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Feldman 2015
Feldman 2015
S
online and in print.)
C E
I N
A
D V A
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
10.1
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The purpose of this brief review is to outline the basis for determining whether there are
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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.
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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
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head-to-head RCT definition) important outcomes assessed in blinded fashion? Was there
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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
database research) For database research, have the chosen codes been
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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
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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 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).
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did not find any difference in the rate of death or hospitalization for stroke, heart failure, or my-
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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.
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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
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a
Data from Lexicomp
R
.
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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
Annu. Rev. Pharmacol. Toxicol. 2015.55. Downloaded from www.annualreviews.org
in two large, placebo-controlled RCTs examining renal disease progression in patients with type
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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
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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.
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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).
in hypertensives with concomitant heart disease (86). Early placebo trials demonstrated β-blocker
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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
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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,
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and further RCTs examining cardiovascular outcomes would be needed to investigate this.
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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.
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Abbreviations: bid, bis in die (twice daily); od, omne in die (once daily); qid, quater in die (four times daily).
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a
Data adapted from Reference 124.
b
+, minimal; ++, moderate; +++, extensive
c
Data adapted from Reference 125.
d
Unless in slow-release capsule, then od.
e
Data adapted from Reference 126.
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
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PA55CH10-Feldman ARI 15 September 2014 12:15
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
Annu. Rev. Pharmacol. Toxicol. 2015.55. Downloaded from www.annualreviews.org
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.
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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.
Annu. Rev. Pharmacol. Toxicol. 2015.55. Downloaded from www.annualreviews.org
LITERATURE CITED
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1. Lawes CMM, Vander Hoorn S, Rodgers A. 2008. Global burden of blood-pressure-related disease, 2001.
Lancet 371:1513–18
2. Lawes CMM, Vander Hoorn S, Law MR, Elliott P, MacMahon S, Rodgers A. 2006. Blood pressure and
the global burden of disease 2000. Part II: estimates of attributable burden. J. Hypertens. 24:423–30
3. Wang JG, Staessen JA, Franklin SS, Fagard R, Gueyffier F. 2005. Systolic and diastolic blood pressure
lowering as determinants of cardiovascular outcome. Hypertension 45:907–13
4. Turnbull F, Neal B, Ninomiya T, Algert C, Arima H, et al. 2008. Effects of different regimens to lower
blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised
trials. BMJ 336:1121
5. Law MR, Morris JK, Wald NJ. 2009. Use of blood pressure lowering drugs in the prevention of cardio-
vascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective
epidemiological studies. BMJ 338:b1665
6. Fretheim A, Odgaard-Jensen J, Brørs O, Madsen S, Njølstad I, et al. 2012. Comparative effectiveness
of antihypertensive medication for primary prevention of cardiovascular disease: systematic review and
multiple treatments meta-analysis. BMC Med. 10:33
7. McAlister FA, Laupacis A, Wells GA, Sackett DL. 1999. Users’ guides to the medical literature: XIX.
Applying clinical trial results: B. Guidelines for determining whether a drug is exerting (more than) a
