. 2020 Feb 4;141(5):338-351.

doi: 10.1161/CIRCULATIONAHA.119.044491. Epub 2019 Nov 17.

Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF

John J V McMurray¹, Alice M Jackson¹, Carolyn S P Lam^{2

3

4}, Margaret M Redfield⁵, Inder S Anand⁶, Junbo Ge⁷, Marty P Lefkowitz⁸, Aldo P Maggioni⁹, Felipe Martinez¹⁰, Milton Packer¹¹, Marc A Pfeffer¹², Burkert Pieske¹³, Adel R Rizkala⁸, Shalini V Sabarwal⁸, Amil M Shah¹², Sanjiv J Shah¹⁴, Victor C Shi⁸, Dirk J van Veldhuisen³, Faiez Zannad¹⁵, Michael R Zile¹⁶, Maja Cikes¹⁷, Eva Goncalvesova¹⁸, Tzvetana Katova¹⁹, Anamaria Kosztin²⁰, Malgorzata Lelonek²¹, Nancy Sweitzer²², Orly Vardeny²³, Brian Claggett¹², Pardeep S Jhund¹, Scott D Solomon¹²

Affiliations

¹ BHF Cardiovascular Research Centre, University of Glasgow, UK (J.J.V.M., A.M.J., P.S.J.).
² National Heart Center Singapore and Duke-National University of Singapore (C.S.P.L.).
³ Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (C.S.P.L., D.J.v.V.).
⁴ The George Institute for Global Health, Newtown, Australia (C.S.P.L.).
⁵ Mayo Clinic, Rochester, MN (M.M.R.).
⁶ University of Minnesota, Minneapolis (I.S.A.).
⁷ Shanghai Institute of Cardiovascular Diseases, China (J.G.).
⁸ Novartis Pharmaceuticals, East Hanover, NJ (M.P.L., A.R.R., S.V.S., V.C.S.).
⁹ National Association of Hospital Cardiologists Research Center, Florence, Italy (A.P.M.).
¹⁰ National University of Cordoba, Argentina (F.M.).
¹¹ Baylor University Medical Center, Dallas, TX (M.P.).
¹² Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (M.A.P., A.M.S., B.C., S.D.S.).
¹³ Department of Internal Medicine and Cardiology, German Center for Cardiovascular Research Partner Site Berlin, Germany (B.P.).
¹⁴ Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (S.J.S.).
¹⁵ INSERM Centre d'Investigation Clinic 1433 and Universite de Lorraine, Centre Hospitalier Regional et Universitaire, Nancy, France (F.Z.).
¹⁶ Medical University of South Carolina and the Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston (M.R.Z.).
¹⁷ Department of Cardiovascular Diseases, University of Zagreb School of Medicine and University Hospital Centre Zagreb, Croatia (M.C.).
¹⁸ Department of Heart Failure-Transplantation, National Cardiovascular Institute, Bratislava, Slovakia (E.G.).
¹⁹ Clinic of Cardiology, National Cardiology Hospital, Sofia, Bulgaria (T.K.).
²⁰ Heart and Vascular Center, Semmelweis University, Budapest, Hungary (A.K.).
²¹ Department of Noninvasive Cardiology, Medical University of Lodz, Poland (M.L.).
²² University of Arizona Sarver Heart, Tucson (N.S.).
²³ Minneapolis VA Center for Care Delivery and Outcomes Research, University of Minnesota (O.V.).

PMID: 31736337
PMCID: PMC12611550
DOI: 10.1161/CIRCULATIONAHA.119.044491

Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF

John J V McMurray et al. Circulation. 2020.

. 2020 Feb 4;141(5):338-351.

doi: 10.1161/CIRCULATIONAHA.119.044491. Epub 2019 Nov 17.

