Author + information
- Received November 23, 2018
- Revision received February 8, 2019
- Accepted February 10, 2019
- Published online May 27, 2019.
- Craig Balmforth, MBChBa,
- Joanne Simpson, MBChB, PhDa,
- Li Shen, MBChB, PhDa,
- Pardeep S. Jhund, MBChB, MSc, PhDa,
- Martin Lefkowitz, MDb,
- Adel R. Rizkala, PharmDb,
- Jean L. Rouleau, MDc,
- Victor Shi, MDb,
- Scott D. Solomon, MDd,
- Karl Swedberg, MD, PhDe,
- Michael R. Zile, MDf,
- Milton Packer, MDg and
- John J.V. McMurray, MBChB, MDa,∗ ()
- aBHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
- bNovartis Pharmaceuticals Corporation, East Hanover, New Jersey
- cMontreal Heart Institute and University of Montreal, Montreal, Quebec, Canada
- dBrigham and Women's Hospital, Boston, Massachusetts
- eUniversity of Gothenburg, Gothenburg, Sweden
- fMedical University of South Carolina and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina
- gBaylor University Medical Center, Dallas, Texas
- ↵∗Address for correspondence:
Dr. John J.V. McMurray, British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom.
Objectives The purpose of this study was to compare outcomes (and the effect of sacubitril/valsartan) according to etiology in the PARADIGM-HF (Prospective comparison of angiotensin-receptor-neprilysin inhibitor [ARNI] with angiotensin-converting-enzyme inhibitor [ACEI] to Determine Impact on Global Mortality and morbidity in Heart Failure) trial.
Background Etiology of heart failure (HF) has changed over time in more developed countries and is also evolving in non-Western societies. Outcomes may vary according to etiology, as may the effects of therapy.
Methods We examined outcomes and the effect of sacubtril/valsartan according to investigator-reported etiology in PARADIGM-HF. The outcomes analyzed were the primary composite of cardiovascular death or HF hospitalization, and components, and death from any cause. Outcomes were adjusted for known prognostic variables including N terminal pro-B type natriuretic peptide.
Results Among the 8,399 patients randomized, 5,036 patients (60.0%) had an ischemic etiology. Among the 3,363 patients (40.0%) with a nonischemic etiology, 1,595 (19.0% of all patients; 47% of nonischemic patients) had idiopathic dilated cardiomyopathy, 968 (11.5% of all patients; 28.8% of nonischemic patients) had a hypertensive cause, and 800 (9.5% of all patients, 23.8% of nonischemic patients) another cause (185 infective/viral, 158 alcoholic, 110 valvular, 66 diabetes, 30 drug-related, 14 peripartum–related, and 237 other). Whereas the unadjusted rates of all outcomes were highest in patients with an ischemic etiology, the adjusted hazard ratios (HRs) were not different from patients in the 2 major nonischemic etiology categories; for example, for the primary outcome, compared with ischemic (HR: 1.00), hypertensive 0.87 (95% confidence interval [CI]: 0.75 to 1.02), idiopathic 0.92 (95% CI: 0.82 to 1.04) and other 1.00 (95% CI: 0.85 to 1.17). The benefit of sacubitril/valsartan over enalapril was consistent across etiologic categories (interaction for primary outcome; p = 0.11).
Conclusions Just under one-half of patients in this global trial had nonischemic HF with reduced ejection fraction, with idiopathic and hypertensive the most commonly ascribed etiologies. Adjusted outcomes were similar across etiologic categories, as was the benefit of sacubitril/valsartan over enalapril. (Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure; NCT01035255)
- angiotensin receptor blocker
- angiotensin-converting enzyme inhibitor
- heart failure
- natriuretic peptides
Dr. Jhund has received personal fees from Novartis. Drs. Lefkowitz and Rizkala are employees of Novartis Pharmaceuticals. Dr. Rizkala owns Novartis stock. Dr. Rouleau has received personal fees from Novartis and AstraZeneca. Dr. Solomon has received grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, Novartis, Sanofi, Pasteur, and Theracos; and has received personal fees from Akros, Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Corvia, Cytokinetics, Gilead, GlaxoSmithKline, Ironwood, Merck, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, and Cardiac Dimensions. Dr. Swedberg has been a consultant to and received honoraria from Astrazeneca, Novartis, Pfizer, and Vifor Pharma. Dr. Zile has received personal fees from Novartis. Dr. Packer has received personal fees from Abbott, Amgen, Actavis, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi-Sankyo, Gilead, NovoNordisk, Relypsa, AstraZeneca, Sanofi, Synthetic Biologies, and Theravance. Dr. McMurray’s employer, Glasgow University, has been paid by Novartis for time spent as Executive Committee member and then co-principal investigator of ATMOSPHERE, co-principal investigator of the PARADIGM-HF and PARAGON-HF trials, and Executive/Steering Committee member for PARADISE-MI and PERSPECTIVE trials (with sacubitril/valsartan) and meetings/presentations related to these trials and aliskiren and sacubitril/valsartan. Novartis has also paid his travel and accommodation for some of these meetings. These payments were made through a consultancy with Glasgow University and he has not received personal payments in relation to these trials/drugs. Drs. McMurray, Packer, Rouleau, Solomon, Swedberg, and Zile have participated in executive steering committee activities for clinical studies sponsored by Novartis. Drs. Jhund, McMurray and Zile are performing research sponsored by Novartis and they or their institutions have received consulting fees from Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received November 23, 2018.
- Revision received February 8, 2019.
- Accepted February 10, 2019.
- 2019 The Authors