class effect. JAMA 282:1371–77
8. McAlister FA, Sackett DL. 2001. Active-control equivalence trials and antihypertensive agents. Am. J.
Med. 111:553–58
9. Greene WL, Concato J, Feinstein AR. 2000. Claims of equivalence in medical research: Are they sup-
ported by the evidence? Ann. Intern. Med. 132:715–22
10. Bucher HC, Guyatt GH, Griffith LE, Walter SD. 1997. The results of direct and indirect treatment
comparisons in meta-analysis of randomized controlled trials. J. Clin. Epidemiol. 50:683–91
11. Jansen JP, Fleurence R, Devine B, Itzler R, Barrett A, et al. 2011. Interpreting indirect treatment com-
parisons and network meta-analysis for health-care decision making: report of the ISPOR task force on
Indirect Treatment Comparisons Good Research Practices: part 1. Value Health 14:417–28
12. Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH, et al. 1990. Blood pressure, stroke, and coronary
heart disease: part 2, short-term reductions in blood pressure: overview of randomised drug trials in their
epidemiological context. Lancet 335:827–38
13. McAlister FA. 2002. Commentary: Relative treatment effects are consistent across the spectrum of
underlying risks . . . usually. Int. J. Epidemiol. 31:76–77
14. Song F, Altman DG, Glenny AM, Deeks JJ. 2003. Validity of indirect comparison for estimating efficacy
of competing interventions: empirical evidence from published meta-analyses. BMJ 326:472
15. Floyd JS, Psaty BM. 2012. Observational comparative effectiveness studies of drug therapies: high-quality
answers or important clinical questions? Arch. Intern. Med. 172:1412–14
Changes may still occur before final publication online and in print
PA55CH10-Feldman ARI 15 September 2014 12:15
16. Shrank WH, Patrick AR, Brookhart MA. 2011. Healthy user and related biases in observational studies
of preventive interventions: a primer for physicians. J. Gen. Intern. Med. 26:546–50
17. Beyer KH, Baer JE. 1961. Physiological basis for the action of newer diuretic agents. Pharmacol. Rev.
13:517–62
18. Tamargo J, Segura J, Ruilope LM. 2014. Diuretics in the treatment of hypertension. Part 1: thiazide and
thiazide-like diuretics. Expert Opin. Pharmacother. 15:527–47
19. Mroczek WJ. 1983. Indapamide: clinical pharmacology, therapeutic efficacy in hypertension, and adverse
effects. Pharmacotherapy 3:61–67
20. Ernst ME, Carter BL, Goerdt CJ, Steffensmeier JJG, Phillips BB, et al. 2006. Comparative antihy-
pertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure.
Hypertension 47:352–58
21. Ernst ME, Carter BL, Zheng S, Grimm RH Jr. 2010. Meta-analysis of dose-response characteristics
of hydrochlorothiazide and chlorthalidone: effects on systolic blood pressure and potassium. Am. J.
Hypertens. 23:440–46
Annu. Rev. Pharmacol. Toxicol. 2015.55. Downloaded from www.annualreviews.org
22. Peterzan MA, Hardy R, Chaturvedi N, Hughes AD. 2012. Meta-analysis of dose-response relationships
Access provided by University of Reading on 12/27/14. For personal use only.
Changes may still occur before final publication online and in print
PA55CH10-Feldman ARI 15 September 2014 12:15
39. Ahuja K, Charap MH. 2010. Management of perioperative hypertensive urgencies with parenteral med-
ications. J. Hosp. Med. 5:E11–16
40. Flack JM, Nasser SA. 2011. Benefits of once-daily therapies in the treatment of hypertension. Vasc. Health
Risk Manag. 7:777–87
41. Furberg CD, Psaty BM. 2003. Should evidence-based proof of drug efficacy be extrapolated to a “class
of agents”? Circulation 108:2608–10
42. Shah AD, Arora RR. 2005. Tissue angiotensin-converting enzyme inhibitors: Are they more effective
than serum angiotensin-converting enzyme inhibitors? Clin. Cardiol. 28:551–55
43. Hilleman DE, Lucas BD Jr. 2004. Angiotensin-converting enzyme inhibitors and stroke risk: benefit
beyond blood pressure reduction? Pharmacotherapy 24:1064–76
44. Sica DA. 2001. The Heart Outcomes Prevention Evaluation study: angiotensin-converting enzyme
inhibitors: Are their benefits a class effect or do individual agents differ? Curr. Opin. Nephrol. Hypertens.
10:597–601
45. Svensson P, de Faire U, Sleight P, Yusuf S, Östergren J. 2001. Comparative effects of ramipril on
Annu. Rev. Pharmacol. Toxicol. 2015.55. Downloaded from www.annualreviews.org
46. Staessen JA, Wang JG, Thijs L. 2001. Cardiovascular protection and blood pressure reduction: a meta-
analysis. Lancet 358:1305–15
47. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, et al. 2008. Telmisartan, ramipril, or both in patients at
high risk for vascular events. N. Engl. J. Med. 358:1547–59
48. McAlister FA. 2012. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are
beneficial in normotensive atherosclerotic patients: a collaborative meta-analysis of randomized trials.