Authors

Affiliations

¹ BHF Cardiovascular Research Centre, University of Glasgow, UK (J.J.V.M., A.M.J., P.S.J.).
² National Heart Center Singapore and Duke-National University of Singapore (C.S.P.L.).
³ Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (C.S.P.L., D.J.v.V.).
⁴ The George Institute for Global Health, Newtown, Australia (C.S.P.L.).
⁵ Mayo Clinic, Rochester, MN (M.M.R.).
⁶ University of Minnesota, Minneapolis (I.S.A.).
⁷ Shanghai Institute of Cardiovascular Diseases, China (J.G.).
⁸ Novartis Pharmaceuticals, East Hanover, NJ (M.P.L., A.R.R., S.V.S., V.C.S.).
⁹ National Association of Hospital Cardiologists Research Center, Florence, Italy (A.P.M.).
¹⁰ National University of Cordoba, Argentina (F.M.).
¹¹ Baylor University Medical Center, Dallas, TX (M.P.).
¹² Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (M.A.P., A.M.S., B.C., S.D.S.).
¹³ Department of Internal Medicine and Cardiology, German Center for Cardiovascular Research Partner Site Berlin, Germany (B.P.).
¹⁴ Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (S.J.S.).
¹⁵ INSERM Centre d'Investigation Clinic 1433 and Universite de Lorraine, Centre Hospitalier Regional et Universitaire, Nancy, France (F.Z.).
¹⁶ Medical University of South Carolina and the Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston (M.R.Z.).
¹⁷ Department of Cardiovascular Diseases, University of Zagreb School of Medicine and University Hospital Centre Zagreb, Croatia (M.C.).
¹⁸ Department of Heart Failure-Transplantation, National Cardiovascular Institute, Bratislava, Slovakia (E.G.).
¹⁹ Clinic of Cardiology, National Cardiology Hospital, Sofia, Bulgaria (T.K.).
²⁰ Heart and Vascular Center, Semmelweis University, Budapest, Hungary (A.K.).
²¹ Department of Noninvasive Cardiology, Medical University of Lodz, Poland (M.L.).
²² University of Arizona Sarver Heart, Tucson (N.S.).
²³ Minneapolis VA Center for Care Delivery and Outcomes Research, University of Minnesota (O.V.).

PMID: 31736337
PMCID: PMC12611550
DOI: 10.1161/CIRCULATIONAHA.119.044491

Abstract

Background: Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction, the predominant phenotype in women. Therefore, there is a greater heart failure therapeutic deficit in women compared with men.

Methods: In a prespecified subgroup analysis, we examined outcomes according to sex in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction), which compared sacubitril-valsartan and valsartan in patients with heart failure with preserved ejection fraction. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes. We also report secondary efficacy and safety outcomes.

Results: Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older and had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels than men. For the primary outcome, the rate ratio for sacubitril-valsartan versus valsartan was 0.73 (95% CI, 0.59-0.90) in women and 1.03 (95% CI, 0.84-1.25) in men (P interaction = 0.017). The benefit from sacubitril-valsartan was attributable to reduction in heart failure hospitalization. The improvement in New York Heart Association class and renal function with sacubitril-valsartan was similar in women and men, whereas the improvement in Kansas City Cardiomyopathy Questionnaire clinical summary score was less in women than in men. The difference in adverse events between sacubitril-valsartan and valsartan was similar in women and men.

Conclusions: As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men. Whereas the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding.

Clinical trial registration: https://www.clinicaltrials.gov. Unique identifier: NCT01920711.

Keywords: heart failure; hospitalization; neprilysin; women.

