N Engl J Med 2001;344:1651-1658
Background: The MERIT-HF trial demonstrated the efficacy of the selective beta blocker metoprolol CR/XL for well selected patients with chronic systolic heart failure who were on optimal therapy with an ACEi and diuretic. The trial randomized nearly 4,000 patients and was stopped early due to the benefit of the drug on all-cause mortality but it also reduced major morbidity as indicated by significant reductions in hospitalization. It represented the first large scale trial to show a morbidity and mortality benefit for beta blockers in patients with chronic systolic heart failure.
Prior to MERIT-HF, the nonselective beta blocker carvedilol reduced morbidity and mortality in a smaller trial of patients with chronic stable heart failure. Limitations of the trial included its size and the fact that it was not originally designed to test mortality. Furthermore, it was stopped early without clearly prespecified stopping rules and 8% of total patients selected for participation in the trial were excluded prior to randomization after a 2 week, open-label run-in phase with the study drug. During the run-in period, 24 patients (2%) experienced worsening heart failure or death and were excluded from participation in the trial - the difference in total deaths between groups was 9 when the trial was stopped. In our opinion, the results of this trial were far from definitive and there are theoretical reasons why selective and nonselective beta blockers could have different effects on cardiac outcomes.
The primary difference between selective and nonselective beta blockers lies in their specificity of action; while both types block adrenaline from binding to beta receptors on nerves, selective beta blockers primarily affect those found in the heart whereas nonselective ones also impact those located in the lungs and blood vessels. In the lungs, adrenaline causes bronchodilation and in the blood vessels, vasoconstriction. Thus, nonselective beta blockers also reduce afterload, which can improve cardiac hemodynamics in the failing heart.
The Carvedilol Prospective Randomized Cumulative Survival Study was a large-scale trial that sought to test the hypothesis that the nonselective beta blocker carvedilol reduces mortality in patients with chronic stable heart failure who are on optimal treatment.
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Patients: Patients with “severe chronic heart failure” were recruited from 334 sites in 21 countries. Severe chronic heart failure was defined by the presence of dyspnea or fatigue at rest or on minimal exertion for at least 2 months and a LVEF of <25%, despite optimal treatment with diuretics at a dose to achieve euvolemia and an ACEi or ARB. Treatment with other common agents was allowed but not required. Hospitalized patients could be enrolled if they did not have any continuing requirements for inpatient care. Recent adjustments in medicines were allowed, but intravenous inotropes or intravenous vasodilators were not permitted within 4 days of screening.
Patients were excluded if: they had heart failure caused by uncorrected primary valvular disease or a reversible form of cardiomyopathy; had severe primary pulmonary, renal, or hepatic disease; or had a contraindication to beta blocker therapy; if SBP <85 mmHg; heart rate <68 bpm; serum Cr >2.8 mg/dl; serum K <3.5 mmol/l or >5.2 mmol/l; or an increase of more than 0.5 mg/dl in serum Cr or a change in body weight of >1.5 kg during the screening period (3 to 14 days).
Baseline characteristics: The mean age of patients was 63 years and approximately 80% were male. The average EF was 20%. The average SBP was 123 mmHg and heart rate was 83 bpm. Ischemic cardiomyopathy accounted for 67% of cases and nonischemic causes accounted for 33%. Most patients were on an ACE inhibitor or ARB (97%) and diuretic (99%). Digoxin was used in 66%.
Trial procedures: All patients who met the entry criteria were randomly assigned in a 1:1 ratio and in a double-blind fashion to receive either carvedilol or matching placebo at an initial dose of 3.125 mg twice daily. This was increased at 2-week intervals (if tolerated), to 6.25 mg, then to 12.5 mg, and finally to a target dose of 25 mg twice daily. Thus, the standard patient would go from the starting dose of 3.125 mg twice daily to the target dose of 25 mg twice daily over a 6 week period. During this period of up-titration, patients were followed closely and the study drug could be decreased, if such an adjustment was clinically warranted. After this period, patients were evaluated every 2 months until the end of the study. If the patient’s condition deteriorated during the study, investigators could use any interventions that were clinically indicated; however, investigators were instructed not to institute open-label treatment with a beta-blocker.
