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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carvedilol (Coreg), a beta- and alpha-blocker and an antioxidant drug, was evaluated for moderate to severe heart failure patients in a program containing four United States and one Australia/New Zealand study. The data were evaluated twice by the Cardiovascular and Renal Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA). These meetings resulted in opposite decisions by the advisory committee. The crux of the argumentation was the two-positive-trial FDA paradigm. Carvedilol did not meet the usual paradigm because an exercise end point was not statistically different from placebo in three U.S. trials. Most other end points were highly significant, and death, which was monitored across the U.S. program, was different with p < 0.0001. Here we argue that the usual paradigm is very useful but not an absolute principle, that the usual paradigm can sometimes miss the strength of evidence even in the primary end points, and that rational decision making requires on occasion that other evidence must lead to approval. Control of the type I error rate should be taken very seriously, should rarely be violated, and serves the biomedical community well. It is not an absolute principle, however, but rather must be considered in context.
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PMID:Carvedilol and the Food and Drug Administration (FDA) approval process: the FDA paradigm and reflections on hypothesis testing. 1002 97

In this study, we examine the cost effectiveness of carvedilol for the treatment of chronic heart failure (CHF). We use a Markov model to project life expectancy and lifetime medical care costs for a hypothetical cohort of patients with CHF who were assumed alternatively to receive carvedilol plus conventional therapy (digoxin, diuretics, and angiotensin-converting enzyme inhibitors) or conventional therapy alone. Patients on carvedilol were assumed to experience a reduced risk of death and hospitalization for CHF, which is consistent with findings from the US Carvedilol Heart Failure Trials Program. The benefits of carvedilol were projected under 2 alternative scenarios. In the first ("limited benefits"), benefits were conservatively assumed to persist for 6 months, the average duration of follow-up in these clinical trials, and then end abruptly. In the other ("extended benefits"), they were arbitrarily assumed to persist for 6 months and then decline gradually over time, vanishing by the end of 3 years. We estimated our model using data from the US Carvedilol Heart Failure Trials Program and other sources. For patients receiving conventional therapy alone, estimated life expectancy was 6.67 years; corresponding figures for those also receiving carvedilol were 6.98 and 7.62 years under the limited and extended benefits scenarios, respectively. Expected lifetime costs of CHF-related care were estimated to be $28,756 for conventional therapy, and $36,420 and $38,867 for carvedilol (limited and extended benefits, respectively). Cost per life-year saved for carvedilol was $29,477 and $12,799 under limited and extended benefits assumptions, respectively. The cost effectiveness of carvedilol for CHF compares favorably to that of other generally accepted medical interventions, even under conservative assumptions regarding the duration of therapeutic benefit.
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PMID:Cost effectiveness of carvedilol for heart failure. 1019 Apr 5

Carvedilol is a non-selective beta-blocker, and the only one, in recent clinical trials, to have shown a clear reduction in mortality. It is suggested that, compared with other beta-blockers, carvedilol has additional advantageous effects in heart failure, and should be considered as part of the routine treatment of heart failure.
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PMID:Carvedilol for heart failure: more than just a beta-blocker? 1019 51

Carvedilol is the first beta-blocker to obtain approval for treatment of heart failure. Improvement in hemodynamic parameters was initially documented in three methodologically sound studies involving 156 patients. Follow up was limited to 16 weeks. A placebo-controlled, double-blind trial involving 1094 patients showed beneficial effects on overall mortality of 4.6% in absolute terms after a median follow up of 6.5 months. This benefit was not found in another trial involving 415 patients followed on average for 19 months. Results for symptom-based criteria conflict. When treatment is introduced very gradually, adverse effects (malaise) seem to be minor and infrequent. Carvedilol's place in the treatment of heart failure is not yet precisely documented.
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PMID:Carvedilol. 1034 47

The authors present contemporary findings on the treatment with beta-blockers in patients with chronic heart failure. It is important to differentiate acute and chronic administration. The authors discuss theoretical prerequisites for the administration of beta-blockers in chronic heart failure. They give an account of indications, contraindications and mode of treatment. The dosage pattern for different preparations is given. The authors summarize the results of major studies with beta-blockers: MDC, CIBIS, ANZ, US Carvedilol Trials and they outline the trends of future research and indications for treatment with beta-blockers.
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PMID:[Beta blockers in the treatment of chronic cardiac failure]. 1035 70