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Conflict of interest statement

AMJ reports no conflicts. JJVM reports that his employer, Glasgow University, has been paid by Novartis for serving as an Executive Committee member and co-principal investigator of ATMOSPHERE, PARADIGM-HF and PARAGON-HF trials and Executive/Steering Committee member of the PARADISE-MI and PERSPECTIVE trials (with sacubitril-valsartan) and for meetings/presentations related to these trials, aliskiren, and sacubitril-valsartan. Novartis has also paid for his travel and accommodation for some of these meetings, Glasgow University has also been paid by Novartis for advisory board, by Bayer for serving as a Steering Committee member of the PANACHE trial using neladenoson bialanate (BAY 1067197), by Cardiorentis for serving as a Steering Committee member and Endpoint committee Chair for the TRUE-AHF trial and attending meetings related to this trial, by Cardiorentis for travel and accommodation to attend some of these meetings, by Amgen for serving as Steering Committee member for the ATOMIC-HF and COSMIC-HF trials and attending meetings related to this trial, by Amgen for travel and accommodation for some of these meetings, by Oxford University (who received a grant from Bayer who manufacture acarbose) for serving as a Steering Committee member for the ACE trial (using acarbose) and attending meetings related to this trial, by Theracos for serving as Principal Investigator for the BEST trial and attending meetings related to this trial, by Theracos for travel and accommodation to attend some of these meetings, by Abbvie (who manufacture atrasentan) for serving as Steering Committee member for the SONAR trial (using atrasentan) and to attend meetings related to this trial, by Abbvie has for his travel and accommodation to attend some of these meetings, by DalCor Pharmaceuticals for serving as Steering Committee member for the Dal-GenE trial and to attend meetings related to this trial; by Pfizer for serving on the Data Safety Monitoring Committee for the SPIRE trial and to attend meetings related to this trial, by Merck for serving on the Data Safety Monitoring Committee for the MK-3102 program, for the VICTORIA trial, and to attend meetings related to these trials, by AstraZeneca (who market dapagliflozin) for serving as Principal Investigator of DAPA-HF and Co-principal Investigator of DELIVER (trials using dapagliflozin on heart failure) and to attend meetings related trial, by AstraZeneca for his travel and accommodation to attend meetings; by GSK for serving as Co-principal Investigator and Steering Committee member, respectively, for the Harmony-Outcomes trial (albiglutide) and two trials, ASCEND-D and ASCEND-ND, using daprodustat, and to attend meetings related to these trials, by GSK for his travel and accommodation to attend some of the meetings, by BMS for serving as a Steering Committee member for the STAND-UP clinical trial (using a HNO donor) on heart failure and to attend meetings related to this trial, by Kings College Hospital (who have received a grant from KRUK and Vifor-Fresenius who manufacture intravenous iron) for serving as Steering Committee member for the PIVOTAL trial (using intravenous iron) and for running the Endpoint Adjudication Committee for this trial, to attend meetings related to PIVOTAL, and for his travel and accommodation for to attend some of the meetings. All payments were made through Consultancies with Glasgow University and JJVM has not received any personal payments in relation to the trials/or drugs. CSPL reports receiving grant support and fees for serving on an advisory board from Boston Scientific and Roche Diagnostics, grant support, fees for serving on an advisory board, and fees for serving on steering committees from Bayer, grant support from Medtronics, grant support and fees for serving on a steering committee from Vifor Pharma, fees for serving on an advisory board and fees for serving on steering committees from AstraZeneca and Novartis, fees for serving on an advisory board from Amgen, Boehringer Ingelheim, and Abbott Diagnostics, consulting fees from Merck and Stealth BioTherapeutics, fees for serving on a steering committee from Janssen Research and Development, lecture fees and consulting fees from Menarini, and fees for serving on a scientific committee from Corvia Medical and holding a pending patent (PCT/SG2016/050217) on a method regarding diagnosis and prognosis of chronic heart failure. MMR reports being a non-paid consultant or Novartis. ISA reports receiving fees for serving on a steering committee from AstraZeneca, ARCA Biopharma, Amgen, and LivaNova, fees for serving as chair of a data and safety monitoring board from Boston Scientific, fees for serving on an end-point committee from Boehringer Ingelheim, and fees for serving on an advisory board from Zensun. JG reports no conflicts. MPL, ARR, SVS and VCS are salaried employees of Novartis and ARR owns Novartis stock. APM reports receiving fees for serving on a study committee from Bayer and Fresenius. FM reports receiving personal fees from Novartis. MP reports receiving consulting fees from Abbvie, Akcea, Actavis, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead, Johnson & Johson, NovoNordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance. MAP reports grants paid to his institution, for serving on