Eur. Heart J. 33:505–14
49. Turnbull F, Neal B, Pfeffer M, Kostis J, Algert C, et al. 2007. Blood pressure-dependent and independent
effects of agents that inhibit the renin-angiotensin system. J. Hypertens. 25:951–58
50. Siegl PK. 1993. Discovery of losartan, the first specific non-peptide angiotensin II receptor antagonist.
J. Hypertens. Suppl. 11:S19–22
51. Kassler-Taub K, Littlejohn T, Elliott W, Ruddy T, Adler E. 1998. Comparative efficacy of two an-
giotensin II receptor antagonists, irbesartan and losartan, in mild-to-moderate hypertension. Am. J.
Hypertens. 11:445–53
52. Takagi H, Niwa M, Mizuno Y, Goto SN, Umemoto T. 2013. A meta-analysis of randomized trials of
telmisartan versus losartan for reduction of ambulatory blood pressure. Hypertens. Res. 36:959–66
53. Hamada T, Ichida K, Hosoyamada M, Mizuta E, Yanagihara K, et al. 2008. Uricosuric action of losartan
via the inhibition of urate transporter 1 (URAT 1) in hypertensive patients. Am. J. Hypertens. 21:1157–62
54. Choi HK, Soriano LC, Zhang Y, Rodrı́guez LAG. 2012. Antihypertensive drugs and risk of incident
gout among patients with hypertension: population based case-control study. BMJ 344:d8190
55. Soltani Z, Rasheed K, Kapusta DR, Reisin E. 2013. Potential role of uric acid in metabolic syndrome,
hypertension, kidney injury, and cardiovascular diseases: Is it time for reappraisal? Curr. Hypertens. Rep.
15:175–81
56. Derosa G, Cicero AFG, D’angelo A, Ragonesi PD, Ciccarelli L, et al. 2006. Telmisartan and irbesartan
therapy in type 2 diabetic patients treated with rosiglitazone: effects on insulin-resistance, leptin and
tumor necrosis factor-α. Hypertens. Res. 29:849–56
57. Murakami K, Wada J, Ogawa D, Horiguchi CS, Miyoshi T, et al. 2013. The effects of telmisartan
treatment on the abdominal fat depot in patients with metabolic syndrome and essential hypertension:
Abdominal fat Depot Intervention Program of Okayama (ADIPO). Diabetes Vasc. Dis. Res. 10:93–96
58. Suksomboon N, Poolsup N, Prasit T. 2012. Systematic review of the effect of telmisartan on insulin
sensitivity in hypertensive patients with insulin resistance or diabetes. J. Clin. Pharm. Ther. 37:319–27
59. Antoniou T, Camacho X, Yao Z, Gomes T, Juurlink DN, Mamdani MM. 2013. Comparative effective-
ness of angiotensin-receptor blockers for preventing macrovascular disease in patients with diabetes: a
population-based cohort study. CMAJ 185:1035–41
60. Haller H, Ito S, Izzo JL Jr, Januszewicz A, Katayama S, et al. 2011. Olmesartan for the delay or prevention
of microalbuminuria in type 2 diabetes. N. Engl. J. Med. 364:907–17
Changes may still occur before final publication online and in print
PA55CH10-Feldman ARI 15 September 2014 12:15
61. Imai E, Chan JC, Ito S, Yamasaki T, Kobayashi F, et al. 2011. Effects of olmesartan on renal and
cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-
controlled study. Diabetologia 54:2978–86
62. Padwal R, Lin M, Etminan M, Eurich DT. 2014. Comparative effectiveness of olmesartan and other
angiotensin receptor blockers in diabetes mellitus: retrospective cohort study. Hypertension 63:977–83
63. US Food Drug Adm. 2013. Olmesartan Medoxomil: drug safety communication - label changes to include intesti-
nal problems (sprue-like enteropathy). Silver Spring, MD: US Food Drug Adm. http://www.fda.gov/safety/
medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm359528.htm
64. US Food Drug Adm. 2011. FDA drug safety communication: safety review update of Benicar (olmesar-
tan) and cardiovascular events. Silver Spring, MD: US Food Drug Adm. http://www.fda.gov/Drugs/
DrugSafety/ucm251268.htm
