Association Between Use of Long-Acting Nitrates and Outcomes in Heart Failure With Preserved Ejection Fraction

Shir Lynn Lim, Lina Benson, Ulf Dahlström, Carolyn S P Lam, Lars H Lund

Nitrates may be beneficial in heart failure with preserved ejection fraction (HFpEF) by enhancing cGMP signaling and improving hemodynamics, but real-world data on potential efficacy are lacking. We linked the Swedish Heart Failure Registry to national registries with International Classification of Diseases, Tenth Revision comorbidity diagnoses and demographic and socioeconomic data. In HFpEF, defined as left ventricular ejection fraction ≥40%, we derived propensity scores for nitrate use using 52 baseline variables. The association between nitrate use and all-cause mortality and the composite of all-cause mortality or first heart failure hospitalization was assessed in a cohort matched 2:1 untreated to treated based on age and propensity score. In the overall HFpEF cohort (n=19 047; mean [SD] age, 76 [12] years; 46% women), nitrates were used in 17%, and the crude 1-year survival for treated versus untreated patients was 79% (95% confidence interval [CI], 78%-80%) versus 84% (95% CI, 83%-84%) respectively; hazard ratio was 1.48 (95% CI, 1.40-1.56; P<0.001) during a median 755-day follow-up. Matching yielded 2235 treated versus 4470 untreated patients, with 1-year survival of 80% (95% CI, 78%-82%) versus 79% (95% CI, 78%-81%) and hazard ratio of 1.06 (95% CI, 0.98-1.15; P=0.12). Nitrates were associated with worse composite outcome in the matched HFpEF cohort, with 1-year event-free survival of 62% (95% CI, 60%-64%) versus 65% (95% CI, 63%-66%) and hazard ratio of 1.11 (95% CI, 1.04-1.18; P=0.003). These patterns were reproduced in several consistency analyses. In HFpEF, the use of nitrates was not associated with improvements in all-cause mortality or heart failure hospitalization.