US Carvedilol Heart Failure Research Articles

COUNTERPOINT: the Seductive Trap of Relying on Exaggerated Effects in Short-Term Heart Failure Trials to Predict Benefits and Risks in Patients With Long-Term Disease

COUNTERPOINT: the Seductive Trap of Relying on Exaggerated Effects in Short-Term Heart Failure Trials to Predict Benefits and Risks in Patients With Long-Term Disease

Prophylactic pacemaker use to allow β-blocker therapy in patients with chronic heart failure with bradycardia

Although the benefits of beta-blocker therapy for patients with congestive heart failure (CHF) are independent of pretreatment heart rate, patients with chronic systolic heart failure and low resting heart rates are often excluded from beta-blocker therapy. We investigated the effectiveness and cost-effectiveness of prophylactic pacemaker insertion to facilitate beta-blocker use in these patients. A Markov model simulated the natural history of a cohort of clinically stable patients with CHF (ejection fraction < or = 35%, mean age 60 years) with resting heart rates of < 68 beat/min. Two strategies were evaluated: (1) conventional therapy (conventional)-the risks for death and hospitalization were derived from the angiotensin-converting enzyme inhibitor arm of the SOLVD treatment trial; and (2) pacemaker insertion with atrial pacing and carvedilol therapy (pacemaker-carvedilol)-risk reductions for death and CHF-related hospitalizations for carvedilol compared with conventional therapy were derived from the US Carvedilol Heart Failure Study. We assumed full carvedilol benefits for 2 years, declining benefits for the next 3 and no additional benefits after 5 years, whereas pacemaker-related adverse events persisted. In the base case, the pacemaker-carvedilol strategy increased mean survival by 1.3 years at an incremental cost of $7800, for an incremental cost-effectiveness of $6100 per year of life saved. Results were most sensitive to theoretical pacing-induced harm, changes in hospitalization cost, and reductions in beta-blocker benefits. Prophylactic pacemaker insertion to facilitate beta-blocker treatment in patients with CHF with low resting heart rates has the potential to produce clinical benefits in a highly cost-effective manner.

Landmark studies: the Australia/New Zealand Heart Failure Collaborative Group (ANZ) Trial and the US Carvedilol Trials Program

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.

Use of beta-blockers in congestive heart failure

While β-adrenergic blockers have been used for decades in a variety of cardiovascular illnesses, they have traditionally been avoided in chronic heart failure. In spite of significant advances in management, mortality in patients suffering from heart failure remains unacceptably high and new therapies are urgently needed. Recently, several large clinical trials have shown a significant reduction in both morbidity and mortality in heart failure patients when β-blockers are added to standard therapy. While further investigation is warranted in certain subgroups, the use of β-adrenergic blockers in New York Heart Association (NYHA) class II to IV heart failure should now be considered routine. The purpose of this article is to outline and review the five major clinical trials of β-blocker therapy in chronic heart failure; the US Carvedilol heart failure Program (USCP), the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), the Metoprolol CR/XL Randomized Intervention Trial in chronic Heart Failure (MERIT-HF), the Beta-blocker Evaluation of Survival Trial (BEST) and the Carvedilol Prospective Randomized Cumulative Survival trial (COPERNICUS), and to aid the reader in the selection of appropriate candidates for β-blocker therapy.

Carvedilol: a review of its use in chronic heart failure.

