Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experimental and clinical studies indicate that carvedilol exerts multiple antiadrenergic effects in addition to beta(1)-receptor blockade, but the prognostic importance of these actions has long been debated. This controversy has now been substantially advanced by the results of the recently completed Carvedilol Or Metoprolol European Trial (COMET), which showed that carvedilol (25 mg twice daily) reduced mortality by 17% when compared with metoprolol (50 mg twice daily), P=.0017--a result that was consistent with the differences seen across earlier controlled trials with beta-blockers in survivors of an acute myocardial infarction and in patients with chronic heart failure. Questions have been raised about the interpretation of these findings in view of the fact that the trial did not use the dose or formulation of metoprolol that was shown to prolong life in a placebo-controlled trial (ie, Metoprolol CR/XL [Controlled Release] Randomized Intervention Trial in Heart Failure). Pharmacokinetic and pharmacodynamic analyses, however, indicate that the dosing regimen of metoprolol selected for use in the COMET trial produces a magnitude and time course of beta(1)-blockade during a 24-hour period that is similar to the dose of carvedilol targeted for use in the trial. These analyses suggest that the observed difference in the mortality effects of metoprolol and carvedilol is not related to a difference in the magnitude or time course of their beta(1)-blocking effects but instead reflect antiadrenergic effects of carvedilol in addition to beta(1)-blockade.
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PMID:Do beta-blockers prolong survival in heart failure only by inhibiting the beta1-receptor? A perspective on the results of the COMET trial. 1496 85

In 1983, carvedilol [1-[carbazolyl-(4)-oxy]-3-[(2-methoxyphenoxyethyl)amino]-2-propanol] was designed and developed as a beta-adrenoceptor antagonist with vasodilating activity for efficacious and safe treatment of hypertension and coronary artery disease. Carvedilol belongs to the 'third generation' of beta-adrenoceptor antagonists and shows selectivity for the beta1- rather than beta2-adrenoceptor. Carvedilol is also an alpha1-blocking agents, with around 2- to 3-fold more selectivity for beta1- than alpha1-adrenoceptors. This degree of alpha1-blockade is responsible for the moderate vasodilator properties of carvedilol, being different from other beta-adrenoceptor antagonists. In addition, carvedilol is a potent antioxidant, with a 10-fold greater activity than vitamin E. Some carvedilol metabolites found in human plasma also exhibit antioxidative activity approximately 50- to 100-fold greater than carvedilol and other antioxidants. These unique properties of carvedilol, i.e. adrenergic (beta1, beta2 and alpha1) blockade and antioxidative activity, may be important in preventing progressive deterioration of left ventricular dysfunction and chronic heart failure. Recently, carvedilol has been demonstrated to reverse multidrug resistance (MDR) to anticancer drugs in tumor cells in vitro and its reversal effects were comparable with verapamil, which has been used in the first clinical trial for the reversal of MDR. This review introduces the reversal activity and usefulness against MDR, as well as an overview of the pharmacological and pharmacokinetic properties, of carvedilol.
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PMID:Carvedilol: a new candidate for reversal of MDR1/P-glycoprotein-mediated multidrug resistance. 1505 33

Cardiac remodeling is a central mechanism of heart failure progression in patients with coronary artery disease (CAD). The remodeling effect of beta-blockade with carvedilol has been studied in patients with left ventricular dysfunction after myocardial infarction and in patients with chronic heart failure of ischemic etiology. Carvedilol has been found to prevent progressive adverse ventricular remodeling in both conditions. This effect is concordant with the improvement in long-term clinical outcomes established for carvedilol in such patients. Thus, ventricular remodeling appears to be an important treatment target in patients with CAD and is likely to mediate at least part of the clinical improvement achieved with carvedilol.
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PMID:Cardiac remodeling in coronary artery disease. 1514 32

The safety, tolerability, and hemodynamic effects of carvedilol in patients with heart failure were first studied in the mid 1990s. Positive results in these early trials led to 5 prospective, randomized, double-blind, placebo-controlled trials-the Australia/New Zealand Heart Failure Collaborative Group (ANZ) study and the 4 component studies of the US Carvedilol Heart Failure Trials Program. These studies were conducted to determine the clinical impact of long-term carvedilol therapy. Findings from these trials showed that carvedilol is a powerful therapy (1) in patients with chronic heart failure caused by left ventricular (LV) systolic dysfunction, improving morbidity and mortality; and (2) in patients with symptomatic heart failure, improving LV ejection fraction, improving clinical status, and slowing disease progression, resulting in reduction of the combined risk of hospitalization and mortality. This article discusses the design, results, and clinical implications of these trials.
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PMID:Landmark studies: the Australia/New Zealand Heart Failure Collaborative Group (ANZ) Trial and the US Carvedilol Trials Program. 1514 34

