Feldman 2015

PA55CH10-Feldman ARI 15 September 2014 12:15
Review in Advance first posted online

V I E W
E on September 22, 2014. (Changes may
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still occur before final publication
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online and in print.)
C E
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D V A
Intraclass Differences Among

Antihypertensive Drugs
R.D. Feldman,1 Y. Hussain,1 L.M. Kuyper,2
Annu. Rev. Pharmacol. Toxicol. 2015.55. Downloaded from www.annualreviews.org
F.A. McAlister,3 R.S. Padwal,3 and S.W. Tobe4

Access provided by University of Reading on 12/27/14. For personal use only.
1
Departments of Medicine and of Physiology and Pharmacology, Western University,
London, Ontario N6A 5B7, Canada; email: feldmanr@lhsc.on.ca
2
British Columbia Centre for Excellence in HIV/AIDS, St. Paul’s Hospital, University of British
Columbia, Vancouver, British Columbia V6Z 1Y6, Canada
3
Department of Medicine, University of Alberta, Edmonton, Alberta T6G 2G3, Canada
4
Department of Aboriginal and Rural Health, Northern Ontario School of Medicine,
Sudbury, Ontario P3E 2C6, Canada
Annu. Rev. Pharmacol. Toxicol. 2015. Keywords

55:10.1–10.20
hypertension, β blockers, diuretics, calcium channel blockers,
The Annual Review of Pharmacology and Toxicology
is online at pharmtox.annualreviews.org angiotensin-converting enzyme inhibitors, angiotensin receptor blockers
This article’s doi: Abstract
10.1146/annurev-pharmtox-010814-124446
The four major classes of antihypertensive drugs—diuretics, β blockers,
Copyright c 2015 by Annual Reviews.
All rights reserved calcium channel blockers, and renin-angiotensin system inhibitors (includ-
ing angiotensin-converting enzyme inhibitors and angiotensin receptor
blockers)—have significant qualitative and quantitative differences in the ad-
verse effects they cause. Structural and chemical differences have been iden-
tified within these classes, especially among the calcium channel blockers
and, to a lesser extent, among the thiazide/thiazide-like diuretics. However,
it has been more difficult to demonstrate that these differences translate into
differential effects with respect to either the surrogate endpoint of blood
pressure reduction or, more importantly, to hypertension-related cardiovas-
cular complications. Based on a hierarchy-of-evidence approach, differences
are apparent between hydrochlorothiazide and chlorthalidone based on ev-
idence of moderate quality. Low-quality evidence suggests atenolol is less
effective than other β blockers. However, no significant intraclass differences
have been established among the other classes of antihypertensive drugs.
10.1
Changes may still occur before final publication online and in print
THE HIERARCHY OF EVIDENCE FOR ESTABLISHING INTRACLASS

DIFFERENCES AMONG DRUGS
High blood pressure (BP) is a key modifiable risk factor for premature death and disability (1),
with two-thirds of strokes and half of myocardial infarctions attributed to suboptimal BP control
(2). A plethora of randomized trials have clearly established that effective BP treatment prevents
atherosclerotic cardiovascular events (3–5). With little evidence for outcome differences among an-
tihypertensive drug classes (4–6), investigators are increasingly focusing their attention on whether
there are intraclass differences among antihypertensive agents. A drug class is defined as a group
of drugs having a similar chemical structure and mechanism of action; however, whether all drugs
in a class confer similar effects on biological and clinical outcomes (class effects) or whether some
drugs within a class are superior or inferior to the others is a frequent point of debate. If all drugs
within a class exert the same effect, then the choice of agent can be based on side-effect profiles,
convenience, cost, and the potential for drug-drug interactions with the patient’s other therapies.
The purpose of this brief review is to outline the basis for determining whether there are
intraclass differences and how this might be applied to the consideration of within-class distinctions
for the four major classes of antihypertensive therapies {i.e., β adrenergic blockers [β-blockers],
calcium channel blockers, diuretics, and renin-angiotensin system (RAS) inhibitors [angiotensin-
converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)]}.
Table 1 presents a hierarchy for weighing the evidence from comparative effectiveness studies
to determine whether one or more drugs within a class are superior or whether all drugs exhibit
the same class effect (7). We reference clinically important outcomes in this table: These are not
the same for all comparisons and depend on the condition being treated and the intervention.
In the case of therapies designed to prevent atherosclerotic events (such as antihypertensive
drugs), the highest levels of clinically important outcomes would include fatal and nonfatal
myocardial infarction, stroke, and all-cause mortality at the very least, and more recent studies
have expanded this to include outcomes such as renal failure, cognitive impairment, and new onset
heart failure. For interventions designed to treat symptomatic diseases (such as gastroesophageal
reflux), clinically important outcomes could include symptom scores or other quality of life
measures.
The highest quality of evidence for establishing or refuting intraclass differences comes from
randomized clinical trials (RCTs) with head-to-head comparisons of two or more drugs within
a class for their effects on clinically important outcomes. In hypertension, these would primar-
ily mean coronary artery disease and stroke outcomes. In addition to the usual methodological
factors that must be evaluated in judging the validity of any RCT, several additional issues must
be considered if the head-to-head RCT purports to show equivalence or noninferiority [these
are summarized in Table 1 but described in full elsewhere (8)]. Although it is well recognized
that equivalence trials require much larger sample sizes than standard trials designed to show
superiority, less well appreciated is that any laxity in trial conduct, participant compliance, or
outcome follow-up tends to mask differences between treatment arms (and thus the need to con-
duct on-treatment analyses for proper interpretation of equivalence trials). As the authors of one
systematic review pointed out when discussing the frequency of erroneous conclusions in pub-
lished equivalence RCTs, “claims of therapeutic equivalence may not be reviewed with the same
quantitative rigor” as claims of one drug’s superiority over another (9, p. 715). In hypertension, in
the context of hard-outcome trials (i.e., assessing cardiovascular disease risk reduction, e.g., stroke
and coronary artery disease risks), head-to-head RCTs within drug classes are exceedingly rare.
Especially in the therapeutic area of hypertension, where in most jurisdictions the patent rights
for these drugs have expired, it is doubtful that such RCTs will ever be launched.
10.2 Feldman et al.
Head-to-head RCTs comparing drugs of the same class for their effectiveness on validated
surrogate outcomes (such as BP levels) could provide moderate-quality evidence supporting or
refuting intraclass differences, but such trials are also becoming increasingly rare. This, in part,
relates to the current US Food and Drug Administration (FDA) requirement for new agents
within an established drug class (me-too drugs) to demonstrate efficacy in reducing hard clinical
outcomes rather than just equivalence to older drugs within the class for a surrogate such as short-
term BP reduction. The medical literature is replete with examples of agents that reduced the
levels of even-validated surrogate outcomes (such as BP, low-density lipoprotein cholesterol, or
Table 1 Hierarchy of study designs for determining within-class differences in treatment effect
Quality of Potential threats to validity that may negatively
evidence Comparison Study patients Outcomes impact quality-of-evidence rating
High Within a Identical (by Clinically Was treatment allocation concealed? Were
head-to-head RCT definition) important outcomes assessed in blinded fashion? Was there
or a systematic outcomes sufficient sample size to detect a difference? If a