65. MERIT-HF Study Gr. 1999. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL
Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 353:2001–7
66. Freemantle N, Cleland J, Young P, Mason J, Harrison J. 1999. β Blockade after myocardial infarction:
Annu. Rev. Pharmacol. Toxicol. 2015.55. Downloaded from www.annualreviews.org
67. Borer JS, Comerford MB, Sowton E. 1976. Assessment of metoprolol, a cardioselective beta-blocking
agent, during chronic therapy in patients with angina pectoris. J. Int. Med. Res. 4:15–22
68. Khan N, McAlister FA. 2006. Re-examining the efficacy of β-blockers for the treatment of hypertension:
a meta-analysis. CMAJ 174:1737–42
69. Messerli FH, Grossman E, Goldbourt U. 1998. Are β-blockers efficacious as first-line therapy for
hypertension in the elderly? A systematic review. JAMA 279:1903–7
70. Kuyper LM, Khan NA. 2014. Atenolol vs nonatenolol β-blockers for the treatment of hypertension: a
meta-analysis. Can. J. Cardiol. 30:S47–53
71. Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, et al. 2006. Differential impact of blood
pressure–lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit
Artery Function Evaluation (CAFE) study. Circulation 113:1213–25
72. Schiffrin EL, Deng LY, Larochelle P. 1994. Effects of a β-blocker or a converting enzyme inhibitor on
resistance arteries in essential hypertension. Hypertension 23:83–91
73. Kirstein SL, Insel PA. 2004. Autonomic nervous system pharmacogenomics: a progress report. Pharmacol.
Rev. 56:31–52
74. Lund-Johansen P. 1979. Hemodynamic consequences of long-term beta-blocker therapy: a 5-year
follow-up study of atenolol. J. Cardiovasc. Pharmacol. 1:487–95
75. Teisman ACH, van Veldhuisen DJ, Boomsma F, de Kam PJ, Tjeerdsma G, et al. 2000. Chronic beta-
blocker treatment in patients with advanced heart failure: effects on neurohormones. Int. J. Cardiol.
73:7–12
76. Minneman KP, Pittman RN, Molinoff PB. 1981. β-Adrenergic receptor subtypes: properties, distribu-
tion, and regulation. Annu. Rev. Neurosci. 4:419–61
77. Berglund G, Andersson O. 1981. Beta-blockers or diuretics in hypertension? A six year follow-up of
blood pressure and metabolic side effects. Lancet 1:744–47
78. Bangalore S, Parkar S, Grossman E, Messerli FH. 2007. A meta-analysis of 94,492 patients with hyper-
tension treated with beta blockers to determine the risk of new-onset diabetes mellitus. Am. J. Cardiol.
100:1254–62
79. Poirier L, Lacourcière Y. 2012. The evolving role of β-adrenergic receptor blockers in managing hy-
pertension. Can. J. Cardiol. 28:334–40
80. Ekbom T, Dahlöf B, Hansson L, Lindholm LH, Scherstén B, Wester PO. 1992. Antihypertensive
efficacy and side effects of three beta-blockers and a diuretic in elderly hypertensives: a report from the
STOP-Hypertension study. J. Hypertens. 10:1525–30
81. Bakris GL, Fonseca V, Katholi RE, McGill JB, Messerli FH, et al. 2004. Metabolic effects of carvedilol
versus metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled
trial. JAMA 292:2227–36
82. Agabiti-Rosei E, Porteri E, Rizzoni D. 2009. Arterial stiffness, hypertension, and rational use of nebivolol.
Vasc. Health Risk Manag. 5:353–60
Changes may still occur before final publication online and in print
PA55CH10-Feldman ARI 15 September 2014 12:15
83. Mahmud A, Feely J. 2008. β-Blockers reduce aortic stiffness in hypertension but nebivolol, not atenolol,
reduces wave reflection. Am. J. Hypertens. 21:663–67
84. Jt. Natl. Comm. Detect. Eval. Treat. High Blood Press. 1993. The fifth report of the Joint National
Committee on Detection, Evaluation, and Treatment of High Blood Pressure ( JNC V). Arch. Intern.
