Effect of Selective Heart Rate Slowing in Heart Failure With Preserved Ejection Fraction

Nikhil Pal, Nadiya Sivaswamy, Masliza Mahmod, Arash Yavari, Amelia Rudd, Satnam Singh, Dana K Dawson, Jane M Francis, Jeremy S Dwight, Hugh Watkins, Stefan Neubauer, Michael Frenneaux, Houman Ashrafian, Nikhil Pal, Nadiya Sivaswamy, Masliza Mahmod, Arash Yavari, Amelia Rudd, Satnam Singh, Dana K Dawson, Jane M Francis, Jeremy S Dwight, Hugh Watkins, Stefan Neubauer, Michael Frenneaux, Houman Ashrafian

Abstract

Background: Heart failure with preserved ejection fraction (HFpEF) is associated with significant morbidity and mortality but is currently refractory to therapy. Despite limited evidence, heart rate reduction has been advocated, on the basis of physiological considerations, as a therapeutic strategy in HFpEF. We tested the hypothesis that heart rate reduction improves exercise capacity in HFpEF.

Methods and results: We conducted a randomized, crossover study comparing selective heart rate reduction with the If blocker ivabradine at 7.5 mg twice daily versus placebo for 2 weeks each in 22 symptomatic patients with HFpEF who had objective evidence of exercise limitation (peak oxygen consumption at maximal exercise [o2 peak] <80% predicted for age and sex). The result was compared with 22 similarly treated matched asymptomatic hypertensive volunteers. The primary end point was the change in o2 peak. Secondary outcomes included tissue Doppler-derived E/e' at echocardiography, plasma brain natriuretic peptide, and quality-of-life scores. Ivabradine significantly reduced peak heart rate compared with placebo in the HFpEF (107 versus 129 bpm; P<0.0001) and hypertensive (127 versus 145 bpm; P=0.003) cohorts. Ivabradine compared with placebo significantly worsened the change in o2 peak in the HFpEF cohort (-2.1 versus 0.9 mL·kg(-1)·min(-1); P=0.003) and significantly reduced submaximal exercise capacity, as determined by the oxygen uptake efficiency slope. No significant effects on the secondary end points were discernable.

Conclusion: Our observations bring into question the value of heart rate reduction with ivabradine for improving symptoms in a HFpEF population characterized by exercise limitation.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02354573.

Keywords: exercise; heart failure; heart rate.

© 2015 The Authors.

Figures

Figure 1.
Figure 1.
Flow diagram of the study. CPEX indicates cardiopulmonary exercise testing; ECHO, echocardiography; HFpEF, heart failure with preserved ejection fraction; and MRI, magnetic resonance imaging.
Figure 2.
Figure 2.
Effect of ivabradine on Vo2 peak in the heart failure with preserved ejection fraction (HFpEF) cohort. Depicts the change in Vo2 peak (mL·kg−1·min−1) with placebo (left) and ivabradine (right; ivabradine vs placebo, P=0.003) in the HFpEF cohort.

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