Download Hypertension, Heart Failure, and Beta-Adrenergic Blocking

Journal of the American College of Cardiology
© 2008 by the American College of Cardiology Foundation
Published by Elsevier Inc.
EDITORIAL COMMENT
Hypertension, Heart
Failure, and Beta-Adrenergic
Blocking Drugs*
Michael B. Fowler, MB, FRCP, FACC
Stanford, California
Beta-adrenergic receptor blocking drugs have arguably prevented or delayed more deaths in patients with established
heart disease that any other class of pharmaceutical agent
(1). These drugs fundamentally alter the clinical course of
patients with heart failure and a reduced left ventricular
ejection fraction, improving left ventricular performance,
reversing left ventricular remodeling, and reducing the risk
of hospitalization or dying (2). Beta-adrenergic receptor
blocking drugs (beta-blockers) were also the first, and still
arguably one of the more powerful, interventions to improve
survival when prescribed as long-term therapy after acute
myocardial infarction (3). The role of beta-blockers to
prevent the development of heart failure is less clear. Some
agents have been shown to reduce reinfarction, one important contributor to subsequent heart failure. Beta-blockers
were included with the optimal therapy prescribed in the
COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial (4), the result
testifying to the efficacy of medical therapy for coronary
artery disease. These drugs protect against acute myocardial
infarction in patients undergoing noncardiac surgery (5), but
this indication has been associated with increased stroke
risk, especially in patients in whom sepsis or hypotension
developed (6). Even the presentation of ischemic heart
disease seems to be influenced by beta-blockers, with fewer
patients on these drugs experiencing acute myocardial
infarction (7).
See page 1062
The American College of Cardiology/American Heart
Association guidelines for the treatment of heart failure
emphasize control of blood pressure as an important strategy to prevent heart failure. This is an important issue
*Editorials published in the Journal of the American College of Cardiology reflect the
views of the authors and do not necessarily represent the views of JACC or the
American College of Cardiology.
From the Division of Cardiovascular Medicine, Stanford University School of
Medicine, Stanford, California.
Vol. 52, No. 13, 2008
ISSN 0735-1097/08/$34.00
doi:10.1016/j.jacc.2008.06.032
because hypertension precedes heart failure in the majority
of patients who develop this devastating condition (8,9).
Hypertension is especially significant in patients with heart
failure and a preserved left ventricular ejection fraction.
Insulin resistance, diabetes, and obesity are also important
in the development of heart failure and are closely linked to
hypertension (10).
Introduced in the 1960s as drugs to treat angina, betablockers were soon realized to be effective and, compared
with many other available agents at that time, well tolerated
antihypertensive agents. Based on the limited trials data
available beta-blockers were included as first-line therapy in
national guidelines for the treatment of hypertension (11).
Most of the evidence for this recommendation came from
trials that compared thiazide-type diuretics and/or betablockers to placebo or usual care. Reduced risk of stroke or
heart failure was the benefit most commonly reported. The
impact on coronary artery disease events was modest, and at
the time was attributed to the short duration of the trials.
Subsequently the SHEP (Systolic Hypertension in the
Elderly Program) trial (12), which evaluated chlorthalidone
in elderly hypertensive patients, did show a reduction in
major coronary events and a substantial reduction by 49% in
the risk of developing heart failure. The ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial) (13) study results suggested that most
of the benefits of treating hypertension were related to
lowering blood pressure with little impact dependant on a
specific drug class. All of the comparison therapies were
found to be similar to chlorthalidone (again, perhaps significantly, chosen to represent the thiazide diuretic class,
and associated with the greatest reduction in blood pressure)
in preventing the primary composite coronary heart disease
end point. Doxazosin, an alpha-blocker, was shown to be
the least effective in preventing heart failure, a secondary
end point. Heart failure was also 38% more frequent in the
amlodipine group and 15% more frequent in the lisinopril
group. Beta-blockers were not included in the randomized
drug classes but were included as one potential add-on
therapy. In the ANBP2 (Second Australian National Blood
Pressure Study) trial (14), in which 6,085 hypertensive
patients were followed up for 4.1 years, hydrochlorothiazide
was associated with 15% more heart failure than enalapril.