Carvedilol (Dilatrend) blocks beta(1)-, beta(2)- and alpha(1)-adrenoceptors, and has antioxidant and antiproliferative effects. Carvedilol improved left ventricular ejection fraction (LVEF) in patients with chronic heart failure (CHF) in numerous studies. Moreover, significantly greater increases from baseline in LVEF were seen with carvedilol than with metoprolol in a double-blind, randomised study and in a meta-analysis. Carvedilol also reversed or attenuated left ventricular remodelling in patients with CHF and in those with left ventricular dysfunction after acute myocardial infarction (MI). Combined analysis of studies in the US Carvedilol Heart Failure Trials Program (patients had varying severities of CHF; n = 1094) revealed that mortality was significantly lower in carvedilol than in placebo recipients. In addition, the risk of hospitalisation for any cardiovascular cause was significantly lower with carvedilol than with placebo. Mortality was significantly lower with carvedilol than with metoprolol in patients with mild to severe CHF in the Carvedilol Or Metoprolol European Trial (COMET) [n = 3029]. The Carvedilol Prospective Randomised Cumulative Survival (COPERNICUS) trial (n = 2289) demonstrated that compared with placebo, carvedilol was associated with significant reductions in all-cause mortality and the combined endpoint of death or hospitalisation for any reason in severe CHF. All-cause mortality was reduced in patients who received carvedilol in addition to conventional therapy compared with those who received placebo plus conventional therapy in the Carvedilol Post-Infarct Survival Control in LV Dysfunction (CAPRICORN) trial (enrolling 1959 patients with left ventricular dysfunction following acute MI). Carvedilol was generally well tolerated in patients with CHF. Adverse events associated with the alpha- and beta-blocking effects of the drug occurred more commonly with carvedilol than with placebo, whereas placebo recipients were more likely to experience worsening heart failure. In conclusion, carvedilol blocks beta(1)-, beta(2)- and alpha(1)-adrenoceptors and has a unique pharmacological profile. It is thought that additional properties of carvedilol (e.g. antioxidant and antiproliferative effects) contribute to its beneficial effects in CHF. Carvedilol improves ventricular function and reduces mortality and morbidity in patients with mild to severe CHF, and should be considered a standard treatment option in this setting. Administering carvedilol in addition to conventional therapy reduces mortality and attenuates myocardial remodelling in patients with left ventricular dysfunction following acute MI. Moreover, mortality was significantly lower with carvedilol than with metoprolol in patients with mild to severe CHF, suggesting that carvedilol may be the preferred beta-blocker.

Evaluation and Treatment of Patients With Systemic Hypertension

A 65-year-old man presented for evaluation of high blood pressure found on screening at a local health fair. History and physical examination did not show any signs or symptoms suggestive of a secondary cause, nor was there evidence of target end-organ damage except for grade 1 Keith-Wagener-Barker retinopathy. The patient denied taking any prescription or over-the-counter medications. Hypertension is the most common disease-specific reason Americans visit a physician. Despite the risks associated with an elevated blood pressure (BP), there is still woefully low achievement of recommended BP goals. From 1991 to 1994, only 27.4% of hypertensive Americans aged 18 to 74 years had a BP <140/90 mm Hg, the current stated goal for most people with hypertension, and in those with diabetes, less than half that number (11%) were controlled to the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure VI (JNC VI) recommended goal of <130/85 mm Hg.1 The present update will provide an overview of the evaluation and management of essential hypertension and help to guide clinicians in developing a management plan for a patient like the one described above. Taking a proper BP is an important first step in the diagnosis of hypertension.2 Using the proper cuff size with patients resting quietly and comfortably (with back support if seated) for at least 5 minutes before measurement, 2 or more readings separated by 2 minutes should be taken and averaged. Initial elevated BP readings should be confirmed on at least 2 subsequent visits over a period of 1 week or more. A value that is consistently ≥140/90 mm Hg is diagnostic in healthy patients; a value >130/80 mm Hg should be used for those with diabetes or kidney disease and proteinuria. Initial evaluation of the hypertensive patient focuses on the presence …

Effect of carvedilol on survival and hemodynamics in patients with atrial fibrillation and left ventricular dysfunction: Retrospective analysis of the US Carvedilol Heart Failure Trials Program