review including negative study, was there adequate power such
head-to-head that the 95% CI excludes a clinically important
RCTs difference? Was analysis by intention-to-treat?
Was there adequate follow-up such that missing
data would not materially affect results? Are there
multiple RCTs with consistent results?
Additional criteria to consider if RCT purports to
show equivalence or noninferiority: Was analysis
by on-treatment as well as intention-to-treat? Was
the equivalence margin prespecified and the
appropriate null hypothesis tested? Were both
regimens applied in optimal fashion (i.e.,
equipotent doses, low cointervention rates, and
high compliance rates)? Was the active control
previously shown to be effective in patients at
similar baseline risk for these outcomes?
Moderate Within a Identical (by Validated In addition to those listed for high-quality evidence:
head-to-head RCT definition) surrogate Are the surrogate outcomes valid proxies for
outcomes clinically important outcomes [i.e., consistently
shown to be associated with clinically important
outcomes in multiple studies (observational or
RCT)? Have RCTs consistently demonstrated
that improvement in the surrogate translates into
predictable improvement in clinically important
outcomes]?
Moderate Across RCTs of Similar or Clinically In addition to those listed for high-quality evidence
different drugs different (in important (which deal with methodological quality): Is there
versus placebo, disease and/or outcomes or effect modification or interaction (i.e., drug effects
including network baseline risk) validated vary in different study populations such as men
meta-analyses that surrogate versus women, blacks versus whites, or young
do not include outcomes versus old)? What is the impact of differences
head-to-head between trials in magnitude of treatment effect,
RCTs endpoints and their definitions, baseline risks, and
cointerventions?
(Continued )
www.annualreviews.org • Antihypertensives Intraclass Differences 10.3
Table 1 (Continued )
Quality of Potential threats to validity that may negatively
evidence Comparison Study patients Outcomes impact quality-of-evidence rating
Low RCTs or systematic Similar or Nonvalidated Surrogate outcomes rarely capture all the effects
reviews different surrogate (beneficial or hazardous) of a therapeutic agent.
outcomes
Low Between Similar or Clinically Multiple potential biases exist, even if robust
nonrandomized different important methodologies such as propensity score matching
studies outcomes and multivariate regression are done. These
(observational include:
studies, including confounding by indication, compliance, and/or
pharmacoepidemi- calendar time

ologic healthy user/adherer effect
administrative unknown/unmeasured confounders

database research) For database research, have the chosen codes been
validated for the disease state/outcomes under

study? (Frequently the answer is no)
Abbreviations: CI, confidence interval; RCT, randomized clinical trial.
glycosylated hemoglobin) in the short term but failed to confer benefits (and in some cases even
caused harm) in longer-term studies.
A second form of moderate-quality evidence comes from between-study comparisons in which
treatment effect sizes between RCTs with drug A are compared with those reported with drug B
to impute the relative impact of A versus B. An indirect estimate of the association between drugs
A and B could be obtained by comparing the odds ratio (OR) [or relative risk (RR)] from studies of
drug A versus C and from studies comparing drug B versus C: ORA versus B = ORA versus C /ORB versus C
(10, 11). However, this assumes that none of the potential biases outlined in Table 1 are operative
and that an intervention’s relative efficacy is consistent across different patient subgroups (an
assumption that appears safe for antihypertensive therapy, at least within the usual range of BPs
for which these agents are prescribed) (12, 13). If there are multiple indirect comparisons (A versus
C, B versus D, C versus D, etc.), a network meta-analysis can be done to explore all potential
associations. Although results from adjusted indirect comparisons are usually similar to those of
direct comparisons, it is important to recognize that this is not always so (a recent comprehensive
examination of this topic documented significant discrepancies between the direct and adjusted
indirect estimates in 3 of 44 published meta-analyses) (14).
Finally, although we would place observational studies on the lowest rung of our evidence hier-
archy, we do recognize that such studies are often the only source of evidence available to explore
the possibility that there are intraclass differences in treatment efficacy or safety. Notwithstand-
ing this fact, and even with the increasing rigor with which such studies are now analyzed (15),
there are unavoidable pitfalls with any observational study because many potential confounders
are either unknown, immeasurable (even in primary data collection studies), or uncapturable (in
administrative data studies). Moreover, many observational studies use only baseline values and do
not adjust for variable follow-up times (raising the specter of immortal time bias), nonadherence to
prescribed therapies, crossovers, and variable cointervention rates. Also, no amount of adjustment,
restriction, or propensity matching can remove the potential biases arising from confounding by
indication (i.e., when a therapy is prescribed for sicker patients, thereby becoming a marker for
the severity or the duration of the disease in question) or the healthy user effect (i.e., the concept
10.4 Feldman et al.
that individuals who fill certain prescriptions are also more likely to pursue healthier lifestyles,
have more screening tests, etc.) (16).
The final step in judging the quality of evidence supporting or refuting within-class drug dif-
ferences is to assimilate the various studies and determine whether the high-, moderate-, and
low-quality evidence is consistent. As outlined below, we conclude that there is at least moderate-
quality evidence for within-class differences among diuretics when used to treat hypertension;
lower-quality evidence differentiating atenolol from other β-blockers; and weaker, inconsistent
evidence to support important intraclass differences for any of the other major classes of antihy-
pertensive drugs.
THIAZIDE AND THIAZIDE-LIKE DIURETICS