the Steering Committee of PARAGON-HF, and for serving as Study Chair of PARADISE-MI from Novartis and personal fees for consulting from AstraZeneca, DalCor, GlaxoSmithKline, NovoNordisk, Sanofi, Jazz Pharmaceuticals, MyoKardia, Servier, Takeda, Corvidia. MAP also owns Stock Options of DalCor. BP reports receiving fees for serving on a steering committee, fees for serving on an advisory board, and lecture fees from Bayer HealthCare Pharmaceuticals and MSD, lecture fees from AstraZeneca, fees for serving on an advisory board and lecture fees from Bristol-Myers Squibb, fees for serving on an advisory board from Daiichi Sankyo, and lecture fees and honoraria from Medscape. AMS reports receipt of research support from Novartis, Gilead, and Actelion and consulting fees from Myocardia. SJS reports receiving grant support, fees for serving as a principal investigator of a clinical trial, and consulting fees from Actelion and AstraZeneca, grant support and fees for serving as a principal investigator of a clinical trial from Corvia Medical, consulting fees from Amgen, Cardiora, Eisai, Merck, Sanofi, Pfizer, MyoKardia, Axon Therapies, Ionis Pharmaceuticals, and Bristol- Myers Squibb, fees for serving as a principal investigator of a clinical trial and consulting fees from Bayer, fees for serving on a steering committee and consulting fees from Boehringer Ingelheim and Ironwood Pharma–Cyclerion Therapeutics, fees for serving on a steering committee from United Therapeutics, and fees for serving on a clinical-events committee from CVRx. DJvV reports receiving fees for serving on a steering committee and travel support from ARCA Biopharma and Corvia Medical. FZ reports receiving fees for serving on a steering committee from Janssen, Bayer, Boston Scientific, CVRx, and Boehringer Ingelheim, consulting fees from Amgen, Vifor Pharma–Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, and Merck, and consulting fees and fees for serving on a steering committee from AstraZeneca and serving as founder of cardiorenal and CVCT. MRZ reports grants and personal fees from Novartis for being a member of the PARAGON-HF Executive Steering Committee and a local investigator; personal fees from Abbott for serving on the executive committee of the GUIDE-HF trial, personal fees for consulting on product development from Boston Scientific, grants and personal fees for serving on the Executive Steering Committee and being a local investigator for the BeAT HF trial from CVRx; personal fees for serving on the Eligibility Committee of the SOLVE trial from EBR, personal fees for serving on the Clinical Events Committee of the SIRONA trial from Endotronics, personal fees for serving on the Executive Steering Committee of the CAPACITY HFpEF trial from Ironwood, personal fees for serving on the Data Safety Monitoring Board, Ertugliflozin (MK-8835/PF-04971729) trial from Merck; grants and personal fees for serving on the Executive Steering Committee, Revamp Trial, Alleviate Trial, Link HF trial, Intervene trial and being a local investigator from Medtronic; personal fees for consulting for product development from Myokardia, and personal fees for serving on the Eligibility Committee of the RELIEVE trial from V Wave. MC reports receiving personal fees from Novartis, personal fees from Sanofi Genzyme, personal fees and non-financial support from Pfizer, personal fees from Orion Pharma, personal fees and nonfinancial support from Abbott, personal fees from Medtronic, personal fees from Boehringer-Ingelheim, personal fees from Bayer, personal fees from Sandoz, personal fees and non-financial support from Teva Pharmaceutical Industries., personal fees from Servier, and personal fees from Roche diagnostics outside the submitted work.EG reports receiving grant support, consulting fees, lecture fees, and travel support from Novartis, consulting fees, lecture fees, and travel support from Servier and Boehringer Ingelheim, consulting fees and lecture fees from Medtronic, consulting fees and travel support from Janssen Pharmaceuticals, and consulting fees from Bayer. TK reports receiving lecture fees, fees for serving on an advisory board, and travel support from Novartis and lecture fees, consulting fees, and fees for serving on an advisory board from AstraZeneca. AK reports no conflicts. ML reports receiving honoraria and lecture fees from Servier, AstraZeneca, Gedeon Richter, Boehringer Ingelheim, and Bausch Health. NKS reports research grants from Novartis and Merck. BC reports receiving consulting fees from AOBiome, Biogen, Boehringer Ingelheim, Corvia Medical, Gilead Sciences, and MyoKardia.OV reports receiving research and consultant support from Novartis. PSJ reports receiving grant support from Boehringer Ingelheim and fees for serving on an advisory board from Cytokinetics. SDS reports grants paid to his institution for chairing PARAGON-HF from Novartis; grants paid to Brigham and Women’s Hospital from Alnylam, Amgen, AstraZeneca, Bayer, Bellerophon, BMS, Celladon, Cytokinetics, Gilead, Celladon, Eidos, GSK, Ionis, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, Novartis, Sanofi Pasteur, and Theracos; and consulting fees from Alnylam, Amgen, AoBiome, AstraZeneca, Bayer, BMS, Cardiac Dimensions, Corvia, Cytokinetics, Daichi-Sankyo; Gilead, GSK, Ironwood, Janssen, Merck, MyoKardia, Novartis, Quantum Genomics, Roche, Takeda, Tenaya, and Theracos.