Endpoints: The primary outcome was all-cause mortality. It was estimated that 900 deaths would need to occur to detect a 20% reduction with carvedilol based on an anticipated 1-year mortality rate of 28% in the placebo group. This would provide 90% power with a two-sided alpha of 0.05.
The study was monitored by an independent safety committee who periodically reviewed unblinded results and was empowered to recommend early termination if the treatment effect on survival exceeded prespecified boundaries.
Subgroup analysis was performed on patients < vs >/= 65 years; based on sex; LVEF < vs >/= 20%; ischemic vs nonischemic cardiomyopathy; location of study center (North or South America vs Other); and history or lack of history of hospitalization for heart failure within 1 year before enrollment in the study. Additional post-hoc subgroups analyses were performed.
Results: The trial was stopped early based on the finding of a significant benefit of carvedilol on survival that exceeded the prespecified interim monitoring boundaries. At the time of stopping, 2289 patients had been randomized with 1133 to the placebo group and 1156 to the carvedilol group. The mean duration of follow-up was 10.4 months. After 4 months, 78% of surviving patients in the placebo group and 65% of those in the carvedilol group were receiving the target doses. The mean dose of placebo was 41 mg daily and carvedilol was 37 mg daily.
Compared to placebo, carvedilol significantly reduced the risk of death by 35% (11.2% vs 16.8%; P=0.0014). The survival curves began to separate at 3 months and steadily diverge thereafter. Carvedilol also significantly reduced the risk of death or being hospitalized by 24% (36.8% vs 44.7%; P<0.001). No significant subgroup interactions were identified, including in patient groups who were at the highest absolute risk of dying or being hospitalized.
Less patients in the carvedilol group required permanent discontinuation of treatment because of adverse effects or for reasons other than death (P=0.02)
Conclusions: In this trial of patients with severe chronic systolic heart failure, who were optimized on an ACEi or ARB and diuretic, the nonselective beta blocker carvedilol significantly reduced all-cause mortality as well as the combined endpoint of death or hospitalization. Approximately 18 patients would need to be treated with carvedilol compared to placebo for 10.4 months to prevent 1 death.
This trial represents another significant win for beta blockade in patients with chronic systolic heart failure. The NNT in this trial is lower than in any trial of patients with chronic systolic heart failure that we have reviewed, with the exception of the CONSENSUS trial that compared enalapril to placebo in patients with NYHA class IV heart failure. While the 1-year death totals were high in this trial at 18.5% in the placebo group, they were significantly lower than in CONSENSUS, where the 1-year rate was 52%. This suggests that patients in the current trial, defined as having “severe chronic heart failure” were not as sick as those with classically defined NYHA class IV heart failure. This is also supported by data from MERIT-HF where the 1-year death rate for NYHA class IV patients in the placebo group was 25% (it was 18.5% in the current trial).
Strengths of this trial are that it did not employ a run-in phase, like the earlier trial we reviewed on carvedilol, and it had more statistical power. While it was still stopped early, prespecified rules for stopping are described in the methods but not prespecified rules for when to look at the data. It is curious that the anticipated 1-year death rate in the placebo group was so much higher than it turned out to be and yet, the effect size was so significant. It is certainly possible that with longer follow up the effect size would not have been so large.
The external validity in this trial is limited by patient selection; however, not nearly to the extent that it is in many other trials we have reviewed thus far. Results cannot be applied to patients with severe kidney disease, primary pulmonary disease or hypotension. Finally, a large percentage of patients were taking digoxin.
In conclusion, this is a strong trial in patients with severe chronic heart failure that supports the efficacy of the nonselective beta blocker carvedilol for reducing death and hospitalization.
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