Angiotensin converting enzyme (ACE) inhibitors are associated with a greater reduction in mortality in non-ischaemic cardiomyopathy than in ischaemic cardiomyopathy after the results of the V-HeFT-II and SOLVD trials in symptomatic patients. However, a recent analysis of the global, symptomatic and therapeutic, results of the SOLVD trials, demonstrated a similar reduction in mortality with ACE inhibitors in ischaemic and non-ischaemic cardiomyopathies. Moreover, after myocardial infarction, the beneficial effects of ACE inhibitors have been well established in patients with left ventricular dysfunction. Betablockers, especially bisoprolol in the CIBIS-I trial, also seem to be more effective in non-ischaemic cardiomyopathy. However, CIBIS-II and the US Carvedilol Heart Failure Trial Program clearly showed that the benefits of betablockade were identical whether ischaemic or not. The beneficial effects of betablockers in the post-infarction period are more marked when left ventricular dysfunction is severe. The PROVED and RADIANCE trials suggest that digitalis is more effective in non-ischaemic cardiomyopathy. These results were not confirmed by the DIG trial which showed a significant reduction in the combined criterion, mortality and hospital admission for aggravation of cardiac failure, both in ischaemic and in non-ischaemic cardiomyopathy. However, the use of digitalis should be prudent during ischaemic cardiomyopathy, the neutral effect on global mortality in the DIG trial masking divergent results with a tendency to reducing mortality due to aggravation of cardiac failure and a significant increase of other causes of cardiac death, especially from myocardial infarction and arrhythmias. Amiodarone could also be useful in non-ischaemic cardiomyopathy. The reduction in risk of death in the GESICA study, which comprised 60% of patients with non-ischaemic cardiomyopathy, contrasting with the absence of an effect with this molecule in the STAT-CHF trial which only comprised 29% of patients with non-ischaemic cardiomyopathy. The new generation of calcium antagonists could also be more effective in non-ischaemic cardiomyopathy. Although amlodipine significantly reduced mortality in the PRAISE trial in non-ischaemic cardiomyopathy, there was no favourable effect with felodipine in the V-HeFT-III tria. Finally, if in the earlier studies oral anticoagulants were more effective in non-ischaemic cardiomyopathy, the recent results of the SOLVD trial showed that warfarin decreased the mortality in both ischaemic and non-ischaemic cardiomyopathy. The value of anti-aggregant therapy is not questioned in coronary artery disease, but its role in dilated cardiomyopathy has not yet been established. In conclusion, apart from the use of digitalis which must be prudent in post-infarction cardiomyopathy or in patients with ventricular arrhythmias, the treatment of cardiac failure differs little with respect to its ischaemic or non-ischaemic aetiology, and should be based on the NYHA (New York Heart Association) classification.
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PMID:[Treatment of cardiac insufficiency: does treatment depend on whether its cause is ischemic or idiopathic?]. 1041 Aug 11

Carvedilol ((+/-)-1-(carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]am ino]-2-propanol), a beta-adrenoceptor-blocking agent with vasodilator properties, has been reported to produce dose-related improvements in left ventricular function and reduction in mortality in patients with chronic heart failure. However, its electrophysiological effects have not been elucidated. We studied ion channel and action potential modulation by carvedilol in rabbit ventricular preparations using whole-cell voltage-clamp and standard microelectrode techniques. In ventricular myocytes, carvedilol blocked the rapidly activating component of the delayed rectifier K+ current (I(Kr)) in a concentration-dependent manner (IC50 = 0.35 microM). This block was voltage- and time-independent; a prolongation of the depolarizing pulses from a holding potential of -50 mV to +10 mV within the range of 100-3000 ms did not affect the extent of I(Kr) block. Carvedilol also inhibited the L-type Ca2+ current (I(Ca)), the transient outward K+ current (I(to)) and the slowly activating component of the delayed rectifier K+ current (I(Ks)) with IC50 of 3.59, 3.34, and 12.54 microM, respectively. Carvedilol (0.3-30 microM) had no significant effects on the inward rectifier K+ current. In papillary muscles from rabbits pretreated with reserpine, action potential duration was prolonged by 7-12% with 1 microM and by 12-24% with 3 microM carvedilol at stimulation frequencies of 0.1-3.0 Hz. No further action potential duration prolongation was observed at concentrations higher than 3 microM. These results suggest that concomitant block of K+ and Ca2+ currents by carvedilol resulted in a moderate prolongation of action potential duration with minimal reverse frequency-dependence. Such electrophysiological effects of carvedilol would be beneficial in the treatment of ventricular tachyarrhythmias.
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PMID:Carvedilol blocks the repolarizing K+ currents and the L-type Ca2+ current in rabbit ventricular myocytes. 1044 Jan 4