The very broad grouping of diuretics includes the thiazide and thiazide-like diuretics, loop
diuretics (Na-K-Cl2 cotransporter inhibitors such furosemide, torsemide, and bumetanide),

and potassium-sparing diuretics (including aldosterone antagonists such as spironolactone and

eplerenone and sodium channel blockers such as amiloride). However, our discussion is restricted
to the thiazide/thiazide-like diuretics, as this is the subclass of diuretics most commonly used and
the only subclass included among first-line antihypertensive drugs.
Thiazide Diuretics
All thiazides have a central backbone of benzothiadiazine, a bicyclic heterocyclic benzene deriva-
tive in which the heterocycle contains two nitrogen and one sulfur atoms (17). The differences
among thiazides reflect differences in side chains (17). Hydrochlorothiazide (HCTZ) is the most
commonly used member of this group (18). Other members include bendroflumethiazide, ben-
drofluazide, chlorothiazide, and cyclothiazide.
Thiazide-Like Diuretics
The thiazide-like diuretics include indapamide, chlorthalidone (CTDN), and metolazone. These
drugs do not possess the benzothiadiazine heterocycle backbone of a thiazide (17). However,
they do contain a sulphonamide moiety in common with the thiazide diuretics (17). Indapamide
contains a sulfamoyl benzamide moiety (19), and CTDN contains a benzensulfonamide moiety
(17). However, both the thiazide and thiazide-like diuretics have common mechanisms of action,
i.e., inhibition of sodium and chloride reabsorption from the distal convoluted tubule by blocking
the sodium/chloride cotransporter (symporter). Furthermore, there are no significant qualita-
tive or quantitative differences between thiazide diuretics with respect to adverse effects (insulin
resistance, hyponatremia, hypokalemia, and hyperuricemia) (18).
Comparison of the Effectiveness of Hydrochlorothiazide Versus Chlorthalidone

Currently, one of the key questions in hypertension pharmacotherapy faced by clinicians and
guideline developers is whether there are intraclass differences for diuretics. Although there is
some indirect evidence on the effectiveness and safety of indapamide (18), research on this class
has mainly focused on the evidence hierarchy with respect to comparative effectiveness studies of
HCTZ and CTDN.
As noted above, head-to-head studies for hard clinical outcomes are lacking for thiazides;
however, there are some studies evaluating differences in the validated surrogate endpoint of BP
lowering to support intraclass differences. In terms of the duration of antihypertensive action,

HCTZ has been shown to have a significantly shorter duration of action compared with CTDN
(20, 21). Notably, a systematic review exploring the therapeutic index and bioequivalent doses for
HCTZ versus CTDN has been recently published (22).
A network meta-analysis of three HCTZ and six CTDN RCTs (in which the comparator
drugs were ACE inhibitors or calcium channel blockers for both diuretics) demonstrated that
CTDN appears to provide better control of BP and substantially more reduction in the frequency
of cardiovascular events than HCTZ [indirect estimate of RR for total cardiovascular events in
patients randomized to CTDN versus HCTZ 0.79, 95% confidence interval (CI) 0.72–0.88],
even when the results were adjusted for differences in achieved BP (estimated RR 0.82, 95% CI
0.70–0.97) (23). This is moderately strong evidence in favor of CTDN over HCTZ.
Two recently published observational studies have compared different diuretics for the treat-
ment of hypertension. Although a propensity score–matched analysis of elderly new diuretic users
did not find any difference in the rate of death or hospitalization for stroke, heart failure, or my-
ocardial infarction for CTDN users compared to HCTZ users [adjusted hazard ratio (aHR) 0.93,
95% CI 0.81–1.06] (24), a secondary analysis (25) of participants in the Multiple Risk Factor Inter-
vention Trial (MRFIT) that used a more robust adjustment for multiple time-varying covariates
including BP levels, smoking status, and laboratory values demonstrated significantly fewer first
cardiovascular events in those treated with CTDN compared with HCTZ (aHR 0.79, 95% CI
0.68–0.92). These differing results serve to highlight the fact that sample size is less important in
observational studies than robustness of covariate adjustment—the first study was nearly 5-fold
larger but was based on administrative data and thus did not have access to the same rich clin-
ical data as the MRFIT analysis. In summary, there is at least moderate-quality evidence for a
within-class difference between HCTZ and CTDN when used to treat hypertension.
RENIN-ANGIOTENSIN SYSTEM INHIBITORS

RAS inhibition is a well-established, efficacious treatment to lower BP and improve outcomes in
patients with hypertension, cardiovascular disease, diabetes, and chronic kidney disease (26–30).
Angiotensin II exerts diverse systemic actions, including stimulation of aldosterone production,
sodium and water retention, sympathetic nervous system activity, thirst, and arginine vasopressin
release (31). Angiotensin II also exhibits prothrombotic and lipolytic actions and stimulates cardiac
cell hypertrophy, fibrosis, apoptosis, inflammation, and endothelial dysfunction (32, 33). These
actions are primarily mediated through stimulation of the angiotensin II receptor type 1 (AT1 re-
ceptor) (32). Here, we focus on clinically related issues regarding the intraclass differences between
ACE inhibitors and between ARBs. In-depth reviews of pharmacokinetic and pharmacodynamic
intraclass differences between ACE inhibitors and ARBs have been published elsewhere (34, 35).
Angiotensin Converting Enzyme Inhibitors

ACE inhibitors reduce BP by inhibiting production of angiotensin II and increasing bradykinin
levels (36). Captopril, the first orally administered ACE inhibitor, was approved for use in 1981 and
is limited by a short half-life, which necessitates administration three times daily (37). Captopril-
specific adverse effects (e.g., neutropenia, rash, and metallic taste disturbances), related to the
drug’s sulfhydryl moiety, were also problematic (37). This sulfhydryl moiety was substituted with
a phosphinyl group in fosinopril and a carboxyl group in all other agents (38). Newer drugs were
also formulated as prodrugs to increase bioavailability and were longer acting to facilitate once-
daily administration (Table 2). Enalaprilat, another ACE inhibitor, can be used intravenously (39).
10.6 Feldman et al.
Table 2 Angiotensin-converting enzyme inhibitorsa