Diabetic hypertensive patients are at especially high risk
for developing heart failure and were shown to have 57%
less risk of developing heart failure with more aggressive
blood pressure control in a UKPDS (UK Prospective
Diabetes Study) trial (15). Interestingly, in this trial the
more aggressive multiple agent regimens could be based on
atenolol or captopril.
The paper by Bangalore et al. (16) in this issue of the
Journal used meta-analysis to examine the role of betablockers to prevent heart failure in patients being treated for
hypertension and to compare them with other classes of
antihypertensive drugs. The Bangalore et al. (16) meta-
1074
Fowler
Editorial Comment
analysis found that beta-adrenergic blocking drugs were as
effective as any other class of agents in preventing heart
failure. Heart failure was not the primary end point in any
of the individual trials of antihypertensive therapy examined
in this analysis, nor was there a uniform definition for the
development of this syndrome. Another analysis has suggested that calcium channel blockers may be inferior as
first-line agents to prevent heart failure, but as the investigators point out, this analysis may have been impacted
though inclusion of comparison trials that included diuretics
with beta-blockers. Based on this meta-analysis, betaadrenergic blocking drugs are rightly included among the
agents used to prevent the development of heart failure.
Although it is not possible to predict which complication of
hypertension may be inflicted on an individual patient,
practitioners should be reassured that they can include
beta-blocking drugs as cardioprotective agents supporting
their use in patients with pre-existing heart disease.
Both diuretics and beta-blockers are recognized to have
important limitations that argue against their routine use as
first-line antihypertensive agents (11,17). An adverse effect
on glucose metabolism poses a significant disadvantage in a
therapy given to protect against the adverse cardiovascular
consequences of hypertension. Both diuretics and betablockers have been associated with the development of
diabetes (11,18). Meta-analysis has shown a 32% increased
risk of new-onset diabetes with beta-blockers in trials
comparing placebo or nondiuretic therapy. With diuretics,
the increased risk of diabetes was 35% compared with
placebo or nonbeta-blocker antihypertensive agents (11). It
is conceivable that the adverse metabolic consequence of
thiazide diuretics may be less than that seen with conventional beta-blockers. The use of chlorthalidone in particular
seems not to be associated with any diminution of benefit
(13). The results of the ACCOMPLISH (Avoiding Cardiovascular events through COMbination therapy in Patients Living with Systolic Hypertension) study do question
our complacency regarding this adverse effect of all thiazides
(19). Although this study design was criticized for being of
limited scientific relevance, the results, reported at the
American College of Cardiology annual meeting this year,
showed fewer events in the group on the combination of an
angiotensin-converting enzyme (ACE) inhibitor with amlodipine compared with the group on an ACE inhibitor and
hydrochlorothiazide. These findings indicate the importance of considering drug combinations rather than extrapolating from the results based on choice of first-line therapy.
The results also suggest that different drugs within a class
may not be equally effective. Beta-blockers should be recognized as having more heterogeneity within a drug class
than other agents. Beta-blockers vary in their affinity for
beta-1 and -2 receptors; some also block alpha receptors,
conferring vasodilator properties even to nonselective
agents. Some have intrinsic sympathomimetic activity.
These different characteristics have been found to be significant in outcome trials after acute myocardial infarction (3)
JACC Vol. 52, No. 13, 2008
September 23, 2008:1073–5
and heart failure (2). The adverse metabolic effect of
nonvasodilating beta-blockers is likely to assume even
greater significance in hypertension when the therapy is
being prescribed for long periods to prevent the vascular and
cardiac consequences of high blood pressure. Two comparison trials with atenolol, a lipophobic beta-1 selective agent,
not only showed less stroke prevention but also more new
development of diabetes compared with the patients randomized, in one trial, to the angiotensin receptor blocking
(ARB) drug lorsartan (20), and in the other, to the dihydropyridine calcium channel blocking drug amlodipine (21).
