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22 September 2009
This meta-analysis found that heart rate reduction was significantly associated with survival benefit in patients in beta-blocker chronic heart failure trials, whereas the dose of beta-blocker was not. For every 5 beats/min reduction in heart rate using beta blocker treatment, the relative risk of death was lowered by 18%, although the heart rate reduction at which this benefit stops is not known.
Level of evidence:
Level 2 (limited-quality patient-oriented evidence) according to the SORT criteria.
Action
Prescribers should follow NICE guidance on chronic heart failure. People who develop heart failure due to left ventricular systolic dysfunction (LVSD) should normally be offered a beta-blocker licensed for heart failure (bisoprolol, carvedilol or nevibolol) after diuretic and ACE inhibitor therapy. Beta-blocker treatment should be introduced in a ‘start low, go slow’ manner, i.e. started at a low dose and titrated up to the target or highest tolerated dose. If heart rate has been reduced, patients can be reassured that beta-blocker treatment is beneficial for survival, even if the target dose has not been reached. However, in order to assess treatment efficacy in this way, clinicians will need to record baseline heart rate.
What is the background to this?
There is now consistent evidence that (some) beta-blockers significantly improve mortality and reduce hospitalisation in patients with all grades of heart failure. NICE, SIGN and ESC guidelines all recommend the use of ACE inhibitors and beta-blockers as first- and second-line drug treatments for heart failure, unless they are contraindicated or not tolerated. NICE recommends that beta-blocker treatment should be started at a low dose and gradually increased up to the target dose used in the trials that have proven their efficacy, or the highest tolerated dose. However, studies have shown that many patients do not achieve target doses outside of specialised heart failure clinics.
It has been suggested that the effects of beta-blockers are mediated by the reduction in heart rate that they cause. However, study results have been conflicting. This meta-analysis considered whether the survival benefits of beta-blockade in patients with heart failure are related to the dosage of beta-blocker or the degree of reduction of heart rate.
What does this study claim?
This study found that there was an 18% reduction (95% confidence interval [CI] 6% to 29%; P=0.006) in the risk for death for every heart rate reduction of 5 beats/min with beta-blocker treatment. No significant relationship was observed between all-cause mortality and the dose of beta-blocker (P = 0.69).
So what?
The results of the meta-analysis should be viewed with caution because it has some limitations. For example, it is based on aggregate data from a relatively small number of trials (with moderate heterogeneity) and resting rather than peak exercise or 24-hour average heart rates. In addition, few patients in these trials had bradycardia, atrial fibrillation or diastolic dysfunction at baseline. As the authors say, this is only an exploratory analysis, but the findings call for studies utilising individual patient data to definitively answer the question. Nevertheless, the results are interesting.
They suggest that heart rate reduction is a major determinant of the survival benefit of beta-blockers in patients with heart failure. This provides some reassurance for patients whose heart rate has been reduced despite not being able to tolerate a target dose of beta-blocker. If heart rate has already been reduced by a satisfactory amount, benefits are likely to be seen in terms of survival. However, no heart failure trials have randomised participants receiving beta blockers to different heart rates, so the optimal target heart rate, or target heart rate reduction, is unknown. In addition, it is still unclear whether there is any additional benefit from up-titrating beta-blocker dose to the target dose if substantial heart rate reduction has already been achieved with a lower dose. Also, we do not know if there is any additional benefit from increasing beta-blocker dose above the target dose if heart rate reduction is minimal.
NICE guidance states that a beta-blocker should be initiated in patients with heart failure due to LVSD after diuretic and ACE inhibitor therapy regardless of whether or not symptoms persist. Because it is unclear whether a class effect exists for beta-blockers in heart failure or not, NICE recommends initiating treatment with a licensed beta-blocker. Those currently licensed in the UK for heart failure are carvedilol and bisoprolol, which can be used in any grade of heart failure, and nebivolol, which is licensed only for mild to moderate heart failure in the elderly. Beta-blocker treatment should be introduced in a ‘start low, go slow’ manner, with assessment of heart rate, blood pressure, and clinical status after each titration. If heart rate becomes too low (<50 beats/min) and symptoms are worsening, the dose of beta-blocker should be halved or, if deterioration is severe, stopped. The need to continue treatment with other drugs that slow the heart (e.g. digoxin, amiodarone, diltiazem) should also be considered. An ECG should be arranged to exclude heart block and specialist advice should be sought.
The current NICE clinical guideline, issued in 2003, includes an algorithm to guide the treatment of patients with symptomatic heart failure due to LVSD. A revised alternative algorithm is presented for consideration in a MeReC Bulletin on chronic heart failure. This takes into account more recent evidence and recommendations from the 2007 SIGN guideline. It should be noted that the NICE guideline is currently undergoing a partial update which is expected to be published in August 2010.
More information on heart failure can be found in the suite of educational materials is available on NPC. This includes a patient decision aid to help patients understand the risks and benefits of beta-blocker therapy.
Design: meta-analysis of 23 randomised, placebo-controlled trials that reported all-cause mortality.
Patients: 19,209 patients with heart failure (mean left ventricular ejection fraction ranged from 0.17 to 0.36, 95% had systolic dysfunction). Most patients had NYHA class III or IV symptoms at baseline.
Intervention and comparison: two reviewers independently extracted data on study characteristics, beta-blocker dosing and heart rate reduction, and death. Heart rate reduction was calculated by subtracting the baseline value from the heart rate at the end of the dose titration phase.
Outcomes and results: the overall risk ratio (RR) for death was 0.76, 95%CI, 0.68 to 0.84; however, testing revealed moderate heterogeneity among trials, which was associated with the magnitude of heart rate reduction achieved within each trial (P for meta-regression = 0.006). For every heart rate reduction of 5 beats/min with beta-blocker treatment, a commensurate 18% reduction (95%CI 6% to 29%) in the risk for death occurred. No significant relationship between all-cause mortality and beta-blocker dosing was observed (RR 0.74, 95%CI, 0.64 to 0.86 in high-dose beta-blocker trials vs. 0.78, 95%CI, 0.63 to 0.96 in low-dose beta-blocker trials; P for meta-regression = 0.69).
Sponsorship: No external funding was received for the study.
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