Usual daily dose Active Predominant
Drug (mg) Half-life (h)b Prodrug Metabolism metabolite elimination route
Benazepril 10–80 in 1–2 10–11, terminal Yes Hepatic Yes Urine and feces
doses 22
Captopril 50–150 in 3 doses 1.9 No Hepatic No Urine
Cilazapril 2.5–5.0 in 1 dose 36–49 Yes Hepatic Yes Urine
Enalapril 10–40 in 1–2 11 Yes Hepatic Yes Urine
doses
Fosinopril 10–40 in 1 dose 12 Yes Hepatic Yes Urine and feces
Lisinopril 10–40 in 1 dose 12 No None No Urine
Moexipril 7.5–30 in 1–2 2–9 Yes Hepatic Yes Urine and feces
doses
Perindopril 2–8 in 1 dose 3–10, terminal Yes Hepatic Yes Urine

30–120
Ramipril 2.5–20 in 1–2 13–17, terminal Yes Hepatic Yes Urine
doses >50
Quinapril 10–40 in 1 dose 1.9–2.5, 25 Yes Hepatic Yes Urine
terminal
Trandolapril 1–4 in 1 dose 15–24 terminal Yes Hepatic Yes Urine and feces
a
Data from Lexicomp R
.
b
For prodrugs, reflects the half-life of the active metabolite.
Trough-to-peak ratios, a measure of the uniformity of 24-h BP control, are highest (indicating
more uniform control) with perindopril, trandolapril, ramipril, and fosinopril (40).
Ramipril was the first ACE inhibitor to be studied for its effects on cardiovascular risk re-
duction in patients at high risk for future cardiovascular events but without heart failure or left
ventricular dysfunction. In the landmark Heart Outcomes Prevention Evaluation (HOPE) study,
9,297 subjects with established vascular disease or diabetes plus another cardiovascular risk factor
were randomized to ramipril 10 mg daily versus placebo (29). Notably, over half (52%) of the
study population was normotensive, and the mean baseline BP was 139/79 mm Hg. After a mean
follow-up time of 5 years, the incidence of the primary composite outcome (myocardial infarction,
stroke, or cardiovascular death) was 14.0% in the ramipril arm versus 17.8% for placebo (RR 0.78,
95% CI 0.70 to 0.86) (29).
The HOPE trial generated considerable debate as to whether the results were attributable to
ramipril therapy alone or generalizable to other ACE inhibitors (i.e., a class effect) (41). Contempo-
raneous studies revealed the existence of local (nonrenal) RAS systems in the vascular endothelium,
adrenal glands, brain, adipose tissue, and other organs (33). ACE inhibitors with high tissue pene-
tration, such as ramipril, quinapril, and benazepril, were postulated to have theoretical advantages
over other ACE inhibitors because of greater and longer-lasting RAS inhibition within tissues
(33, 42). Another controversy generated primarily from the HOPE trial was whether the observed
benefits of ACE inhibition were due to BP reduction alone or the result of BP-independent effects
as improvements in endothelial dysfunction or atherosclerosis regression (42, 43). Researchers
also debated whether these putative BP-independent effects were solely attributable to ramipril
or represented a class effect (44).
Although the placebo-subtracted office BP reductions in the main HOPE trial were very small
(3/1 mm Hg), a small 24-h ambulatory BP monitoring substudy conducted in 38 subjects with
Table 3 Angiotensin II receptor blockersa

Usual daily dose Active Predominant
Drug (mg) Half-life (h) Metabolism metabolite elimination route
Azilsartan 40–80 in 1 dose 11 In intestinal wall to Yes Feces (55%) and
active compound urine (42%)
Candesartan 8–32 in 1–2 doses 5–9 In intestinal wall to Yes Urine
active compound
Eprosartan 400–800 in 1–2 5–9 Minimal hepatic No Feces
doses
Irbesartan 150–300 in 1 dose 11–15 Hepatic, primarily via No Feces
CYP2C9
Losartan 50–100 in 1–2 2 (6–9 for active Hepatic, primarily via Yes Urine
doses metabolite) CYP2C9 and 3A4
Olmesartan 20–40 in 1 dose 13 In intestinal wall to Yes Feces (50–65%) and

active compound urine (35–50%)

Telmisartan 40–80 in 1 dose 24 Hepatic via conjugation No Feces
Valsartan 80–320 in 1–2 6 Minimal hepatic No Feces
doses
a
Data from Lexicomp
R
.
peripheral vascular disease reported placebo-subtracted BP reductions of 10/4 mm Hg (P = 0.03)

(45). Furthermore, a meta-regression analysis of over 62,000 patients from 27 RCTs, including the
HOPE trial, examining the relationship between BP reduction and cardiovascular event reduction
concluded that reductions in risk were explained by achieved differences in BP (46). In addition,
subsequent randomized trials and meta-analyses demonstrated that other RAS blockers (ACE
inhibitors and ARBs) exhibited similar reductions in cardiovascular morbidity and mortality in
similar populations to those studied in the HOPE trial (47–49). Thus, a class effect for ACE
inhibition in terms of global vascular risk reduction is now widely accepted to be present, and the
observed benefits are primarily due to BP reduction. Overall, with respect to hypertension and
hypertension-related complications, there is insufficient evidence to suggest intraclass differences
of any clinical significance for ACE inhibitors.
Angiotensin Receptor Blockers

