The safety of amiodarone in patients with heart failure.

BACKGROUND: Uncertainty persists about the safety and efficacy of amiodarone for the management of heart failure. METHODS AND RESULTS: We randomized 3029 patients with chronic heart failure to receive carvedilol or metoprolol and followed patients for a median of 58 months. One hundred fifty-five of 1466 patients in New York Heart Association (NYHA) Class II and 209 of 1563 in Class III or IV received amiodarone at baseline. Persistence with amiodarone treatment was high and 66% received amiodarone after 4 years. During follow-up, 38.7% and 58.9% of patients receiving amiodarone in NYHA Classes II and III + IV died versus 26.2% and 43.3% not receiving amiodarone (P < .001). This difference was maintained in multivariable analysis (hazard ratio [HR] 1.5, 95% confidence interval [CI] 1.2-1.7, P < .001). The difference was explained by an increased risk of death due to circulatory failure (HR 2.4, CI 1.9-3.1, P < .001) in patients receiving amiodarone. Sudden death was not different (HR 1.07, CI 0.8-1.4, P = .7). The increased risk was similar across NYHA classes with HR of 1.60 (CI 1.2-2.1, P < .001) in NYHA Class II versus 1.58 (CI 1.3-1.9, P < .001) in Classes III + IV. CONCLUSIONS: Treatment with amiodarone was associated with an increased risk of death from circulatory failure independent of functional class.

Effect of carvedilol and metoprolol on the mode of death in patients with heart failure.

BACKGROUND: In the COMET study, carvedilol improved survival compared to metoprolol tartrate in 3029 patients with NYHA II-IV heart failure and EF <35%, followed for an average of 58 months. AIMS: To evaluate whether the effect on overall mortality was specific for a particular mode of death. This may help to identify the mechanism of the observed difference. METHODS: Of the 1112 total deaths, 972 were adjudicated as cardiovascular, including 480 sudden, 365 circulatory failure (CF) and 51 stroke deaths. For each mode of death, the effect of pre-specified baseline variables was assessed, including sex, age, NYHA class, aetiology, heart rate, systolic blood pressure, EF, atrial fibrillation, previous myocardial infarction or hypertension, renal function, concomitant medication, and study treatment allocation. RESULTS: In multivariate Cox regression analyses, compared to metoprolol, carvedilol reduced cardiovascular (RR 0.80, CI 0.7-0.91, p=0.0009), sudden (RR 0.77, CI 0.64-0.93, p=0.0073) and stroke deaths (RR 0.37, CI 0.19-0.71, p=0.0027) with a non-significant trend for CF death (RR 0.83, CI 0.66-1.04, p=0.07). Treatment benefit with carvedilol did not differ between modes of death, except for a greater reduction in stroke death with carvedilol (competing risk analysis, p=0.0071 vs CF death). There were no interactions between treatment allocation and baseline characteristics. CONCLUSION: Mortality reduction with carvedilol compared to metoprolol appears relatively non-specific and could be consistent with a superior effect of carvedilol on cardiac function, arrhythmias or, in view of the greater reduction in stroke deaths, on vascular events.

Treatment of chronic heart failure with carvedilol in daily practice: the SATELLITE survey experience.

BACKGROUND: Beta-blockers are well established for treatment of chronic heart failure (CHF). However, the extent of implementation of trial results and guidelines in daily practice remains limited, and information regarding how patients feel is scarce. METHODS: In this prospective observational survey of 6 months duration, 531 physicians from 10 countries recruited 3748 beta-blockers untreated patients with CHF. We assessed the efficacy, tolerability and achieved dosage of carvedilol. In addition, patients assessed their well-being 3 times: at baseline, after 3 and 6 months of treatment. RESULTS: Carvedilol was started in 3721 patients with CHF (median age 65 years, 60% men). NYHA class, clinical symptoms and signs, vital signs, 5-item well-being rating scale and visual analogue scale improved during the survey. Side effects, mostly fatigue, hypotension, and dizziness, were reported for 6.5% and 5% of patients at 3 and 6 months and carvedilol had to be discontinued in 63 patients. A total of 55 deaths (1.5%) and 520 hospitalisations in 466 patients (13%) were recorded. At 6 months the mean daily dose of carvedilol was 31+/-11 mg; 25 mg/day was prescribed to 35% and 50 mg/day to 26% of patients. CONCLUSIONS: Initiation and up-titration of carvedilol in ambulatory care patients with CHF is feasible and safe. Its efficacy and tolerability were at least as good as in clinical trials, while the amelioration of patients' well-being was significant despite sub-optimal dosing. An additional effort should be done by physicians to treat their patients with CHF in daily practice with the recommended beta-blockers at optimal doses.