Background Atrial fibrillation (AF) is present in a significant number of patients with congestive heart failure (CHF) caused by left ventricular dysfunction and is associated with significant morbidity and increased mortality rates. Thus it is necessary to establish therapy to improve the outcome in this high-risk population. Methods We conducted a retrospective analysis of data from the US Carvedilol Heart Failure Trials Program and identified patients with AF at the time of enrollment. In these trials, 1094 patients with at least 3 months of heart failure symptoms and an ejection fraction ≤0.35 were randomly assigned to receive carvedilol or placebo in a double-blind, stratified program according to performance on an exercise test. Results One hundred thirty-six patients with concomitant AF and CHF were identified during the screening visit (84 assigned to carvedilol and 52 to placebo). Therapy with carvedilol resulted in a significant improvement in left ventricular ejection fraction (from 23% to 33% with carvedilol and from 24% to 27% with placebo, P =.001). The physician global assessment improved in a greater number of patients treated with carvedilol than in those treated with placebo (71% vs 48%, P =.025). A trend toward a reduction in the combined end point of death or CHF hospitalization was also observed (19% in patients treated with placebo and 7% in patients on carvedilol; relative risk, 0.35; 95% confidence interval, 0.12, 1.02; P =.055). Conclusions In patients with AF complicating CHF, carvedilol significantly improves left ventricular ejection fraction and physician global assessment and probably reduces the combined end point of CHF hospitalizations or death. (Am Heart J 2001;142:498-501.)

Cost-Effectiveness Results from the US Carvedilol Heart Failure Trials Program

OBJECTIVE:To evaluate the cost-effectiveness of carvedilol, a β-blocker that is approved for use in the US for the treatment of heart failure, based on data from Phase III clinical trials.METHODS:We conducted an economic evaluation alongside the US Carvedilol Heart Failure Trials Program, which consisted of four concurrent, randomized, double-blind, placebo-controlled clinical trials; the mean duration of follow-up across these four trials was 6.5 months (the program was terminated prematurely based on a finding of a 65% mortality benefit). Using data from these trials, we examined the cost-effectiveness of carvedilol in terms of the estimated cost per death averted among patients randomized to such therapy versus those receiving placebo. Attention was focused on the cost of carvedilol therapy plus the cost of cardiovascular-related inpatient care. Costs of care were estimated by combining information on healthcare utilization from the clinical trials with secondary sources of cost data.RESULTS:Patients randomized to receive carvedilol had lower mean ± SD estimated costs of cardiovascular-related inpatient care over 6.5 months compared with those receiving placebo ($1912 ± $7595 vs. $4463 ± $20 565, respectively). As mortality also was lower among carvedilol patients, the estimated cost per death averted was negative. The probability that carvedilol would both increase survival and decrease costs of cardiovascular-related care over a 6.5-month period was estimated to be 0.98.CONCLUSIONS:Data from the US Carvedilol Heart Failure Trials Program indicate that carvedilol reduces mortality in patients with heart failure; our study suggests that it also may be cost-saving over a period of approximately six months.

Random research.

Advances in computing have combined with the rapid dissemination of treatment discoveries for diseases of public health importance to create pressure for accelerated promulgation of promising research results to the medical community. The 2 recent examples of the US Carvedilol Heart Failure program and the Evaluation of Losartan In the Elderly (ELITE) study demonstrate the importance of the prospective nature of research design, as well as the consequences of its abandonment. This article explains in nonmathematical terms the rationale for the tenet "first say what you will do, then do what you said" in sample-based research.

Cardiovascular News

Cardiovascular News

Carvedilol in the treatment of chronic heart failure

Along with the angiotensin-converting enzyme inhibitors (ACEIs), the β-adrenergic receptor blockers have gradually emerged to be standard in the therapy of heart failure. Individual β-blockers that have been shown to reduce all-cause mortality in patients with heart failure include bisoprolol, metoprolol and carvedilol. Carvedilol distinguishes from the other β-blockers as being a non-selective 1- and 2-receptor blocker with 1-receptor blockade effect and anti-oxidant properties. The drug does not have sympathomimetic activity and has vasodilatory effects attributable to its 1-receptor blockade property. Experimental and clinical studies have confirmed carvedilol’s vasodilator, anti-oxidant and anti-apoptotic properties, which may contribute to its effect in reversing cardiac remodelling in animal models and patients with heart failure. These pharmacological properties render carvedilol a potentially useful agent in the treatment of patients with heart failure. Early studies of carvedilol in heart failure have reported beneficial haemodynamic effects but variable effects on exercise tolerance and clinical well being. The large-scale US Carvedilol Heart Failure Program and the Australian/New Zealand Heart Failure Collaborative Research Group reported beneficial effects of carvedilol on mortality, morbidity and clinical well being in patients with mild-to-moderate heart failure. The recently reported but yet unpublished preliminary results of the COPERNICUS study suggest that carvedilol improves mortality and morbidity in patients with advanced heart failure and severe symptoms. At this time, it is unclear whether the ancillary pharmacological properties of carvedilol can be translated to more superior clinical benefit compared to the other β-blockers. Preliminary studies examining surrogate end points suggest that carvedilol may improve left ventricular ejection fraction (LVEF) more than metoprolol. More conclusive information regarding their relative effects of clinical outcomes will await the completion of the COMET study, which compares the effect of metoprolol and carvedilol on mortality and morbidity, expected at the end of the year 2002.