The impact of carvedilol on the survival of patients with severe heart failure was examined in the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial. The trial recruited 2,289 patients with symptoms at rest or on minimal exertion despite therapy with angiotensin-converting enzyme inhibitors and a left ventricular ejection fraction of < or = 0.25. After an average follow-up period of 10.4 months, mortality was reduced by 34% in the carvedilol group. Carvedilol also reduced the number of days spent in the hospital for any cause by 27% and the number of days spent in the hospital for heart failure by 40%. Patients in the carvedilol group felt better and were less likely to have a serious adverse event. The benefits of carvedilol appeared early and were detected during the up-titration period.
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PMID:Carvedilol prospective randomized cumulative survival (COPERNICUS) trial: carvedilol in severe heart failure. 1514 35

beta-Adrenergic blockade is commonly and successfully used to treat chronic heart failure. Until recently, few data were available on which to base selection of a particular beta-blocking agent. The Carvedilol or Metoprolol European Trial (COMET) provides evidence that beta-blockers are not interchangeable. The trial compared carvedilol, a nonselective beta-blocker with alpha-adrenergic blocking and numerous ancillary activities, with metoprolol tartrate. In comparison to metoprolol tartrate, significant reductions in all-cause mortality and cardiovascular mortality were observed with carvedilol. These data indicate that cardiovascular benefit may be obtained from switching patients from metoprolol tartrate to carvedilol.
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PMID:Commentary on the Carvedilol or Metoprolol European Trial (COMET). 1514 36

Atrial fibrillation affects approximately 2 million people in the United States and is a common comorbidity among patients with heart failure. Clinical studies indicate that the benefits of the beta-blocker carvedilol in patients with heart failure extend to patients with heart failure complicated by atrial fibrillation. The results of the Carvedilol in Atrial Fibrillation Evaluation (CAFE) trial provide support that carvedilol has incremental benefit when added to digoxin for the management of atrial fibrillation in patients with heart failure. Additional recent studies suggest that carvedilol may be useful in managing postsurgical atrial fibrillation and also may prevent recurrence of atrial fibrillation among patients who undergo cardioversion.
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PMID:Role of carvedilol in atrial fibrillation: insights from clinical trials. 1514 39

An extensive clinical trials database now exists to support the therapeutic efficacy of beta-blockers in systolic heart failure. However, concerns remain about the tolerability of these agents. These concerns relate to perceived complexity in initiation and uptitration, risk of worsening heart failure clinical status, and delay in beneficial effects on outcomes. All of the above concerns are thought especially relevant in patients with advanced disease. However, these perceptions are not borne out in the controlled clinical trial experience or in open-label studies and postmarketing surveillance programs with carvedilol. Specifically, in clinical studies, discontinuation rates (because of adverse events), serious adverse event rates, mean achieved dose, and percentage reaching target dose strongly suggest good tolerability. This is especially notable, considering that beta-blockade is used in addition to other background neurohormonal antagonists, such as angiotensin-converting enzyme inhibitors. Furthermore, tolerability in the everyday community setting also appears to be high. Carvedilol, specifically, is also well tolerated during initiation of therapy, with fewer withdrawals for heart failure during the first 8 weeks of uptitration, and no delay in the accrual of beneficial clinical outcomes, as observed in the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study. Thus, in contrast to widely held perceptions about tolerability of beta-blockade in heart failure, carvedilol appears to be an extremely well-tolerated agent, even during initiation and in the most advanced patients.
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PMID:Tolerability of carvedilol in heart failure: clinical trials experience. 1514 40

The use of beta-blockers for the treatment of heart failure in the United States is inadequate, despite available data and current guidelines that support their use. The Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) study was designed to determine whether initiation of beta-blockade before hospital discharge is safe and effective in improving the 60-day use of beta-blockers in patients with heart failure. IMPACT-HF compared the strategy of the initiation of carvedilol before patients were discharged versus usual care (Heart Failure Society of America guidelines recommend waiting 2 to 4 weeks after hospitalization for heart failure before initiating beta-blocker therapy) in 363 randomized patients with heart failure. The entry criteria were non-restrictive to ensure inclusion of patients reflective of the general heart failure population. The primary end point of the study (the number of patients treated with any beta-blocker at 60 days) was statistically significantly higher in the predischarge group versus the postdischarge group (91.2% vs 73.4%, respectively). Based on the study's results, predischarge initiation may be a successful strategy to improve the use of beta-blocker therapy for patients with heart failure.
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PMID:Predischarge initiation of carvedilol in patients hospitalized for decompensated heart failure. 1514 43

The abundance of evidence supporting beta-blocker therapy has resulted in the widespread acceptance of these drugs in the treatment of heart-failure patients. However, beta-blockers are not a homogeneous class of drugs, and important differences in efficacy have been noted between different members of the class. Thus, practicing physicians are faced with a choice when selecting a particular beta-blocker for treating heart failure. One of the considerations is whether to choose a selective or a nonselective beta-blocker. The results of the Carvedilol or Metoprolol European Trial indicate that carvedilol, a third-generation, nonselective beta-blocker with additional a-blocking, antioxidant, and other properties, is clearly superior to a beta1-blocking drug, metoprolol tartrate. The choice between these drugs is therefore unambiguously in favor of carvedilol.
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PMID:Nonselective versus selective beta-blockers in the management of chronic heart failure: clinical implications of the carvedilol or Metoprolol European Trial. 1518 35


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