Efficacy of Dapagliflozin According to Heart Rate: A Patient-Level Pooled Analysis of DAPA-HF and DELIVER

Abstract

Background: Although elevated resting heart rate (HR) is associated with a higher risk of cardiovascular events in patients with heart failure with reduced ejection fraction in sinus rhythm (SR), the relationship between HR and outcomes among patients with heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction and in those with atrial fibrillation (AF) is uncertain. The aims of this study were to examine the association between baseline HR and outcomes across the range of left ventricular ejection fraction, in patients with and without AF, and evaluate the effect of dapagliflozin according to HR. Methods: A patient-level pooled analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; heart failure with reduced ejection fraction) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure trial; heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction) trials. The primary outcome of each was the composite of worsening heart failure or cardiovascular death. Results: Among patients with SR (n=6401, 64%), the rate of the primary outcome was higher in those with higher HR: 16.8 versus 7.7 per 100 person-years for ≥80 bpm versus <60 bpm. The relationship between HR and risk was steeper in heart failure with reduced ejection fraction versus heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction. HR was not associated with outcomes in patients in AF for either heart failure phenotype. The benefit of dapagliflozin on the primary outcome was consistent across the HR range in both SR ( P interaction =0.28) and AF ( P interaction =0.56), for example, for SR <60 bpm, hazard ratio for dapagliflozin versus placebo 0.72 (95% CI, 0.55–0.95); 60 to 69 bpm, 0.78 (0.63–0.97); 70 to 79 bpm, 0.73 (0.59–0.91); ≥80 bpm, 0.77 (0.61–0.97). The benefit was consistent across HR range in both heart failure with reduced ejection fraction and heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction. Conclusions: The risk of worsening heart failure or cardiovascular death increased with increasing baseline HR among patients in SR, but this association was not seen among patients in AF, irrespective of left ventricular ejection fraction. The benefit of dapagliflozin was consistent across HR range, irrespective of left ventricular ejection fraction or rhythm. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03036124 and NCT03619213.