Beta-adrenergic receptor signaling: an acute compensatory adjustment-inappropriate for the chronic stress of heart failure? Insights from Gsalpha overexpression and other genetically engineered animal models.

Under normal physiological conditions, the heart must be able to increase its output 5-fold to supply the required blood flow to the coronary circulation and skeletal muscles during severe stress. This is normally met by ≈5-fold increases in myocardial contractility, ≈3-fold increases in heart rate, and additional increases in stroke volume.1 This increased load requires a commensurate increase in myocardial blood flow, because oxygen extraction across the heart is nearly complete, even under normal conditions. Accordingly, the design of the cardiovascular system evolved to conserve myocardial metabolic demand, and consequently coronary blood flow, at rest, but with considerable reserve that can be called on rapidly in times of stress. There is a host of compensatory adjustments, including changes in metabolic substrates and kinetics, as well as oxygen-carrying capacity, that may be recruited in response to stress. However, none is more important than the autonomic nervous system in general, and the sympathetic arm in particular, in terms of providing large, rapid changes in cardiac function. When this compensatory mechanism is unavailable, eg, after treatment with propranolol, the 3-fold increases in heart rate and 5-fold increases in myocardial contractility in response to exercise cannot be achieved.1 In this connection, it is recognized that heart failure is a state characterized by enhanced sympathetic tone, but when the failing myocardium is challenged by β-adrenergic stimulation in vivo or in vitro, the most frequent result is β-adrenergic downregulation or desensitization.2 3 4 5 An impairment of cardiac function leads to autocrine, paracrine, and neurohormonal adjustments, including a strong sympathetic component (Figure 1⇓); under acute conditions, these reflex adjustments are beneficial, as noted above. However, when the sympathetic nervous system is chronically and tonically stimulated, as occurs in the pathogenesis of heart failure, desensitization mechanisms are called into play, such that the …

Recent clinical data regarding the use of β blockers in heart failure: focus on CIBIS II

From studies which first started in Sweden many years ago, the evidence for the beneficial role of β blockers in the management of heart failure is now very substantial. We...

Cost effectiveness of carvedilol for heart failure

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.

Assuming the worst may not be bad at all. Carvedilol in heart failure treatment.

Carvedilol, a beta-adrenoceptor blocking agent with additional alpha(1)-adrenoceptor blocking properties, has been shown to improve left ventricular function in chronic heart failure (CHF). However, its effect on mortality has recently been the subject of controversial discussion. The aim of this meta-analysis is to review the data on mortality from two large study programs (the US Carvedilol Heart Failure Study and the study by the Australia/New Zealand Heart Failure Research Collaborative Group) on additional carvedilol treatment in CHF standard therapy and to analyse the design and limitations of the individual studies. For determination of overall, mortality, all patients who died and all patients who were withdrawn for other reasons during the open run-in phase of the studies were assigned to the carvedilol group to create a "worst-case analysis." Meta-analysis of mortality data using the random effects model shows a significantly reduced relative risk of 0.55 x 95%-confidence interval 0.325-0.924; p < 0.05 of death in patients treated with carvedilol compared with patient on standard treatment only. Treatment of CHF using carvedilol significantly reduces mortality in patients with CHF, even if the "worst case" is assumed by assigning all deaths in the open run-in phase to carvedilol.