A subsequent meta-analysis, not confined to atenolol, reported 16% more stroke with beta-blockers and contributed
to the recommendation that beta-blockers as a class should
no longer be chosen routinely as first-line agents to treat
hypertension (22). Whether this adverse effect is common to
all beta-blocking drugs, or whether the absence of an
adverse impact on glucose metabolism as demonstrated
with the vasodilating beta-blocking drug carvedilol in the
GEMINI (Glycemic Effects in Diabetes Mellitus:
Carvedilol-Metoprolol Comparison in Hypertensives) study
(23) has a mitigating effect on stroke prevention has not
been established. The American Association of Clinical
Endocrinologists do advise in their guidelines (24) that
beta-blockers with vasodilating properties are preferable as
second-line or third-line agents. But other factors not
related to insulin resistance, such as a differential impact on
central aortic pressure, may be of equal importance. A
randomized trial in hypertension is needed to determine
whether beta-adrenergic blocking drugs with vasodilator
properties, especially if combined with an ACE inhibitor or
an ARB, would result in improved protection from all the
adverse outcomes associated with hypertension, including
stroke and heart failure, than can be achieved with traditional beta-blocking drugs. Based on the available data and
in the absence of any other new outcomes trial, betablockers cannot be recommended as routine first-line therapy to treat hypertension (16,21,25).
The majority of patients with hypertension will require
more than one agent to achieve target blood pressure. The
impact of beta-blockers when combined with other classes
of drugs, especially ACE inhibitors in patients with established cardiac disease, support their use in hypertensive
patients who are not at target blood pressure. These patients
are especially likely to progress to heart failure. It is
conceivable that the combination of beta-blockers with
ACE inhibitors or ARBs, shown to be beneficial after acute
myocardial infarction or in heart failure, irrespective of an
effect on blood pressure, would also be advantageous at an
earlier stage of the disease even in the absence of hypertension. Given the importance of insulin resistance in the
development of heart failure, it is reassuring that the
conventional nonvasodilating beta-blockers, the principal
agents evaluated in the meta-analysis by Bangalore et al.
(16), were found to be effective in preventing heart failure.
JACC Vol. 52, No. 13, 2008
September 23, 2008:1073–5
Treatment of patients with hypertension should be based
on the outcomes observed in randomized trials or metaanalyses. Ultimately, drug choices in individual patients will
be determined by tolerability and response to specific agents,
and especially by the need to manage concomitant conditions. Despite the number of inexpensive well-tolerated
drugs, only one-half of patients with hypertension are
adequately treated. The tendency to demonize one class of
drugs, especially a drug class with profound benefits to
patients with established cardiac disease, can only contribute
to further therapeutic nihilism. Although it is becoming
increasingly apparent that differences do exist between
different classes of antihypertensive agents, it is also apparent that these differences, although important, are of trivial
consequence compared with the adverse impact of inadequate treatment. Calcium-channel blockers were erroneously targeted in the 1990s (26). Thiazide diuretics, lauded
after the findings of the ALLHAT study, are now under
scrutiny after finding hydrochlorothiazide (given in combination with benazapril) was less effective in preventing adverse
outcomes than a combination benazapril/amlodipine preparation. In an era when scientific discourse regarding drug
therapy is played out in the lay press, it is hardly surprising
that patients do not persist with effective antihypertensive
therapy but turn instead to alternative medicines, blissfully
unaware that the subsequent development of heart failure
could have been prevented.
Reprint requests and correspondence: Dr. Michael B. Fowler,
Division of Cardiovascular Medicine, Stanford University School
of Medicine, 300 Pasteur Drive, Falk CVRC 295, Stanford,
California 94305-5406. E-mail: [email protected].
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Key Words: beta-blockers y heart failure y hypertension y
meta-analysis.