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Association Between Use of Long-Acting Nitrates and Outcomes in Heart Failure With Preserved Ejection Fraction
Shir Lynn Lim1, Lina Benson1, Ulf Dahlström1
1From the Department of Cardiology, National University Heart Center, Singapore (S.L.L.); Department of Clinical Science and Education, Södersjukhuset (L.B.) and Department of Medicine (L.H.L.), Karolinska Institutet, Stockholm, Sweden; Department of Cardiology (U.D.) and Department of Medicine and Health Sciences (U.D.), Linköping University, Sweden; Department of Cardiology, National Heart Center, Singapore (C.S.P.L.); Duke-NUS Graduate Medical School, Singapore (C.S.P.L.); and Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden (L.H.L.).
Insights
Nitrate use in heart failure with preserved ejection fraction (HFpEF) did not improve survival or reduce hospitalizations. Real-world data indicate nitrates may be associated with worse outcomes in HFpEF patients.
Area of Science:
- Cardiology
- Pharmacology
- Public Health
Background:
- Nitrates are hypothesized to benefit heart failure with preserved ejection fraction (HFpEF) by enhancing cGMP signaling and improving hemodynamics.
- Limited real-world data exist on the efficacy of nitrates in HFpEF patients.
Purpose of the Study:
- To investigate the association between nitrate use and clinical outcomes in a real-world HFpEF population.
- To evaluate the impact of nitrates on all-cause mortality and heart failure hospitalizations in HFpEF.
Main Methods:
- A cohort of 19,047 HFpEF patients (left ventricular ejection fraction ≥40%) was identified by linking the Swedish Heart Failure Registry to national registries.
- Propensity scores for nitrate use were derived using 52 baseline variables.
- A 2:1 matched cohort (2235 treated vs. 4470 untreated) was created based on age and propensity score to assess outcomes.
Main Results:
- In the matched cohort, nitrate use was not associated with a significant reduction in all-cause mortality (Hazard Ratio: 1.06; P=0.12).
- Nitrate use was associated with a worse composite outcome of all-cause mortality or heart failure hospitalization (Hazard Ratio: 1.11; P=0.003).
- Crude 1-year survival was 79% for nitrate users versus 84% for non-users, with a hazard ratio of 1.48 (P<0.001) in the overall cohort.
Conclusions:
- Nitrate use in patients with HFpEF was not associated with improved all-cause mortality or reduced heart failure hospitalizations.
- Real-world evidence suggests potential harm or lack of benefit from nitrates in the HFpEF population.
Background:
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.
Methods And Results:
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.
Conclusions:
In HFpEF, the use of nitrates was not associated with improvements in all-cause mortality or heart failure hospitalization.