ARBs, which block the AT1 receptor, have indications similar to ACE inhibitors (26, 30, 47).
Losartan, approved for use in 1985, was the original drug in its class (50). It has a relatively
short half-life compared to other ARBs (Table 3) and is converted in the liver to E-3174, a 40-
fold more potent active metabolite (50). Longer-acting ARBs such as irbesartan and telmisartan
reduce trough or ambulatory systolic BP levels by 2–5 mm Hg more than losartan (51, 52).
Unlike other ARBs, losartan is uricosuric, an effect that appears secondary to reduction in
urate reabsorption through inhibition of urate transporter 1 (53). Losartan use, which has been
consistently shown to reduce uric acid levels by 20–25%, reduced the risk of gout compared to
nonlosartan use in a population-based case-control study of over 28,000 primary care patients
in the United Kingdom (RR 0.81, 95% CI 0.70–0.94) (54). Uric acid has been independently
associated with incident cardiovascular disease, but this has not been a consistent finding and
may be secondary to its association with more traditional cardiovascular risk factors (55). Thus,
the broader significance of losartan’s uric acid–lowering effect relative to other ARBs in terms of
10.8 Feldman et al.
cardiovascular event reduction is unclear in the absence of active comparison trials powered to
examine cardiovascular events.
Much attention has focused on AT1 receptor–independent effects of ARBs and, in particular,
the peroxisome proliferator-activated receptor γ partial agonist activity of telmisartan and irbesar-
tan (34). Small clinical trials have reported that telmisartan improves glycemic control, increases
adiponectin levels, and reduces visceral fat to a greater extent than other ARBs (including irbe-
sartan) (56–58). A population-based retrospective cohort study of nearly 55,000 subjects reported
that telmisartan significantly reduced the risk of hospitalization for myocardial infarction, stroke,
or heart failure relative to irbesartan (aHR 0.85, 95% CI 0.74–0.97) (59). However, valsartan was
also associated with reduced risk (aHR 0.86, 95% CI 0.77–0.95). No rigorous RCT data have
been published to date demonstrating the superiority of telmisartan over other ARBs in reducing
cardiovascular events or mortality.
An association between olmesartan therapy and increased cardiovascular mortality was found
in two large, placebo-controlled RCTs examining renal disease progression in patients with type
2 diabetes (60, 61). In both, the absolute number of events was low (<20 in each trial), and
cardiovascular mortality was not the primary endpoint. In an observational study of 45,185 ARB
users, no robust signal for harm was seen with olmesartan relative to other ARBs (62). Olmesartan
has also been associated with an increased risk of sprue-like enteropathy, prompting an FDA-
mandated warning label (63). The FDA is currently monitoring both adverse effects, and further
study is warranted (63, 64). However, with respect to considerations of both effectiveness and
safety, there is insufficient evidence at present to suggest intraclass differences of any clinical
significance for ARBs.
β-BLOCKERS
Intraclass Differences Between β-Adrenergic Receptor Blockers

β-Adrenergic receptor blocking agents (β-blockers) are associated with significant improvements
in cardiovascular outcomes in various conditions including recent myocardial infarction, heart
failure, and angina (65–67). For many years, β-blockers were a mainstay of therapy for primary
hypertension, although more recent evidence points to their lack of efficacy compared with other
antihypertensive agents, particularly among hypertensives older than age 60 (68, 69). It remains
unclear whether this represents a true age-related lack of benefit or intraclass differences between
β-blockers (and the overrepresentation of a single β-blocker of lesser efficacy, i.e., atenolol; see
below), although recent studies have examined this problem (70).
Mechanism of Action: Antihypertensive and Adverse Effects

β-Blockers are known to reduce brachial BP to a similar degree as other antihypertensive agents
(71). Most β-blockers do not reduce central aortic pressure to the same degree as other antihyper-
tensive agents (71), and they do not improve the vascular remodeling that occurs in long-standing
hypertension (72).
The major antihypertensive effects of β-blockers are largely related to their β-1 adrenoceptor–
blocking properties. β-1 Adrenoceptors predominate in the heart and juxtaglomerular cells of the
kidney (73). Blockade of these adrenoceptors reduces heart rate and myocardial contractility,
thereby lowering cardiac output (74); decreases nodal conduction; and inhibits renin release (75).
The cardiac effects of β-blockers distinguish them from most other antihypertensive drugs that
act primarily by reducing peripheral vascular resistance.
Table 4 β-Adrenergic receptor blocking agentsa

Intrinsic
Usual daily dose Lipophilic/ sympathomimetic β-1 Peripheral
Drug (mg) Half-life (h) hydrophilic activity Selectiveb vasodilation
Acebutolol 200–800 3–4 Moderate Yes + No
od/bid
Atenolol 25–100 6–9 Low No + No
Bisoprolol 2.5–10 9–12 Moderate No ++ No
Carvedilol 3.125–50 bid 7–10 Moderate No 0 Yes
Labetalol 200–800 3–4 Low Yes + Yes
Metoprolol 12.5–100 bid 3–4 High No ++ No
Nadolol 40–320 12–24 Low No 0 No
Nebivolol 2.5–5 8–27 Moderate No +++ Yes
Pindolol 10–40 bid 3–4 High Yes 0 No

Propranolol 40–180 bid 3–4 High Yes 0 No
Abbreviations: bid, bis in die (twice daily); od, omne in die (once daily).
a
Data reprinted from references 79 and 123.
b
0, none; +, minimal; ++, moderate; +++, extensive.
In contrast, many of the unfavorable effects of β-blockers, both in their antihypertensive profile
and adverse effects, relate to β-2 adrenoceptor blockade. β-2 Receptors exist in the lungs, vascular
smooth muscle, liver, pancreas, and thyroid (73). Acute β-2 blockade leads to contraction of vas-
cular smooth muscle and has been shown to increase peripheral vascular resistance, characteristic
of most, but not all, β-blockers (69). After chronic use, however, total peripheral resistance may
decrease to pretreatment values (74), which possibly relates to the longer-term effect of inhibition
of renin release (75). β-2 Blockade also leads to bronchoconstriction and adverse changes in lipid
and glucose metabolism (76, 77). New-onset diabetes is a well-known adverse effect of β-blocker
use, one that is not associated with antihypertensive agents other than diuretics (78).
Classification of β-Blockers
Differences between β-blockers that may influence therapeutic effectiveness in the treatment
of hypertension and reduction of hypertension-related cardiovascular complications include:
(a) pharmacokinetic considerations including lipophilicity, half-life, and bioavailability—factors
that impact variability in drug dosing and duration of effectiveness; (b) β-adrenoceptor subtype se-
lectivity; (c) intrinsic sympathomimetic activity; and (d ) vasodilator effects. Table 4 (79) illustrates
differences among common β-blockers with regards to pharmacokinetic profiles, lipophilicity,
intrinsic sympathomimetic activity, selectivity, and vasodilatory properties. However, the signif-
icance of any of these intraclass differences regarding either effectiveness or safety has not been
demonstrated.
Intraclass Differences Between β-Blockers in Extent of Blood Pressure

