Background The beneficial effects of beta-blockers and aldosterone receptor antagonists are now well established in patients with severe systolic chronic heart failure (CHF). However, it is unclear whether beta-blockers are able to provide additional benefit in patients already receiving aldosterone antagonists. We therefore examined this question in the COPERNICUS study of 2289 patients with severe CHF receiving the beta(1)-beta(2)/alpha(1) blocker carvedilol compared with placebo.Methods Patients were divided post hoc into subgroups according to whether they were receiving spironolactone (n=445) or not (n=1844) at baseline. Consistency of the effect of carvedilol versus placebo was examined for these subgroups with respect to the predefined end points of all-cause mortality, death or CHF-related hospitalizations, death or cardiovascular hospitalizations, and death or all-cause hospitalizations.Results The beneficial effect of carvedilol was similar among patients who were or were not receiving spironolactone for each of the 4 efficacy measures. For all-cause mortality, the Cox model hazard ratio for carvedilol compared with placebo was 0.65 (95% CI 0.36-1.15) in patients receiving spironolactone and 0.65 (0.51-0.83) in patients not receiving spironolactone. Hazard ratios for death or all-cause hospitalization were 0.76 (0.55-1.05) versus 0.76 (0.66-0.88); for death or cardiovascular hospitalization, 0.61 (0.42-0.89) versus 0.75 (0.64-0.88); and for death or CHF hospitalization, 0.63 (0.43-0.94) versus 0.70 (0.59-0.84), in patients receiving and not receiving spironolactone, respectively. The safety and tolerability of treatment with carvedilol were also similar, regardless of background spironolactone.Conclusion Carvedilol remained clinically efficacious in the COPERNICUS study of patients with severe CHF when added to background spironolactone in patients who were practically all receiving angiotensin-converting enzyme inhibitor (or ongiotensin II antagonist) therapy. Therefore, the use of spironolactone in patients with severe CHF does not obviate the necessity of additional treatment that interferes with the adverse effects of sympathetic activation, specifically beta-blockacle.

BACKGROUND:Chronic heart failure is a disease syndrome characterized in its advanced stages by a poor quality of life, frequent hospitalizations, and a high risk of mortality. In advanced and ultra-advanced chronic heart failure, many treatment options, such as cardiac transplantation and mechanical devices, are severely limited by availability and cost. Short-term Phase II clinical trials suggest that low-dose oral inotropic therapy with enoximone may improve hemodynamics and exercise capacity, without adversely affecting mortality, in selected subjects with advanced chronic heart failure. Based on these data, the ability of enoximone to deliver safe and efficacious palliative treatment of advanced/ultra-advanced chronic heart failure is being evaluated in Phase III clinical trials. METHODS AND RESULTS:The Enoximone Clinical Trials Program is a series of 4 clinical trials designed to evaluate the safety and efficacy of oral enoximone in advanced chronic heart failure. ESSENTIAL I and II (The Studies of Oral Enoximone Therapy in Advanced Heart Failure) will investigate the effects of oral enoximone on all-cause mortality and cardiovascular hospitalization, submaximal exercise capacity, and quality of life in subjects with New York Heart Association Class III/IV chronic heart failure. EMOTE (Oral Enoximone in Intravenous Inotrope-Dependent Subjects) will evaluate the potential of oral enoximone to wean subjects with ultra-advanced chronic heart failure from chronic intravenous inotropic therapy to which they have been shown to be dependent. EMPOWER (Enoximone Plus Extended-Release Metoprolol Succinate in Subjects with Advanced Chronic Heart Failure) will explore the potential of enoximone to increase the tolerability of continuous release metoprolol in subjects shown previously to be hemodynamically intolerant to beta-blocker treatment. CONCLUSION:These studies are Phase III, multicenter, randomized, double-blinded, placebo-controlled trials designed to test the general hypothesis that chronic oral administration of low doses of enoximone can produce beneficial effects in subjects with advanced or ultra-advanced chronic heart failure.

