  Of the 3350 participants with an ABI of 0.95 or lower, aspirin (100 mg daily) did not
Atherosclerosis trial) significantly reduce vascular events more than placebo did
CAPRIE trial  Compared clopidogrel with aspirin for efficacy in preventing ischemic events in
(Clopidogrel versus Aspirin in patients with recent MI, recent ischemic stroke, or PAD.
Patients at Risk of  Overall, an 8.7% reduction in relative risk for MI, ischemic stroke, or vascular death was
Ischemic Events) reported in the group treated with clopidogrel
 Notably, among the 6452 patients in the PAD subgroup, clopidogrel treatment reduced
adverse cardiovascular events by 23.8%

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 CHARISMA trial  Compared the efficacy of dual antiplatelet therapy consisting of clopidogrel plus
(Clopidogrel for High aspirin with aspirin alone in patients with established CAD, cerebrovascular disease, or
Atherothrombotic PAD, as well as in patients with multiple atherosclerotic risk factors
Risk and Ischemic Stabilization,  Overall, dual antiplatelet therapy produced no significant benefit over aspirin alone on
Management, and Avoidance) the primary efficacy endpoint, a composite of MI, stroke, or cardiovascular death.
 Among the 3096 patients with PAD in the CHARISMA trial, dual antiplatelet therapy
reduced rates of MI and hospitalization for ischemic events
CASPAR trial  Combination of clopidogrel and aspirin versus aspirin alone did not affect the primary
(Clopidogrel and AcetylSalicylic composite endpoint of graft occlusion, revascularization, amputation, or death in
acid in Peripheral ARtery) patients undergoing below-knee bypass surgery for PAD
TRA2°P-TIMI 50 trial  Vorapaxar, a novel antagonist of protease-activated receptor-1, a receptor present on
platelets, endothelium, and vascular smooth muscle, reduced the risk for MI, stroke,
and cardiovascular death by 12% in patients with established atherosclerosis, including
previous MI, stroke, or PAD
 Among the patients with PAD in the study, vorapaxar significantly reduced the rates of
hospitalization for acute limb ischemia and peripheral artery revascularization
WAVE trial  Compared combination antiplatelet and oral anticoagulant therapy with antiplatelet
(Warfarin Antiplatelet Vascular therapy alone in patients with PAD
Evaluation)  The two treatments did not differ significantly in the primary composite endpoint of
MI, stroke, or cardiovascular death, but life-threatening bleeding occurred more
frequently in patients receiving combination antiplatelet and anticoagulant therapy
 Current guidelines recommend that symptomatic patients with PAD be treated with an antiplatelet drug, such as aspirin or
clopidogrel, to reduce adverse cardiovascular events
 Oral anticoagulation with warfarin is not recommended to reduce cardiovascular events in patients with PAD because it is no
more effective than antiplatelet therapy and confers a higher risk for bleeding
CLEVER trial  Of patients with iliac artery stenosis, supervised exercise training improved mean walking
(Claudication Exercise time more than endovascular intervention did, and both were more effective than optimal
versus Endoluminal medical therapy; however, quality-of-life measures improved more in the endovascular
Revascularization) intervention group

 Current guidelines recommend that patients with intermittent claudication undergo supervised exercise rehabilitation as
initial therapy
 Supervised exercise training should consist of 30- to 60-minute sessions at least three times per week for a minimum of 12
weeks

CHAPTER 63: Valvular Heart Disease

CHAPTER 73: Pulmonary Embolism

Atherosclerosis Risk in Communities (ARIC)
Study
JUPITER study (Justification for the Use of
Statin in Prevention: An Intervention Trial
 Concentrations of high-sensitivity C-reactive protein (hsCRP) above the 90th
percentile were associated with an increased risk of VTE, compared with
lower hsCRP percentiles
 43% reduction in symptomatic VTE among an initially healthy cohort of
17,802 subjects with asymptomatic elevation of baseline hsCRP levels who

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 Evaluating Rosuvastatin)
Worcester Venous Thromboembolism Study
(A population-based study of the clinical
epidemiology of VTE)
were treated with rosuvastatin 20 mg daily
 Principal postulated mechanism of action is rosuvastatin’s anti
inflammatory effect, evidenced by its reduction of hsCRP levels
23% had undergone surgery and 36% had been hospitalized within the
preceding 3 months. Among those patients, fewer than half had received
anticoagulant prophylaxis. More than half of VTE events occurred in
subjects who were 65 years of age or older

CHAPTER 74: Pulmonary Hypertension

CHAPTER 83: Rheumatic Fever

In the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study
(EPHESUS),3 the selective mineralocorticoid-receptor antagonist eplerenone, added to
recommended medical therapy, reduced the rates of death from any cause and hospitalization for
cardiovascular reasons among patients with acute myocardial infarction complicated by left
ventricular systolic dysfunction and heart failure.

12 arnee anico-tondo2018  “ad miorem dei gloriam”