Heart failure
Analysis of Randomized Controlled Trials on the Effect of Magnitude of Heart Rate Reduction on Clinical Outcomes in Patients With Systolic Chronic Heart Failure Receiving Beta-Blockers

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Beta blockers improve cardiac function and prolong survival in patients with systolic chronic heart failure (CHF). However, the exact mechanisms underlying these benefits are uncertain. Specifically, it is unclear whether a close relation exists between heart rate (HR) reduction and clinical outcomes with these agents. This hypothesis was therefore tested within randomized controlled trials of β blockers in systolic CHF. Left ventricular ejection fraction (LVEF) and HR values at baseline and study end were obtained from available β-blocker randomized clinical trials. The relation between change in HR and all-cause mortality as well as the LVEF was determined using regression analysis. Thirty-five trials, which included 22,926 patients with a mean follow-up duration of 9.6 months, were analyzed for all-cause mortality, the LVEF, and HR. There was a close relation between all-cause annualized mortality rate and HR (adjusted R2 = 0.51, p = 0.004). A strong correlation between change in HR and change in LVEF (adjusted R2 = 0.48, p = 0.000) was also observed. When only trials with >100 patients were included, an even tighter correlation was seen (adjusted R2 = 0.60, p = 0.0004). In conclusion, these analyses indicate that a major contributor to the clinical benefits of β-blocker therapy in systolic CHF may be the HR-lowering effect of these agents. Therefore, the magnitude of HR reduction may be more important than the achievement of target dose in β-blocker treatment of systolic CHF.

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Methods and Results

To begin to evaluate this issue, we performed a regression analysis of all trials of β blockers compared with placebo in patients with systolic CHF that reported mortality outcomes or the surrogate of change in the LVEF, together with absolute HR values and HR change during the course of therapy.

Studies were identified via Medline search, report reference listings, and abstracts of major meetings. Studies had to be ≥2 months in duration. HR values were the last provided, with a minimum duration

Discussion

The present analysis identified a clear relation between change in HR with β blockade and all-cause mortality outcomes. Although this relation may appear to be intuitive, it has thus far not been at all well documented in published medical research.

This finding is of particular significance with regard to β blockade, because it is well known that considerable heterogeneity exists within the class41 and further that individual patients may exhibit widely differing pharmacodynamic responsiveness

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