Figures

**Figure 1.**
Cumulative hazard estimate for the primary composite outcome and total hospitalizations for heart failure (first and repeat) according to sex and treatment in PARAGON-HF. A. Cumulative hazard estimate for the primary composite outcome. B. Cumulative hazard estimate for total hospitalizations for heart failure.

**Figure 2.**
Treatment effect in women and men in PARAGON-HF according to left ventricular ejection fraction. A. Treatment effect on the primary composite outcome in women. B. Treatment effect on the primary composite outcome in men. C. Treatment effect on total hospitalizations for heart failure in women. D. Treatment effect on total hospitalizations for heart failure in men. Rate ratios and 95% confidence intervals shown.

See this image and copyright information in PMC

Comment in

Dissecting the benefits of sacubitril-valsartan for heart failure.
Fernández-Ruiz I. Fernández-Ruiz I. Nat Rev Cardiol. 2020 Feb;17(2):71. doi: 10.1038/s41569-019-0322-y. Nat Rev Cardiol. 2020. PMID: 31792406 No abstract available.
Substance and Substrate: LVEF and Sex Subgroup Analyses of PARAGON-HF and PARADIGM-HF Trials.
Bozkurt B, Ezekowitz J. Bozkurt B, et al. Circulation. 2020 Feb 4;141(5):362-366. doi: 10.1161/CIRCULATIONAHA.120.045008. Epub 2020 Feb 3. Circulation. 2020. PMID: 32011927 No abstract available.
Letter by Wu and Zhao Regarding Article, "Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF".
Wu K, Zhao S. Wu K, et al. Circulation. 2020 Jul 7;142(1):e3-e4. doi: 10.1161/CIRCULATIONAHA.119.045382. Epub 2020 Jul 6. Circulation. 2020. PMID: 32628545 No abstract available.
Response by Jackson et al to Letter Regarding Article, "Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF".
Jackson AM, Jhund PS, Solomon SD, McMurray JJV. Jackson AM, et al. Circulation. 2020 Jul 7;142(1):e5-e6. doi: 10.1161/CIRCULATIONAHA.120.047275. Epub 2020 Jul 6. Circulation. 2020. PMID: 32628550 No abstract available.

References

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Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF

Affiliations

Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF

Authors

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Abstract

Conflict of interest statement

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Comment in

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Publication types

MeSH terms

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Associated data

Grants and funding

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