Med. 153:154–83
85. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, et al. 2007. 2007 guidelines for the
management of arterial hypertension: the task force for the management of arterial hypertension of the
European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur. Heart
J. 28:1462–536
86. Hackam DG, Quinn RR, Ravani P, Rabi DM, Dasgupta K, et al. 2013. The 2013 Canadian hypertension
education program recommendations for blood pressure measurement, diagnosis, assessment of risk,
prevention, and treatment of hypertension. Can. J. Cardiol. 29:528–42
87. Med. Res. Counc. Work. Party. 1985. MRC trial of treatment of mild hypertension: principal results.
BMJ 291:97–104
Annu. Rev. Pharmacol. Toxicol. 2015.55. Downloaded from www.annualreviews.org
88. Dahlöf B, Lindholm LH, Hansson L, Scherstén B, Ekbom T, Wester PO. 1991. Morbidity and mortality
Access provided by University of Reading on 12/27/14. For personal use only.
in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 338:1281–85
89. Wikstrand J, Warnold I, Tuomilehto J, Olsson G, Barber HJ, et al. 1991. Metoprolol versus thiazide
diuretics in hypertension: morbidity results from the MAPHY study. Hypertension 17:579–88
90. Wilhelmsen L, Berglund G, Elmfeldt D, Fitzsimons T, Holzgreve H, et al. 1987. Beta-blockers versus
diuretics in hypertensive men: main results from the HAPPHY trial. J. Hypertens. 5:561–72
91. Med. Res. Counc. Work. Party. 1992. Medical Research Council trial of treatment of hypertension in
older adults: principal results. BMJ 304:405–12
92. Bangalore S, Sawhney S, Messerli FH. 2008. Relation of beta-blocker–induced heart rate lowering and
cardioprotection in hypertension. J. Am. Coll. Cardiol. 52:1482–89
93. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, et al. 2002. Cardiovascular morbidity and mor-
tality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised
trial against atenolol. Lancet 359:995–1003
94. Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, et al. 2005. Prevention of cardiovascular events
with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding
bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure
Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 366:895–906
95. Lindholm LH, Carlberg B, Samuelsson O. 2005. Should β blockers remain first choice in the treatment
of primary hypertension? A meta-analysis. Lancet 366:1545–53
96. Natl. Clin. Guidel. Cent. 2011. Hypertension: The Clinical Management of Primary Hypertension in Adults:
Update of Clinical Guidelines 18 and 34. London: Natl. Clin. Guidel. Cent.
97. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, et al. 2014. 2014 evidence-
based guideline for the management of high blood pressure in adults: report from the panel members
appointed to the eighth Joint National Committee ( JNC 8). JAMA 311:507–20
98. UK Prospective Diabetes Study Group. 1998. Efficacy of atenolol and captopril in reducing risk of
macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 317:713
99. Ferrari R. 1997. Major differences among the three classes of calcium antagonists. Eur. Heart J. 18(Suppl.
A):A56–70
100. Fleckenstein A. 1983. History of calcium antagonists. Circ. Res. 52:I3–16
101. Braunwald E. 1982. Mechanism of action of calcium-channel-blocking agents. N. Engl. J. Med. 307:1618–
27
102. Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J. 2005. International Union of Pharmacol-
ogy. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels.
