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[beta]-blockers for heart failure.

Since the late 1990s, [beta]-blockers have been part of the standard regimen for reducing mortality and hospitalizations among patients with heart failure. Results from several clinical trials showed that [beta]-blocker treatment produces about a 35% reduction in mortality in patients with New York Heart Association class II-IV heart failure. Many specialists also believe that [beta]-blockers are effective for patients with class I disease who also have ischemic heart disease. And results in recent reports have confirmed the effectiveness of [beta]-blockers in special populations, including the elderly and patients with diabetes.

Although the efficacy of bisoprolol, carvedilol, and metoprolol has been documented in studies that compared each of these drugs against placebo, two of these agents were compared with each other in just one reported study, the Carvedilol or Metoprolol European Trial (COMET) (Lancet 2003;362:7-13). This study compared carvedilol, a nonselective agent, to metoprolol, an agent that selectively blocks [[beta].sub.1] receptors.

In COMET, carvedilol was superior to metoprolol for reducing mortality and sudden death. But several experts have said that this study was flawed by the underdosing of metoprolol, and by the use of a short-acting formulation of metoprolol instead of the extended-release form that is approved by the Food and Drug Administration and commonly used for heart failure patients. As a result, many experts continue to believe that the two drugs have similar efficacy.

A small percentage of patients cannot tolerate [beta]-blocker therapy. Some develop symptomatic bradycardia, which should be addressed with a pacemaker before [beta]-blocker therapy is reinitiated. Some patients experience a worsening of heart failure during therapy; these patients should receive a type 3 phosphodiesterase inhibitor, which may enable reinitiation of [beta]-blocker therapy Some patients experience noncardiac adverse events, including reactive airway problems, which may or may not be manageable while continuing [beta]-blocker therapy.

In general, patients with bronchial asthma should not receive [beta]-blockers. However, if alternative regimens are not effective, these patients can be managed with caution on metoprolol because of its [[beta].sub.1] selectivity. Carvedilol is contraindicated in bronchial asthma patients; two cases of fatal bronchospasm have been reported following single doses.

[beta]-Blockers can be used with caution in pregnant women but pose a potential risk of intrauterine growth retardation and reduced placental weight, especially in the second and third trimesters. The risks are higher for metoprolol and bisoprolol, and somewhat lower for carvedilol. None of these agents appears to cause structural defects or death in fetuses. No human data exist on effects from these drugs in human milk, but nursing infants should be observed for symptoms of [beta]blockade.

[beta]-Blocker therapy is started with a gradual titration scheme in all heart failure patients. No systematic dose reductions are needed for elderly patients, but some older patients may not tolerate the maximum dosages that are often tolerated by younger patients. Patients discontinuing [beta]-blocker therapy should receive tapered doses because abrupt discontinuation has been associated with myocardial infarction.

Mitchel L. Zoler, editor

Betsy Bates, writer
Drug          Cost/Day *               Dosage

carvedilol    no generic available     up to 25 mg
[Coreg]       [$3.56 (25 mg b.i.d.)]   b.i.d.

metoprolol    no generic available     up to 200 mg
succinate     [$1.96 (200 mg/day)]     once daily
[Toprol-XL]

bisoprolol    no generic available     up to 10 mg
[Zebeta]      [$1.49 (10 mg/day)]      once daily

metoprolol    $0.27 (100 mg t.i.d.)    50-100 mg t.i.d.
tartrate

Drug          What the Experts Say **

carvedilol    Available in trade formulation only. Noncardioselective
[Coreg]       agent; blocks [[beta].sub.1], [[beta].sub.2], and
              [[alpha].sub.1] receptors. Along with metoprolol,
              considered the top choice. Twice-daily dosing makes
              it somewhat less convenient than once-daily extended-
              release metoprolol. Has vasodilator activity, so may
              be difficult to tolerate for patients with hypotension.
              Contraindicated for patients with bronchial asthma; in
              contrast, metoprolol can be used with caution in
              patients with bronchial asthma. Preferred by some
              experts for patients with diabetes mellitus or
              hyperlipidemia. First [beta]-blocker shown safe and
              effective for patients with heart failure (N. Engl.
              J. Med. 1996;334:1349-55).

metoprolol    Available in trade formulation only. Card ioselective;
succinate     blocks [[beta].sub.1] receptors. Along with carvedilol,
[Toprol-XL]   considered the top choice. Edges carvedilol in
              convenience with once-daily dosing, which also makes
              it more cost effective. Drug of choice for patients
              with reactive airway disease (bronchial asthma)
              because of its selectivity, but must be used with
              caution in such patients. Efficacy was proven in the
              Metoprolol CR/XL Randomized Intervention Trial in
              Congestive Heart Failure (MERIT-HF) (Lancet 1999;353:
              2001-7).

bisoprolol    Available in trade formulation only. Third [beta]-
[Zebeta]      blocker option for heart failure. Was shown effective
              for preventing death in heart failure patients in a
              major trial, the Cardiac Insufficiency Bisoprolol
              Study II (CIBIS-II) (Lancet 1999;353:9-13), but
              manufacturer never sought approval for heart failure
              indication from FDA and so bisoprolol is now the odd
              drug out for treating heart failure in the United
              States. Experts say that the absence of heart failure
              indication alone is sufficient reason to favor
              carvedilol and metoprolol over bisoprolol. Dosage
              is 2.5 mg daily in patients with liver or kidney
              problems.

metoprolol    Generic formulation of metoprolol; requires t.i.d
tartrate      dosage. Proven efficacy limited to patients with
              nonischemic cardiomyopathy, a minority of patients
              with heart failure. In these patients, it is shown
              to reduce mortality and need for heart transplant.
              Dosage schedule and limited evidence of efficacy make
              it a much less attractive option, but cost is far
              lower than for all alternative agents.

* Costs are based on the average wholesale price for the trade
formulation of a 100-unit bottle (or closest size) in the 2004
Red Book. Cost for metoprolol tartrate is based on federal
upper limit price.

** Comments reflect the viewpoints and expertise of the
following sources:

Michael R. Bristow, M.D., Ph.D., professor of medicine, head
of the division of cardiology, and codirector of the
cardiovascular institute at the University of Colorado, Denver.
Reported no conflicts of interest.

Prakash C. Deedwania, M.D., clinical professor of medicine,
University of California, San Francisco, Fresno; chief of
cardiology, Veterans Affairs Central California Health Care
System. Reported no conflicts of interest.

Michael Reiter, M.D., Ph.D., professor of cardiology at the
University of Colorado, Denver. Reported no conflicts of
interest.

Gerald G. Briggs, B. Pharm., pharmacist clinical specialist,
Women's Pavilion, Miller Children's Hospital, Long Beach
(Calif.) Memorial Medical Center. Source on drug safety in
pregnant and nursing women. Reported no conflicts of
interest.
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Title Annotation:Drug Update
Author:Zoler, Mitchel L.
Publication:Family Practice News
Geographic Code:1USA
Date:Sep 1, 2005
Words:1087
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