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Should beta-blockers be titrated to a target dose or a target heart rate in patients with heart failure?

Current heart failure guidelines recommend use of specific beta blockers (ß-blockers) for patients with stable heart failure (HF) due to decreased left ventricular ejection fraction (LVEF).¹ Of the β-blockers studied in heart failure thus far, carvedilol, sustained-release metoprolol succinate, and bisoprolol have been shown to slow disease progression, decrease hospitalization, and reduce mortality in patients with HF; currently, these are the only 3 beta blockers recommended for use in this population. Antiarrhythmic effects, reduced heart rate, improved left ventricular function, slowing or reversal of ventricular remodeling, and reduced cellular death are some of the purported mechanisms of these agents that lead to improved outcomes in patients with HF.²

Since the studies that evaluated these agents were designed to achieve specific doses, guidelines advise clinicians to achieve these target doses when possible.¹ Due to potential worsening of HF symptoms upon initiation of β-blocker therapy, patients should be given low doses to start and titrated to the target dose every 2 weeks based on tolerability.² Patients often, however, do not achieve these target doses unless they are managed by specialized HF clinics. Some data suggest that patients with HF on lower than target doses may still derive benefit from β-blocker therapy.^3,4 The MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure) trial was a double-blind, randomized trial that evaluated the effects on mortality with the addition of sustained-release metoprolol to standard therapy in patients with New York Heart Association (NYHA) class II-IV HF.⁵ Patients were initiated on low doses and titrated to a target dose of 200 mg of sustained-release metoprolol. A 34% relative risk reduction in mortality was observed with active treatment compared to placebo. A post-hoc subgroup analysis of patients in the MERIT-HF trial demonstrated similar reductions in mortality and heart rate in patients who achieved target doses of metoprolol and those who received lower than target doses.³ Other trials have reported conflicting results on heart rate reduction as a mediator of β-blocker effects on HF outcomes.

A recent meta-analysis sought to explain whether the differences in outcomes observed in HF trials could be explained by β-blocker dose or by the degree of reduction in heart rate.⁴ Studies that evaluated β-blocker effects on all-cause mortality in patients with HF were included in the analysis. The effect of individual covariates on the relative risk of death was evaluated through meta-regression analysis. These covariates included age, sex, ischemic cause, LVEF, New York Heart Association (NYHA) class, atrial fibrillation, digoxin use, baseline heart rate, degree of heart rate reduction with treatment, β-blocker dose, baseline systolic blood pressure (SBP), mean SBP reduction, and the β-blocking agent. Degree of heart rate reduction was determined by subtracting the change in heart rate observed in the placebo group from the change observed in the β-blocker group.

Twenty-three trials totaling over 19,000 patients were included in the analysis.⁴ The β-blockers evaluated were carvedilol (9 trials), sustained-release metoprolol (5 trials), bisoprolol (3 trials), atenolol (1 trial), bucindolol (3 trials), and nebivolol (2 trials). The mean LVEF in these trials ranged from 0.17 to 0.36. Most patients (median 54%) in the trials were classified as NYHA class III or IV. Percentages of each NYHA class alone were not reported. Median use of angiotensin-converting enzyme inhibitors (ACEI) and digoxin was 93% and 75%, respectively.

Of all the variables evaluated, the β-blocking agent used and the degree of reduction in heart rate were associated with a lower relative risk (RR) of death.⁴ There was no statistically significant reduction in mortality associated with the dosage of the β-blocker used (RR 1.02, 95% confidence interval [CI] 0.93 to 1.10). Table 1 provides a summary of the pooled data from individual trials by β-blocking agent used. The nonsignificant findings observed with nebivolol and atenolol are based on a fewer number of trials and total number of patients; therefore, effects on mortality of these 2 agents were deemed to be inconclusive.

Table 1. Relative risk of death associated with specific β-blocking agents.⁴

A lower RR of death was found to be associated with trials with a median heart rate reduction of 15 beats/minute (RR 0.64, 95% CI 0.48 to 0.86) compared to trials with a median reduction of 8 beats/minute (RR 0.91, 95% CI 0.83 to 0.99).⁴ Further regression analysis demonstrated an 18% decrease in the RR of death for every 5 beats/minute reduction in heart rate. The study was unable to determine the optimal reduction in heart rate necessary to achieve maximal survival benefit.

These results support the guidelines that recommend use of the 3 aforementioned Β-blockers: sustained-release metoprolol, carvedilol, and bisoprolol. However, the lack of an association between Β-blocker dose and mortality is in contrast to recommendations to titrate these agents to a specific dose. As suggested by some individual trials and this meta-analysis, the magnitude of heart rate reduction may a more important factor associated with survival in patients with heart failure. Whether patients receiving Β-blockers should be titrated to achieve a specific reduction in heart rate rather than to achieve a target dose remains to be further studied in prospective, randomized trials.

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