Pharmacol. Rev. 57:411–25
103. Nelson CR, Knapp DA. 2000. Trends in antihypertensive drug therapy of ambulatory patients by US
office-based physicians. Hypertension 36:600–3
104. Alderman MH, Cohen H, Roque R, Madhavan S. 1997. Effect of long-acting and short-acting calcium
antagonists on cardiovascular outcomes in hypertensive patients. Lancet 349:594–98
Changes may still occur before final publication online and in print
PA55CH10-Feldman ARI 15 September 2014 12:15
105. Pahor M, Guralnik JM, Ferrucci L, Corti MC, Salive ME, et al. 1996. Calcium-channel blockade and
incidence of cancer in aged populations. Lancet 348:493–97
106. Rosenberg L, Rao RS, Palmer JR, Strom BL, Stolley PD, et al. 1998. Calcium channel blockers and the
risk of cancer. JAMA 279:1000–4
107. Bonny A, Lacombe F, Yitemben M, Discazeaux B, Donetti J, et al. 2008. The 2007 ESH/ESC guidelines
for the management of arterial hypertension. J. Hypertens. 26:825–26
108. Campbell NR, Kaczorowski J, Lewanczuk RZ, Feldman R, Poirier L, et al. 2010. 2010 Canadian Hy-
pertension Education Program (CHEP) recommendations: the scientific summary – an update of the
2010 theme and the science behind new CHEP recommendations. Can. J. Cardiol. 26:236–40
109. Wang JG, Kario K, Lau T, Wei YQ, Park CG, et al. 2011. Use of dihydropyridine calcium channel
blockers in the management of hypertension in Eastern Asians: a scientific statement from the Asian
Pacific Heart Association. Hypertens. Res. 34:423–30
110. Bailey DG, Arnold JMO, Bend JR, Tran LT, Spence JD. 1995. Grapefruit juice-felodipine interaction:
reproducibility and characterization with the extended release drug formulation. Br. J. Clin. Pharmacol.
Annu. Rev. Pharmacol. Toxicol. 2015.55. Downloaded from www.annualreviews.org
40:135–40
Access provided by University of Reading on 12/27/14. For personal use only.
111. Sica DA. 2006. Interaction of grapefruit juice and calcium channel blockers. Am. J. Hypertens. 19:768–73
112. Williams DM, Cubeddu LX. 1988. Amlodipine pharmacokinetics in healthy volunteers. J. Clin. Phar-
macol. 28:990–94
113. Sica DA. 2001. Current concepts of pharmacotherapy in hypertension: combination calcium channel
blocker therapy in the treatment of hypertension. J. Clin. Hypertens. 3:322–27
114. Weir MR. 2003. Incidence of pedal edema formation with dihydropyridine calcium channel blockers:
issues and practical significance. J. Clin. Hypertens. 5:330–35
115. Sica DA. 2003. Calcium channel blocker-related periperal edema: Can it be resolved? J. Clin. Hypertens.
5:291–95
116. Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, et al. 1997. Randomised double-blind comparison
of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 350:757–64
117. Wang JG, Staessen JA, Gong L, Liu L. 2000. Chinese trial on isolated systolic hypertension in the
elderly. Arch. Intern. Med. 160:211–20
118. ALLHAT Off. Coord. ALLHAT Collab. Res. Gr. 2002. 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
288:2981–97
119. Hansson L, Hedner T, Lund-Johansen P, Kjeldsen SE, Lindholm LH, et al. 2000. Randomised trial of
effects of calcium antagonists compared with diuretics and β-blockers on cardiovascular morbidity and
mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet 356:359–65
120. Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, et al. 2003. A calcium antag-
onist vs a non–calcium antagonist hypertension treatment strategy for patients with coronary artery
disease: the International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial.
JAMA 290:2805–16
121. Black HR, Elliott WJ, Grandits G, Grambsch P, Lucente T, et al. 2003. Principal results of the Controlled
Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA 289:2073–82
122. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. 2009. Combination therapy versus monotherapy in
reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am. J. Med. 122:290–300
123. López-Sendón J, Swedberg K, McMurray J, Tamargo J, Maggioni AP, et al. 2004. Expert consensus
document on β-adrenergic receptor blockers. Eur. Heart J. 25:1341–62
124. Dresser GK, Spence JD, Bailey DG. 2000. Pharmacokinetic-pharmacodynamic consequences and clin-
ical relevance of cytochrome P450 3A4 inhibition. Clin. Pharmacokinet. 38:41–57
125. Kelly JG, O’Malley K. 1992. Clinical pharmacokinetics of calcium antagonists: an update. Clin. Phar-
macokinet. 22:416–33
126. Bailey DG, Dresser GK. 2004. Interactions between grapefruit juice and cardiovascular drugs. Am. J.
Cardiovasc. Drugs 4:281–97
Changes may still occur before final publication online and in print