Published clinical practice guidelines from the U.S. Agency for Health Care Policy and Research, the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the Task Force of the Working Group on Heart Failure of the European Society of Cardiology--supported by the results of numerous large-scale randomized controlled trials--define the standard universal pharmacologic approach to all patients with left ventricular systolic dysfunction. According to these guidelines, all heart failure patients regardless of etiology (with rare exceptions such as obstructive valvular heart disease) should be treated with an angiotensin-converting enzyme (ACE) inhibitor as first-line treatment of the heart failure. In fact, the non-edematous patient with only mild exertional dyspnea may be treated with an ACE inhibitor as sole therapy of the left ventricular dysfunction. As patients become edematous or complain of more moderate congestive symptoms, it is then appropriate to add a diuretic along with the ACE inhibitor. Digoxin is reserved for those patients who remain symptomatic on an ACE inhibitor and diuretic. Carvedilol, the only beta-adrenergic receptor blocker approved by the U.S. Food and Drug Administration for the treatment of heart failure, has been shown to reduce morbidity and mortality in patients with New York Heart Association Class II or III symptoms. In the U.S. Carvedilol Heart Failure Trials Program, carvedilol's benefit was seen in patients with either ischemic or nonischemic etiologies of heart failure. Similar findings of benefit in both ischemic and nonischemic heart failure have been observed in the recently reported Second Cardiac Insufficiency Bisoprolol Study (CIBIS II) trial as well as in ACE inhibitor heart failure trials. Studies suggesting differences in outcome based on etiology during pharmacologic treatment of heart failure have been too small (inadequately powered) or have assessed this difference only in post-hoc analyses. Thus, the universal pharmacologic management of heart failure with an ACE inhibitor, diuretic, beta-blocker (e.g. carvedilol), and digoxin may be applied to all patients with ischemic or nonischemic heart failure. This makes sense since the pathophysiology of heart failure following myocardial injury is similar for both forms of the disease.
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PMID:Ischemic and nonischemic heart failure do not require different treatment strategies. 1044 79

There is now considerable clinical trial data to support the use of beta-blockers in patients with congestive heart failure (CHF) due to systolic left ventricular dysfunction. A substantial database has accumulated over the last 20 years supporting the benefits of these agents on ventricular function and clinical status. In addition, morbidity and mortality benefits have been suggested, specifically with the non-selective vasodilating agent, carvedilol. More recently, a "new wave" of clinical trials have been conducted to definitively determine the mortality benefits of beta-blockers in patients with mild to moderate CHF as well as addressing other important clinical questions. These questions include whether the beneficial effects of carvedilol on survival can be reproduced by other agents in prospective, adequately powered studies; whether the benefits of carvedilol in systolic heart failure are due to its beta-blocking properties alone or to a combination of the beta-blocking and ancillary effects of the drug; whether beta-blockers are of benefit in patients with severe New York Heart Association (NYHA) Class IIIB-IV CHF; and, whether beta-blockers are of benefit (additional to ACE inhibitors) in patients with evidence of systolic ventricular dysfunction when commenced in the immediate post-myocardial infarction period. Major studies are currently being undertaken to address the above questions. Most are still underway but 3 studies have recently reported their results: the second Cardiac Insufficiency Bisoprolol Study (CIBIS II), the Research in Left Ventricular Dysfunction Study (RESOLVD), and the Metoprolol CR/XL Randomised Intervention Trial in Heart Failure (MERIT-HF) study. These studies have demonstrated that blockade with beta1-selective, non-vasodilating agents (i.e. bisoprolol and metoprolol) improve survival in patients with CHE Comparison of relative risk reduction in these recent studies with the earlier carvedilol studies raises mechanistic questions, specifically whether non-selectivity, vasodilation and other ancillary properties of carvedilol are critical to its benefit in CHF patients. This question is currently being addressed in the Carvedilol and Metoprolol European Trial (COMET), comparing metoprolol with carvedilol. The beneficial effects of beta-blockers on mortality in patients with mild to moderate CHF have also had major implications in ongoing studies of other agents in this condition. Open-label prescribing of beta-blockers is increasing in these studies and this is having an impact on event rates and thus required duration of administration of study drug. Furthermore, it would now appear unethical to deprive suitable NYHA Class II-III CHF patients of beta-blockers as part of the design of such studies. In conclusion, beta-blockers have now become the most extensively studied class of agents in the treatment of CHF, with a database of over 6000 patients in placebo-controlled studies, and ongoing clinical and mechanistic studies. Despite this, further questions remain regarding the use of these agents in CHF, including their role in the extreme elderly, in patients with diabetes mellitus and in patients with renal impairment.
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PMID:Beta-blockers in heart failure. The 'new wave' of clinical trials. 1047 16

Recent investigations have indicated that chronic heart failure can be reversed with agents that inhibit the reninangiotensin-aldosterone or sympathetic nervous system, such as angiontensin-converting enzyme (ACE) inhibitors and beta blockers. A meta-analysis of clinical trials of ACE inhibition in chronic heart failure reported reductions in mortality ranging from 13 to 33%, but as ACE inhibitors do not block chronic noradrenergic stimulation of the heart, mortality remains unacceptably high. Beta blockers have been shown to increase left ventricular ejection fraction, reduce end-systolic and end-diastolic cardiac dimensions, improve quality of life, and reduce mortality. All-cause mortality in the US Carvedilol trial was reduced 65%, and in MERIT-HF there was a 49% reduction in mortality from heart failure among patients receiving metoprolol CR/XL. MERIT-HF was ended early because of evidence of survival benefit. Although certain effects of beta blockers may be considered class effects, it is not yet clear whether there are differences between beta 1-selective antagonists and nonselective agents. The benefits conferred across differences in disease severity, race, and age should be answered as large ongoing and planned clinical trials of beta blockers are completed.
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PMID:Experience with beta blockers in heart failure mortality trials. 1052


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