Scott D Solomon1, Muthiah Vaduganathan1, Brian L Claggett1, Milton Packer2,3, Michael Zile4,5, Karl Swedberg6,7, Jean Rouleau8, Marc A Pfeffer1, Akshay Desai1, Lars H Lund9, Lars Kober10, Inder Anand11, Nancy Sweitzer12, Gerard Linssen13, Bela Merkely14, Juan Luis Arango15, Dragos Vinereanu16, Chen-Huan Chen17, Michele Senni18, Antonio Sibulo19, Sergey Boytsov20, Victor Shi21, Adel Rizkala21, Martin Lefkowitz21, John J V McMurray22. 1. Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.D.S., M.V., B.L.C., M.A.P., A.D.). 2. Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.). 3. Imperial College, London, United Kingdom (M.P.). 4. Medical University of South Carolina, Charleston (M.Z.). 5. Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, SC (M.Z.). 6. Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden (K.S.). 7. National Heart and Lung Institute, Imperial College, London, United Kingdom (K.S.). 8. Institut de Cardiologie de Montréal, Université de Montréal, Canada (J.R.). 9. Department of Medicine, Karolinska Institutet, and Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden (L.H.L.). 10. Department of Cardiology, Heart Centre, Rigshospitalet, Copenhagen University Hospital, Denmark (L.K.). 11. Department of Medicine, VA Medical Center and University of Minnesota, Minneapolis (I.A.). 12. Sarver Heart Center, University of Arizona College of Medicine, Tucson (N.S.). 13. Department of Cardiology, Hospital Group Twente, Almelo and Hengelo, The Netherlands (G.L.). 14. Heart and Vascular Center, Semmelweis University, Budapest, Hungary (B.M.). 15. Guatemalan Heart Institute (J.L.A.). 16. University of Medicine and Pharmacy Carol Davila, University and Emergency Hospital of Bucharest, Romania (D.V.). 17. Department of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China (C.-H.C.). 18. Cardiology Division, Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo, Italy (M.S.). 19. St Luke's Heart Institute, St. Luke's Medical Center, Taguig, Philippines (A.S.). 20. National Research Center for Cardiology of the Ministry of Health of the Russian Federation, Moscow (S.B.). 21. Novartis Pharmaceuticals Corporation, East Hanover, NJ (V.S, A.R., M.L.). 22. British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (J.J.V.M.).
Abstract
BACKGROUND: While disease-modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF (>40%). Sacubitril/valsartan has been compared with a renin-angiotensin-aldosterone-system inhibitor alone in 2 similarly designed clinical trials of patients with reduced and preserved LVEF, permitting examination of its effects across the full spectrum of LVEF. METHODS: We combined data from PARADIGM-HF (LVEF eligibility≤40%; n=8399) and PARAGON-HF (LVEF eligibility≥45%; n=4796) in a prespecified pooled analysis. We divided randomized patients into LVEF categories: ≤22.5% (n=1269), >22.5% to 32.5% (n=3987), >32.5% to 42.5% (n=3143), > 42.5% to 52.5% (n=1427), > 52.5% to 62.5% (n=2166), and >62.5% (n=1202). We assessed time to first cardiovascular death and HF hospitalization, its components, and total heart failure hospitlizations, all-cause mortality, and noncardiovascular mortality. Incidence rates and treatment effects were examined across categories of LVEF. RESULTS: Among 13 195 randomized patients, we observed lower rates of cardiovascular death and HF hospitalization, but similar rates of noncardiovascular death, among patients in the highest versus the lowest groups. Overall sacubitril/valsartan was superior to renin-angiotensin-aldosterone-system inhibition for first cardiovascular death or heart failure hospitalization (Hazard Ratio [HR] 0.84 [95% CI, 0.78-0.90]), cardiovascular death (HR 0.84 [95% CI, 0.76-0.92]), heart failure hospitalization (HR 0.84 [95% CI, 0.77-0.91]), and all-cause mortality (HR 0.88 [95% CI, 0.81-0.96]). The effect of sacubitril/valsartan was modified by LVEF (treatment-by-continuous LVEF interaction P=0.02), and benefit appeared to be present for individuals with EF primarily below the normal range, although the treatment benefit for cardiovascular death diminished at a lower ejection fraction. We observed effect modification by LVEF on the efficacy of sacubitril/valsartan in both men and women with respect to composite total HF hospitalizations and cardiovascular death, although women derived benefit to higher ejection fractions. CONCLUSIONS: The therapeutic effects of sacubitril/valsartan, compared with a renin-angiotensin-aldosterone-system inhibitor alone, vary by LVEF with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction. These therapeutic benefits appeared to extend to a higher LVEF range in women compared with men. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifiers: NCT01920711 (PARAGON-HF), NCT01035255 (PARADIGM-HF).
RCT Entities:
BACKGROUND: While disease-modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF (>40%). Sacubitril/valsartan has been compared with a renin-angiotensin-aldosterone-system inhibitor alone in 2 similarly designed clinical trials of patients with reduced and preserved LVEF, permitting examination of its effects across the full spectrum of LVEF. METHODS: We combined data from PARADIGM-HF (LVEF eligibility≤40%; n=8399) and PARAGON-HF (LVEF eligibility≥45%; n=4796) in a prespecified pooled analysis. We divided randomized patients into LVEF categories: ≤22.5% (n=1269), >22.5% to 32.5% (n=3987), >32.5% to 42.5% (n=3143), > 42.5% to 52.5% (n=1427), > 52.5% to 62.5% (n=2166), and >62.5% (n=1202). We assessed time to first cardiovascular death and HF hospitalization, its components, and total heart failure hospitlizations, all-cause mortality, and noncardiovascular mortality. Incidence rates and treatment effects were examined across categories of LVEF. RESULTS: Among 13 195 randomized patients, we observed lower rates of cardiovascular death and HF hospitalization, but similar rates of noncardiovascular death, among patients in the highest versus the lowest groups. Overall sacubitril/valsartan was superior to renin-angiotensin-aldosterone-system inhibition for first cardiovascular death or heart failure hospitalization (Hazard Ratio [HR] 0.84 [95% CI, 0.78-0.90]), cardiovascular death (HR 0.84 [95% CI, 0.76-0.92]), heart failure hospitalization (HR 0.84 [95% CI, 0.77-0.91]), and all-cause mortality (HR 0.88 [95% CI, 0.81-0.96]). The effect of sacubitril/valsartan was modified by LVEF (treatment-by-continuous LVEF interaction P=0.02), and benefit appeared to be present for individuals with EF primarily below the normal range, although the treatment benefit for cardiovascular death diminished at a lower ejection fraction. We observed effect modification by LVEF on the efficacy of sacubitril/valsartan in both men and women with respect to composite total HF hospitalizations and cardiovascular death, although women derived benefit to higher ejection fractions. CONCLUSIONS: The therapeutic effects of sacubitril/valsartan, compared with a renin-angiotensin-aldosterone-system inhibitor alone, vary by LVEF with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction. These therapeutic benefits appeared to extend to a higher LVEF range in women compared with men. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifiers: NCT01920711 (PARAGON-HF), NCT01035255 (PARADIGM-HF).
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