Reduction and in Adverse Effects
Earlier clinical trials that compared older-generation β-blockers to each other and other antihy-
pertensive agents demonstrated similar brachial BP lowering efficacy (80, 81). More recent studies
10.10 Feldman et al.
comparing older and newer β-blockers have reported similar brachial BP lowering efficacy, but
newer agents (nebivolol) lower central pulse pressure more than older agents (atenolol) (82, 83).
Furthermore, older β-blockers may produce more side effects than newer agents. Most β-blockers,
especially atenolol, increase the risk of new-onset diabetes (78); however, vasodilating β-blockers
may not worsen glycemic control or triglyceride levels, and they may improve microalbuminuria,
particularly in the setting of RAS blockade (81).
Efficacy of β-Blockers in Treatment of Hypertension: Focus on Intraclass

Differences as the Basis for the Variable Effectiveness of β-Blockers in
Reducing Blood Pressure–Related Cardiovascular Complications
For many years, β-blockers were recommended as first-line therapy for primary hypertension in
international guidelines (84, 85), and they continue to be recommended for secondary prevention
in hypertensives with concomitant heart disease (86). Early placebo trials demonstrated β-blocker
efficacy in reducing stroke (87) and mortality (88). The Metoprolol Atherosclerosis Prevention
in Hypertensives (MAPHY) trial published in 1991 demonstrated significantly fewer total and
cardiovascular deaths when metoprolol was compared with thiazide diuretics (89), and this was
attributed to lower mortality related to coronary heart disease and stroke. However, other studies
reported no differences in cardiovascular endpoints when β-blockers were compared with di-
uretics, which challenged the view that β-blockers provided cardioprotective benefits over other
agents. The Heart Attack Primary Prevention in Hypertension (HAPPHY) trial demonstrated
no difference in coronary heart disease events, strokes, or death when atenolol or metoprolol was
compared with thiazide diuretics (90).
Later reports cast serious doubt on the use of β-blockers in hypertension, although the initial
focus was on efficacy in older populations. The Medical Research Council trial in 1992 found no
significant reductions in cardiovascular endpoints when atenolol was compared with placebo in
hypertensives aged 65–74, whereas HCTZ and amiloride significantly reduced strokes and car-
diovascular events (91). More recently, β-blocker-induced reductions in heart rate have been in-
versely correlated with worse cardiovascular outcomes in hypertensives without other compelling
indications for β-blocker use (92).
Messerli et al. (69) performed a meta-analysis in 1998 that demonstrated the inferiority of β-
blockers compared with diuretics in terms of all cardiovascular endpoints in hypertensives over age
60. In 2002, when β-blockers were still considered first-line therapy for hypertension, the Losartan
Intervention For Endpoint (LIFE) trial compared an atenolol-based regimen to a losartan-based
regimen in 9,193 hypertensive individuals with left ventricular hypertrophy and demonstrated a
13% reduction in the primary endpoint of death, myocardial infarction, or stroke in the losartan
group compared with the atenolol group (93). The Anglo-Scandinavian Cardiac Outcomes Trial
(ASCOT) examined whether a combination of newer antihypertensive agents would be more
efficacious than a traditional regimen of β-blockers and diuretics in 19,257 hypertensives with at
least 3 other cardiovascular risk factors. The participants who took amlodipine with perindopril
if needed had fewer nonfatal myocardial infarctions and fatal coronary events than those who
received atenolol with bendroflumethiazide if needed (94). A meta-analysis in 2005 demonstrated
a 16% increased risk of stroke in 105,951 hypertensives across 13 trials when β-blockers were
compared with other antihypertensive agents; the report concluded that all β-blockers should be
avoided as first-line treatment in primary hypertension (95).
Based on these observations, many international guidelines for hypertension treatment now
exclude β-blockers as first-line agents unless there are other compelling indications, although
these recommendations are variable (86, 96, 97). Interestingly, recent reports have suggested that
β-blockers may be as efficacious in reducing death, stroke, or myocardial infarction as other anti-
hypertensive agents in younger hypertensives but not in hypertensives older than 60 years (68, 70).
Other studies suggest that newer β-blockers may be effective at reducing cardiovascular outcomes
in primary hypertension and suggest that the observed lack of benefit of β-blockers in the past has
been attributed to the overrepresentation of atenolol in clinical trials (91, 93, 94, 98), which could
be less efficacious than other β-blockers (79). Lindholm et al. (95) proposed that all β-blockers
should be avoided in primary hypertension; their meta-analysis of all β-blockers compared with
other agents demonstrated inferiority in reducing stroke and a trend toward increased mortal-
ity. When these authors compared atenolol alone with other antihypertensive agents, they found
higher stroke and mortality rates. However, when comparing only nonatenolol β-blockers with
non-β-blocking agents, there was equivalent efficacy in preventing stroke and myocardial infarc-
tion and reducing mortality (95). It remains unclear whether there are cardiovascular benefits of
some β-blockers, particularly those with vasodilating properties, such as nebivolol and carvedilol,
and further RCTs examining cardiovascular outcomes would be needed to investigate this.
In summary, low-quality data suggest that atenolol may not perform as well as other β-blockers.
However, beyond that, no compelling data exist to suggest intraclass differences of any clinical
significance for β-blockers.
CALCIUM CHANNEL BLOCKERS

