β blockers for heart failure: which works best?BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f480 (Published 24 January 2013) Cite this as: BMJ 2013;346:f480
- Robert J Mentz, advanced heart failure fellow
In recent decades, important gains have been made in the treatment of chronic heart failure with reduced ejection fraction.1 β blockers are a cornerstone of the medical management of heart failure. The long term use of certain β blockers in patients with heart failure reduces hospital admissions and improves symptoms, quality of life, and survival. However, it is still unclear whether this is a class effect or whether one β blocker is superior to another. In a linked paper (doi:10.1136/bmj.f55), Chatterjee and colleagues conducted a network meta-analysis of trials to clarify the mortality benefits and tolerability of different β blockers in the treatment of patients with heart failure.2
Three landmark placebo-controlled trials of nearly 9000 patients with heart failure demonstrated the efficacy of carvedilol, long acting metoprolol succinate, and bisoprolol in reducing mortality and hospital admission in patients with heart failure.1 However, large trials of nebivolol and bucindolol found no reductions in all cause mortality compared with placebo, despite benefits in cardiovascular morbidity or mortality.3 4 Taken together, these data provided the evidence base for recommendations that nearly all stable patients with an ejection fraction of 40% or less receive one of the three β blockers proved to reduce mortality (bisoprolol, carvedilol, or metoprolol succinate).1
Given the differential efficacy of β blockers in these trials, clinicians and researchers have questioned whether one of these drugs should be used preferentially. Previous analyses in trial populations and clinical practice cohorts have shown conflicting results regarding a β blocker class effect.5 6 7 8 Only one adequately powered trial has directly compared the efficacy of different β blockers. The Carvedilol or Metoprolol European Trial showed that, in around 3000 patients with symptomatic heart failure, carvedilol increased survival compared with short acting metoprolol tartrate (not the formulation used in key metoprolol trials).9 Thus, a systematic review exploring the comparative efficacy and tolerability of currently available β blockers would inform clinical care.
Chatterjee and colleagues’ systematic review and network meta-analysis considered the comparative efficacy of β blockers in patients with heart failure with reduced ejection fraction.2 The analysis included 21 randomised trials (total of 23 122 patients) that compared β blockers with other β blockers or other treatments. Seven β blockers were investigated: carvedilol, metoprolol (tartrate and succinate), bisoprolol, bucindolol, nebivolol, and atenolol. The primary endpoint was all cause mortality at the longest available follow-up (median of 12 months). The authors found that β blockers provided a mortality benefit versus placebo or standard treatment with an odds ratio of 0.69 (95% confidence interval 0.56 to 0.80). No significant differences were found when the different β blockers were compared head to head for the risk of death or secondary endpoints of cardiovascular death, sudden death, or change in ejection fraction. Rates of discontinuation were also similar between the different study drugs. The authors concluded that β blockers in patients with heart failure seemed to exhibit a class effect rather than an individual drug effect.
Although these findings should be viewed as exploratory outside the context of an adequately powered randomized trial, they support and extend previous evidence for the use of β blockers in patients with heart failure. They confirm the adage that “some β blocker is better than no β blocker.” Although no significant differences were seen between β blockers for the primary endpoint, there was a non-significant differential effect size (even between the three evidence based agents). This analysis is one of the largest to systematically demonstrate similar discontinuation rates of different β blockers in patients with chronic heart failure.
How can these data inform clinical care? The β blockers with the strongest evidence base in heart failure are carvedilol, long acting metoprolol succinate, and bisoprolol. Clinicians should start all patients with reduced ejection fraction (as long as they have no contraindications, such as asthma) on a low dose of one of these drugs and aim for the target doses used in clinical trials or the highest tolerable dose.1 Clinically, we favor carvedilol unless the patient has symptomatic hypotension or ventricular arrhythmias, in which case, metoprolol succinate may be more suitable.
The similar tolerability between β blockers in clinical trials is reassuring. However, if a patient has unwanted effects from one of these agents (such as fatigue, hypotension, or pulmonary or sexual side effects), it may be best to try a different β blocker, with monitoring commensurate to the severity of the side effect. Try to use one of the other “big 3” β blockers. However, for a variety of reasons including cost, drug availability, dosing schedule, and patient preference, an alternative β blocker may be used. Chatterjee and colleagues’ findings support this conclusion.
Several aspects of the use of β blockers in patients with heart failure warrant prospective investigation. For example, chronic obstructive pulmonary disease is a common comorbidity in such patients, and, despite evidence that most tolerate β blockers, research is needed to clarify the use of cardioselective versus non-cardioselective agents and the potential interaction with β agonist bronchodilators.10 Moreover, the variable penetrance of β blockers in different global regions11 and the implications of geographical variation on patient outcomes12 require future study.
Cite this as: BMJ 2013;346:f480
Competing interests: The author has completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declares: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review: Commissioned; not externally peer reviewed.