Effects of Beta Blockers on Symptoms and Functional Capacity in Heart Failure

Beta-adrenergic-blocking drugs ameliorate the progression of disease that usually characterizes heart failure. All of the larger multicenter studies have demonstrated reductions in morbidity, manifested by a reduction in the number of hospitalizations and/or listing for cardiac transplantation, whereas studies with carvedilol have also reported a significant reduction in mortality. The influence of β-adrenergic blocking drugs on the symptomatic and functional status of patients with heart failure has been more difficult to establish. Almost all trials have reported an improvement in New York Heart Association (NYHA) functional class, with few patients experiencing functional deterioration. Improvement in symptom score was reported in the Metoprolol in Dilated Cardiomyopathy (MDC) trial for patients treated with metoprolol. In patients from the US Carvedilol Heart Failure Trials Program who had heart failure from ischemic and nonischemic etiologies, both patients and physicians reported more improvement and less deterioration in an assessment of global status. More formal instruments to assess quality of life, such as the specific activity scale in the Australia-New Zealand trial of carvedilol (that recruited 30% of patients who had improved to NYHA stage I) and the Minnesota Quality of Life questionnaire, did not seem sensitive to the clinical benefits observed in these trials. Serial exercise testing similarly does not seem sensitive to the beneficial influence of β-adrenergic blocking drugs on disease progression, at least in relatively short-term studies.

Carvedilol. A reappraisal of its pharmacological properties and therapeutic use in cardiovascular disorders.

Carvedilol competitively blocks beta 1, beta 2 and alpha 1 receptors. The drug lacks sympathomimetic activity and has vasodilating properties that are exerted primarily through alpha 1-blockade. Animal models indicate that carvedilol confers protection against myocardial necrosis, arrhythmia and cell damage caused by oxidising free radicals, and the drug has no adverse effects on plasma lipid profiles. Recent data have confirmed the antihypertensive efficacy of carvedilol in patients with mild to moderate essential hypertension. Carvedilol has similar efficacy to other beta-blocking agents, calcium antagonists, ACE inhibitors and hydrochlorothiazide. Carvedilol also improves exercise tolerance and ischaemic symptoms in patients with stable angina pectoris. Significant reductions in serious cardiac events after acute myocardial infarction and in frequency and severity of ischaemic events in patients with unstable angina have also been demonstrated. Interest in the use of carvedilol in patients with congestive heart failure (CHF) has culminated in the publication of a cumulative analysis of data from 1094 patients with mild to severe CHF who participated in the US Carvedilol Heart Failure Study Program (4 trials). After a median follow-up of 6.5 months, a significant overall reduction in mortality relative to placebo (3.2 vs 7.8%) was revealed in patients who had received carvedilol 6.25 to 50 mg twice daily (plus diuretics and ACE inhibitors). All-cause mortality, risk of hospitalisation for cardiovascular reasons and hospitalisation costs were also reduced significantly (by 65, 28% and 62%, respectively) in these trials. In addition, the Australia and New Zealand Heart Failure Research Collaborative Group showed a 26% reduction in the combined risk of death or hospitalisation with carvedilol 12.5 to 50 mg/day relative to placebo after a mean 19-month follow-up period in 415 patients with CHF (relative risk 0.74). Adverse events with carvedilol appear to be less frequent than with other beta-blocking agents, are dosage-related and are usually seen early in therapy. Events most commonly reported are related to the vasodilating (postural hypotension, dizziness and headaches) and the beta-blocking (dyspnoea, bronchospasm, bradycardia, malaise and asthenia) properties of the drug. Carvedilol appears to date to have little effect on the incidence of worsening heart failure. Concomitant administration of carvedilol with some medications requires monitoring. Carvedilol is therefore likely to have a beneficial role in the management of controlled CHF, but further clinical studies are required to show the place of beta-adrenoceptor blocking therapy in general in this indication, and the position of carvedilol relative to other similar agents. Carvedilol is also confirmed as effective in the management of mild to moderate hypertension and ischaemic heart disease.