Calcium channel blockers include three main subclasses: the dihydropyridines, the phenylalky-
lamines, and the benzothiazepines (99). The class was initially named calcium antagonists by
Fleckenstein (100) after his discovery in 1964 that verapamil could diminish calcium-dependent
cardiac contractile forces. Later, in 1969, researchers recognized that inhibition of transmem-
brane calcium flux through antagonism of the calcium channels by verapamil, nifedipine, and
diltiazem led to suppression of vasoconstriction, particularly in coronary arteries, and vasodilation
of peripheral resistance vessels, with the greatest vasodilation caused by nifedipine (101). These L-
type calcium currents require depolarization for activation and are blocked by the L-type calcium
channel blockers (102). By the early 1970s, BP lowering effects as well as chronotropic effects,
specifically for diltiazem and verapamil, were noted. In a 1983 review on the subject, Fleckenstein
(100) laments that the name change from calcium antagonists to calcium channel blockers, as he
felt that true blockade of transmembrane calcium entry would be incompatible with life.
Calcium channel blockers were first approved for use in the United States in 1982 and were
first recommended for use by the Joint National Committee IV hypertension guidelines of 1988
(103). The use of these agents for hypertension management visits in the United States increased
dramatically from 1.9% of visits in 1985 to 39.8% in 1995 (103). This led to concern that this
newer but more expensive class of agent was being overused before there were any data available
demonstrating the benefit of RCTs showing reductions of cardiovascular events and mortality.
Also, researchers recognized that the shorter-acting calcium antagonists were associated with an
increased risk of cardiovascular events, and as a result, the clinical practice for BP management
switched to longer-acting agents and drug delivery capsules designed to provide stable 24-h dos-
ing (104). Many clinical trials in hypertensives using long-acting versions of all three subclasses
of calcium channel blockers followed and demonstrated their safety and efficacy in preventing
cardiovascular morbidity and mortality (see below). In 1996, Pahor et al. (105) studied a small
cohort of patients and reported a trend toward an increased risk of cancer with calcium channel
blockers. However, a case-control study of almost 10,000 patients with cancer found that calcium
channel blockers were unrelated to an increase in overall cancer risk (106). After losing patent
protection, the cost of calcium channel blockers has fallen significantly. All major clinical practice
Table 5 Clinical pharmacology of commonly used calcium channel blockers

Effect of grapefruit juice
Extent of P450 on peak plasma drug
Calcium CYP3A4 Half-life Bioavailability Dosing concentration (fold
channel blocker Agent metabolisma,b (h)c (%)c frequency increase)a
Dihydropyridines Amlodipine + 33.8 64 od 1.2
Felodipine +++ 10.2 16 bid 2.5
Nicardipine +++ 11.5 15–40 od 1.3–1.5
Nifedipine ++ 3.4 45 qidd 1.0–1.9
Nisoldipine +++ 15.4 3.9 od 4.1
Benzothiazepines Diltiazem ++ 5.7 39 qidd Nonee
Phenylalkylamines Verapamil ++ 5.7 24 qidd 2.4e
Abbreviations: bid, bis in die (twice daily); od, omne in die (once daily); qid, quater in die (four times daily).
a
Data adapted from Reference 124.
b
+, minimal; ++, moderate; +++, extensive
c
d
Unless in slow-release capsule, then od.
e
guidelines groups in the world now recommend calcium channel blocker use in the management
of hypertension (107, 108).
Table 5 lists the most commonly available calcium channel blockers, but this list is not ex-
haustive. In Eastern Asia, for example, the following dihydropyridine calcium channel blockers
are available on the market and recommended for the management of hypertension: azelnidipine,
barnidipine, benidipine, cilnidipine, efonidipine, isradipine, lacidipine, lercanidipine, manidipine,
nilvadipine, and nitrendipine (109). The dihydropyridines in particular are metabolized by the
cytochrome P450 system CYP3A4 and can interfere with the metabolism of other agents or be
affected by the ingestion of CYP3A4 inhibitors such as grapefruit juice (110). Diltiazem is less
affected, and amlodipine is the least affected (111). Given the short half-lives of most of the agents
[amlodipine being the notable exception (112)], dosing must be frequent in the absence of the ad-
ministration of longer-acting versions based either on use of gastric films and microencapsulation
delivery systems (as for diltiazem) or for formulation in Alza minipump delivery systems (as for
nifedipine).
In regards to cardiac safety, only verapamil and diltiazem delay atrioventricular conduction
and have negative inotropy (113). Calcium channel blockers are often combined together with
other agents, and there is a synergy of effectiveness, as described in the Wald meta-analysis below.
Because of their negative chronotropic effects, combination of diltiazem with β-blockers must be
done cautiously, and combination with verapamil should be avoided. Diltiazem or verapamil can
be added to the dihydropyridines for greater effectiveness, possibly through higher drug levels,
but these combinations are associated with edema in at least 25% of patients (113).
Calcium channel blocker–related edema is common, is particularly associated with dihydropy-
ridine calcium channel blockers (114), and rises with drug dosage (115). The edema results from
a reduction in arteriolar resistance that does not occur on the venous side, leading to increased
interstitial pressure and fluid shifts into the interstitium (115). The edema is not associated with
salt and water retention, as calcium channel blockers are natriuretic. ACE inhibitors may improve
edema by causing vasodilation on the venous side. Notably, treatment with a thiazide diuretic
may also have some benefit but is not recommended. Calcium channel blocker–induced edema is
more common in women, the elderly, and after spending more time upright. It is improved by
reducing the dose or by switching from a dihydropyridine calcium channel blocker to diltiazem
or verapamil. Edema related to the use of calcium channel blockers continues to be a common
complaint for patients. No significant differences in frequency of peripheral edema have been
established between the available dihydropyridine calcium channel blockers.
Studies of calcium channel blocker efficacy in patients with hypertension have shown com-
parable effects in regards to hard outcomes. The Systolic Hypertension in Europe (Syst-Eur)
Trial evaluated patients with isolated systolic hypertension age 60 and above with therapy starting
with nitrendipine compared to placebo and found a 42% reduction of all stroke and 31% reduc-
tion of all cardiovascular endpoints (116). A Chinese trial on isolated systolic hypertension had a
similar methodology and was also placebo controlled and used nitrendipine; these investigators
found reductions in total mortality, stroke, and in all cardiovascular endpoints (117). Outcomes
studies comparing calcium channel blockers to other agents include the Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) in 33,357 hypertensives