Carvedilol protects better against vascular events than metoprolol in heart failure: results from COMET.

OBJECTIVES: We explored whether vascular protection by carvedilol could contribute to its superior effects in the treatment of heart failure (HF) compared with metoprolol tartrate in the COMET (Carvedilol Or Metoprolol European Trial) study. BACKGROUND: Full adrenergic blockade by carvedilol and additional (e.g., antioxidative) properties may lead to vascular protection relative to beta-1 blockade alone, and contribute to its efficacy in HF treatment. METHODS: Three thousand twenty-nine patients with HF due to ischemic (51%) or idiopathic cardiomyopathy (44%) were randomized double-blind to carvedilol (n = 1,511) or metoprolol (n = 1,518) and followed for 58 months. Vascular end points were cardiovascular death, stroke, stroke death, myocardial infarction (MI), and unstable angina. RESULTS: The effect of carvedilol on cardiovascular death improved consistently in subgroups with prespecified baseline variables. Myocardial infarctions were reported in 69 carvedilol and 94 metoprolol patients (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.52 to 0.97, p = 0.03). Cardiovascular death or nonfatal MI combined were reduced by 19% in carvedilol (HR 0.81, 95% CI 0.72 to 0.92, p = 0.0009 vs. metoprolol). Unstable angina was reported as an adverse event in 56 carvedilol and in 77 metoprolol patients (HR 0.71, 95% CI 0.501 to 0.998, p = 0.049). A stroke occurred in 65 carvedilol and 80 metoprolol patients (HR 0.79, 95% CI 0.57 to 1.10). Stroke or MI combined occurred in 130 carvedilol and 168 metoprolol patients (HR 0.75, 95% CI 0.60 to 0.95, p = 0.015), and fatal MI or fatal stroke occurred in 34 carvedilol and in 72 metoprolol patients (HR 0.46, 95% CI 0.31 to 0.69, p = 0.0002). Death after a nonfatal MI or stroke occurred in 61 of 124 carvedilol and in 106 of 160 metoprolol patients (HR 0.66, 95% CI 0.48 to 0.90, p = 0.0086). CONCLUSIONS: Carvedilol improves vascular outcomes better than metoprolol. These results suggest a ubiquitous protective effect of carvedilol against major vascular events.

The impact of new onset anaemia on morbidity and mortality in chronic heart failure: results from COMET.

AIMS: Anaemia is a common comorbidity in chronic heart failure (CHF). The predictors of new onset anaemia (NOA) and its long-term prognostic value, particularly in patients treated with beta-blockers, are not known. METHODS AND RESULTS: In COMET, 3029 patients with CHF in NYHA II-IV and EF <35% were randomized to carvedilol or metoprolol tartrate and were followed for an average of 58 months. Plasma haemoglobin (Hb) concentrations were measured at a central laboratory at randomization, at four monthly intervals for the first year and annually thereafter. According to WHO criteria, anaemia was defined when Hb measured <13 g/dL for men and <12 g/dL for women. We considered anaemia to be severe when Hb <11.5 g/dL for men and <10.5 g/dL for women. The baseline mean Hb was 14.2 +/- 1.5 g/dL (n = 2996) and 15.9% of patients had anaemia (males, 16.0%; females, 15.2%). At baseline, severe anaemia was found in 3.3% of patients (males, 3.6%; females, 2.0%). During the study, all-cause mortality (RR 1.47) death or hospitalization (RR 1.28), and heart failure hospitalization (RR 1.43, all P < 0.0001) were higher in anaemic when compared with non-anaemic patients. In patients without anaemia at baseline, at the end of the study, the cumulative frequency of NOA was 28.1% in males and 27.0% in females. NOA increased over time from 14.2% at year 1 to 27.5% at year 5. Predictors of NOA were: higher age, diuretic dose, creatinine (all P < 0.0001), higher serum potassium, lower serum sodium, body mass index, and use of aldosterone antagonists, carvedilol, and digitalis (all P < 0.03). Treatment with carvedilol (vs. metoprolol tartrate) was associated with a 24% increased risk to develop NOA (P = 0.0047), but not severe anaemia (P = 0.18). Patients with a Hb decrease of >3 g/dL (RR 3.37, P < 0.0001) or of 2.0-3.0 g/dL (RR 1.47, P = 0.011) from baseline had an increased subsequent mortality when compared with patients having Hb increases of 0-1.0 g/dL. CONCLUSION: In stable ambulatory CHF patients, development of NOA is frequent and can be predicted by a set of clinical variables. Decreases in Hb over time relate to future increased morbidity and mortality.