CONTEXT:Beta-blockers remain underused despite their established utility for improving outcome in heart failure. Concerns that initiation of treatment produces few immediate benefits and may have important risks may be deterring widespread use.OBJECTIVE:To evaluate the early effects of the beta-blocker carvedilol in patients with severe heart failure.DESIGN, SETTING, AND PATIENTS:Randomized, double-blind, placebo-controlled trial conducted from October 28, 1997, to March 20, 2000, at 334 hospital centers in 21 countries among 2289 patients with symptoms of heart failure at rest or with minimal exertion who were clinically euvolemic and had a left ventricular ejection fraction of less than 25%.INTERVENTION:Patients were randomly assigned to receive carvedilol, with start dosage of at 3.125 mg twice daily with uptitration to a target dosage of 25 mg twice daily (n = 1156), or placebo (n = 1133), in addition to their usual medications for heart failure.MAIN OUTCOME MEASURES:Death, hospitalization, or permanent withdrawal from study drug, as well as adverse events during the first 8 weeks of treatment.RESULTS:The carvedilol group experienced no increase in cardiovascular risk but instead had fewer patients who died (19 vs 25; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.41-1.35); who died or were hospitalized (134 vs 153; HR, 0.85; 95% CI, 0.67-1.07); or who died, were hospitalized, or were permanently withdrawn from treatment (162 vs 188; HR, 0.83; 95% CI, 0.68-1.03). These effects were similar in direction and magnitude to those observed during the entire study, and were apparent particularly in the 624 patients with recent or recurrent decompensation or a very depressed left ventricular ejection fraction. Differences in favor of carvedilol became apparent as early as 14 to 21 days following initiation of treatment. Worsening heart failure was the only serious adverse event with a frequency greater than 2% and was reported with similar frequency in the placebo and carvedilol groups (6.4% vs 5.1%).CONCLUSIONS:These data suggest that, in clinically euvolemic patients, the relation of benefit to risk during initiation of treatment with carvedilol is similar to that seen during long-term therapy with the drug. Our findings should provide the reassurance needed to encourage the high levels of use that are warranted by the results of long-term clinical trials.

Anemia has been shown to be a risk factor for mortality in mild to moderate heart failure (HF), but its importance in severe HF and its ability to predict hospitalization has not been defined. Methods: We evaluated the relationship between hemoglobin level and mortality and hospitalization in 2286 patients (1822 men, 464 women) with severe HF enrolled in the COPERNICUS study. Enrolled patients had dyspnea or fatigue at rest or on minimal exertion for at least 2 months and a left ventricular ejection fraction <25%. Results: There was a highly significant (P<0.0001) but small (r = −0.089) inverse relationship between baseline hemoglobin and creatinine levels. Patients with low hemoglobin were at significantly higher risk of a major clinical event, the magnitude of risk decreasing with increasing hemoglobin, both in univariate analyses (all P<0.001) and in multivariate analyses which adjusted for sex and other predictors of of risk, including age, ejection fraction, creatinine, body mass index, systolic blood pressure, HF etiology and treatment with carvedilol (all P<0.01). Mean creatinine levels and one-year Kaplan-Meier event rates are shown in table 1 Conclusions: Low hemoglobin is an independent risk factor for adverse outcomes in patients with severe HF. Whether correction of anemia improves outcomes warrants further study.Table 1Hemoglobin (g/dl)NCreatinine (μmol/L)All-Cause Mortality (%)Death or HF Hospitalization (%)Death or Any Hospitalization (%)<11.0115151.123.246.664.111.0-<12.5315135.816.736.151.012.5-<13.5432133.213.530.548.313.5-<15.0834132.715.631.945.515.0-16.5463131.213.126.542.9>16.5127131.59.025.538.0 Open table in a new tab Anemia has been shown to be a risk factor for mortality in mild to moderate heart failure (HF), but its importance in severe HF and its ability to predict hospitalization has not been defined. Methods: We evaluated the relationship between hemoglobin level and mortality and hospitalization in 2286 patients (1822 men, 464 women) with severe HF enrolled in the COPERNICUS study. Enrolled patients had dyspnea or fatigue at rest or on minimal exertion for at least 2 months and a left ventricular ejection fraction <25%. Results: There was a highly significant (P<0.0001) but small (r = −0.089) inverse relationship between baseline hemoglobin and creatinine levels. Patients with low hemoglobin were at significantly higher risk of a major clinical event, the magnitude of risk decreasing with increasing hemoglobin, both in univariate analyses (all P<0.001) and in multivariate analyses which adjusted for sex and other predictors of of risk, including age, ejection fraction, creatinine, body mass index, systolic blood pressure, HF etiology and treatment with carvedilol (all P<0.01). Mean creatinine levels and one-year Kaplan-Meier event rates are shown in table 1 Conclusions: Low hemoglobin is an independent risk factor for adverse outcomes in patients with severe HF. Whether correction of anemia improves outcomes warrants further study.

