Effects on Outcomes of Heart Rate Reduction by Ivabradine in Patients With Congestive Heart Failure: Is There an Influence of Beta-Blocker Dose?: Findings From the SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) Study

Study Questions:

Does the baseline dose of beta-blocker therapy administered to patients with heart failure (HF) impact the clinical benefit of Ivabradine?


This is a secondary analysis of the SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) database. Patients with stable HF, a left ventricular ejection fraction ≤35%, and heart rate ≥70 bpm were randomized to ivabradine versus placebo. Patients were subcategorized based on baseline beta-blocker doses: <25%, 25-50%, 50-100%, and 100% target dose, as defined by the European Society of Cardiology. The primary outcome of interest was the impact of ivabradine on death or HF hospitalization based on beta-blocker dosing category.


With increasing baseline beta-blocker dose, there was a trend toward a reduction in benefit from ivabradine (p = 0.056). In patients on 0-50% of target beta-blocker doses, the primary endpoint was significantly reduced following ivabradine (hazard ratio, 0.71-0.81; p ≤ 0.029). In patients on >50% of beta-blocker target doses, the primary outcome was not significantly reduced following ivabradine (hazard ratio, 0.88-0.99; p > 0.19). However, when correcting for the interaction between resting heart rate and treatment group, the impact of baseline beta-blocker dose on the primary outcome was less significant (p = 0.14). Improvements in the primary outcome were largely driven by reductions in HF admissions.


It is the magnitude of heart rate reduction, not baseline beta-blocker dose, which leads to improved outcomes with ivabradine.


The results of the SHIFT study suggest that the impact of ivabradine may be greatest in those with higher baseline heart rates. Alternatively, one could argue that ivabradine benefits may be greatest in those with higher heart rates because such patients may be on lower doses of beta-blocker therapy. This secondary analysis does show that patients on lower doses of beta-blockers at baseline experience a statistically significant reduction in death/HF admission with ivabradine, and this appears to be of greater magnitude (and significance) than those on higher beta-blocker doses. When controlling for baseline heart rate, the apparent benefit of beta-blocker therapy vanishes. Thus, heart rate reduction (rather than medication class effect) appears to be the key to improved outcomes. For a drug that is likely to be more expensive than generic beta-blockers, the major question that looms is: Were patients really on maximally tolerated beta-blocker doses at baseline to allow for optimal baseline heart rate control?

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: Heart Diseases, Endocarditis, Cardiology, Heart Failure, Stroke Volume, Ventricular Function, Heart Rate, Benzazepines

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