age 55 and over with one other risk factor, which demonstrated that amlodipine provided equal
cardiovascular protection when compared to a thiazide diuretic (CTDN) and an ACE inhibitor
(lisinopril) (118). Diltiazem (initially as a short-acting and then a longer-acting preparation) was as
effective as treatments based on diuretics, β-blockers, or both in the Nordic Diltiazem (NORDIL)
study (119). Verapamil (sustained release) was found to be as clinically effective as an atenolol-
HCTZ-based strategy in the International Verapamil-Trandolapril Study (INVEST) (120). In
the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial,
verapamil (controlled-onset, extended-release) was compared to atenolol or HCTZ. Although the
study was stopped early because there were far fewer endpoints than planned, verapamil was as
clinically effective as the comparator group. In the CONVINCE study, the ability of verapamil
to inhibit platelet aggregation led to more bleeding and reduced myocardial infarction incidence
(121). Large meta-analyses have confirmed these findings.
Calcium channel blockers have demonstrated efficacy in reducing cardiovascular disease in
hypertension equal to the other recommended agents, including thiazide diuretics, ACE inhibitors,
ARBs, and β-blockers, but appear to have added efficacy for stroke prevention (5). Calcium channel
blockers, when combined in low doses with these recommended agents, lower BP more than is
observed when any of these agents are used in isolation at a doubled dose (122).
Overall, there are significant differences in adverse effects between the subclasses of calcium
channel blockers, especially in regards to cardiac effects and peripheral edema. However, there are
no significant interclass differences among the dihydropyridine calcium channel blockers. More
importantly, in regards to effectiveness—both for BP reduction and for reduction of hypertension-
related cardiovascular risks—there is little evidence to suggest intraclass differences of any clinical
significance.
CONCLUSIONS
Despite a wide range of chemical structures and mechanisms of actions, the major antihypertensive
drug classes show remarkably few differences in effectiveness, although there are broad differences
in patterns of adverse effects. Within classes, the strongest evidence for intraclass differences is
among the thiazide/thiazide-like diuretics. Longer-acting agents, especially CTDN, demonstrate
moderate-quality evidence for superiority compared to HCTZ. Lower-quality evidence suggests
that atenolol may demonstrate inferior effectiveness relative to other β-blockers. There is little
evidence to suggest clinically significant intraclass differences among calcium channel blockers
and among RAS inhibitors in the management of hypertension.
DISCLOSURE STATEMENT
R.D.F. has received grants and research support from Servier Canada and speaker honoraria from
Forest, and he has served as a consultant or on advisory boards for Forest, Medtronic, Novartis,
and Servier. R.S.P. has served as a site investigator for clinical trials performed by Novo Nordisk,
CVRx, and Valencia Technologies and has received honoraria for speaking or consulting from
Medtronic, Vivus, Merck, Abbott, and Servier. S.W.T. has served on advisory boards for Otsuka,
Takeda, Pfizer, Merck, and Bristol-Myers Squibb; has received speaker honoraria from Pfizer,
Merck, Amgen, Otsuka, and Takeda; and has served as a site investigator for research projects
for Abbott, AstraZeneca, Pfizer, Merck, Bristol-Myers Squibb, Sanofi-Aventis, Novartis, and Eli
Lilly. The other authors are not aware of any affiliations, memberships, funding, or financial
holdings that might be perceived as affecting the objectivity of this review.
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PA55CH10-Feldman ARI 15 September 2014 12:15

Review in Advance first posted online

still occur before final publication

Intraclass Differences Among

F.A. McAlister,3 R.S. Padwal,3 and S.W. Tobe4

Annu. Rev. Pharmacol. Toxicol. 2015. Keywords

THE HIERARCHY OF EVIDENCE FOR ESTABLISHING INTRACLASS

10.2 Feldman et al.

or a systematic outcomes sufﬁcient sample size to detect a difference? If a

www.annualreviews.org • Antihypertensives Intraclass Differences 10.3

pharmacoepidemi- calendar time

administrative unknown/unmeasured confounders

validated for the disease state/outcomes under

Abbreviations: CI, conﬁdence interval; RCT, randomized clinical trial.

10.4 Feldman et al.

THIAZIDE AND THIAZIDE-LIKE DIURETICS

diuretics (Na-K-Cl2 cotransporter inhibitors such furosemide, torsemide, and bumetanide),

and potassium-sparing diuretics (including aldosterone antagonists such as spironolactone and

Comparison of the Effectiveness of Hydrochlorothiazide Versus Chlorthalidone

www.annualreviews.org • Antihypertensives Intraclass Differences 10.5

lowering to support intraclass differences. In terms of the duration of antihypertensive action,

RENIN-ANGIOTENSIN SYSTEM INHIBITORS

Angiotensin Converting Enzyme Inhibitors

10.6 Feldman et al.

Table 2 Angiotensin-converting enzyme inhibitorsa

Perindopril 2–8 in 1 dose 3–10, terminal Yes Hepatic Yes Urine

www.annualreviews.org • Antihypertensives Intraclass Differences 10.7

Table 3 Angiotensin II receptor blockersa

Olmesartan 20–40 in 1 dose 13 In intestinal wall to Yes Feces (50–65%) and

active compound urine (35–50%)

peripheral vascular disease reported placebo-subtracted BP reductions of 10/4 mm Hg (P = 0.03)

Angiotensin Receptor Blockers

10.8 Feldman et al.

Intraclass Differences Between β-Adrenergic Receptor Blockers

Mechanism of Action: Antihypertensive and Adverse Effects

www.annualreviews.org • Antihypertensives Intraclass Differences 10.9

Table 4 β-Adrenergic receptor blocking agentsa

Pindolol 10–40 bid 3–4 High Yes 0 No

Propranolol 40–180 bid 3–4 High Yes 0 No

Intraclass Differences Between β-Blockers in Extent of Blood Pressure

10.10 Feldman et al.

Efficacy of β-Blockers in Treatment of Hypertension: Focus on Intraclass

www.annualreviews.org • Antihypertensives Intraclass Differences 10.11

CALCIUM CHANNEL BLOCKERS

10.12 Feldman et al.

Table 5 Clinical pharmacology of commonly used calcium channel blockers

www.annualreviews.org • Antihypertensives Intraclass Differences 10.13

Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) in 33,357 hypertensives

10.14 Feldman et al.

www.annualreviews.org • Antihypertensives Intraclass Differences 10.15

for hydrochlorothiazide, chlorthalidone, and bendroﬂumethiazide on blood pressure, serum potassium,

10.16 Feldman et al.

ambulatory and ofﬁce blood pressures: a HOPE substudy. Hypertension 38:E28–32

www.annualreviews.org • Antihypertensives Intraclass Differences 10.17

systematic review and meta regression analysis. BMJ 318:1730

10.18 Feldman et al.

www.annualreviews.org • Antihypertensives Intraclass Differences 10.19

10.20 Feldman et al.

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