BACKGROUND:Beta-blocking agents improve functional status and reduce morbidity in mild-to-moderate heart failure, but it is not known whether they produce such benefits in severe heart failure.METHODS AND RESULTS:We randomly assigned 2289 patients with symptoms of heart failure at rest or on minimal exertion and with an ejection fraction <25% (but not volume-overloaded) to double-blind treatment with either placebo (n=1133) or carvedilol (n=1156) for an average of 10.4 months. Carvedilol reduced the combined risk of death or hospitalization for a cardiovascular reason by 27% (P=0.00002) and the combined risk of death or hospitalization for heart failure by 31% (P=0.000004). Patients in the carvedilol group also spent 27% fewer days in the hospital for any reason (P=0.0005) and 40% fewer days in the hospital for heart failure (P<0.0001). These differences were as a result of both a decrease in the number of hospitalizations and a shorter duration of each admission. More patients felt improved and fewer patients felt worse in the carvedilol group than in the placebo group after 6 months of maintenance therapy (P=0.0009). Carvedilol-treated patients were also less likely than placebo-treated patients to experience a serious adverse event (P=0.002), especially worsening heart failure, sudden death, cardiogenic shock, or ventricular tachycardia.CONCLUSION:In euvolemic patients with symptoms at rest or on minimal exertion, the addition of carvedilol to conventional therapy ameliorates the severity of heart failure and reduces the risk of clinical deterioration, hospitalization, and other serious adverse clinical events.

Background: The results of the MERIT-HF trial suggested that women with heart failure (HF) respond less favorably to ~-blockade than men. To further explore this observation, we evaluated the effect of gender on the response to carvedilol (CRV) in the COPERNICUS trial. Methods: 2289 patients (1824 men, 465 women) with symptoms of CHF at rest or on minimal exertion and ejection fraction <25% were randomly assigned to placebo (PBO) or CRV for up to 29 months. Women were older than men (66 vs 63 yrs; P<0,001) and were more likely to have non-ischemic HF (42% vs 30%; P<0.001) but were similar in other baseline characteristics. Results: Shown below are Cox model (CRV:PBO) hazard ratios, 95% CI and interaction P values: Men Women Interaction P value

Background: Beta-blocking agents reduce the risk of hospitalization and death in patients with mild-to-moderate heart failure, but little is known about their effects in severe heart failure.Methods: We evaluated 2289 patients who had symptoms of heart failure at rest or on minimal exertion, who were clinically euvolemic, and who had an ejection fraction of less than 25 percent. In a double-blind fashion, we randomly assigned 1133 patients to placebo and 1156 patients to treatment with carvedilol for a mean period of 10.4 months, during which standard therapy for heart failure was continued. Patients who required intensive care, had marked fluid retention, or were receiving intravenous vasodilators or positive inotropic drugs were excluded.Results: There were 190 deaths in the placebo group and 130 deaths in the carvedilol group. This difference reflected a 35 percent decrease in the risk of death with carvedilol (95 percent confidence interval, 19 to 48 percent; P=0.0014, adjusted for interim analyses). A total of 507 patients died or were hospitalized in the placebo group, as compared with 425 in the carvedilol group. This difference reflected a 24 percent decrease in the combined risk of death or hospitalization with carvedilol. The favorable effects on both end points were seen consistently in all the subgroups we examined. Fewer patients in the carvedilol group than in the placebo group withdrew because of adverse effects or for other reasons (P=0.02).Conclusions: The previously reported benefits of carvedilol with regard to morbidity and mortality in patients with mild-to-moderate heart failure were also found in the patients with severe heart failure who were evaluated in this trial. (N Engl J Med 2001;344:1651-8.) Copyright (C) 2001 Massachusetts Medical Society.