Author + information
- Received April 28, 2020
- Revision received June 24, 2020
- Accepted June 25, 2020
- Published online September 28, 2020.
- Luis E. Rohde, MD, ScDa,b,
- Neal A. Chatterjee, MD, MScc,
- Muthiah Vaduganathan, MD, MPHa,
- Brian Claggett, PhDa,
- Milton Packer, MDd,
- Akshay S. Desai, MDa,
- Michael Zile, MDe,
- Jean Rouleau, MDf,
- Karl Swedberg, MDg,
- Martin Lefkowitz, MDh,
- Victor Shi, MDh,
- John J.V. McMurray, MDi and
- Scott D. Solomon, MDa,∗ ()
- aCardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- bHospital de Clínicas de Porto Alegre and Universidade Federal do Rio Grande do Sul Medical School, Porto Alegre, RS, Brazil
- cDivision of Cardiology, Department of Medicine, University of Washington, Seattle, Washington
- dBaylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas
- eMedical University of South Carolina and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina
- fInstitut de Cardiologie de Montréal, Université de Montreál, Montreál, Canada
- gDepartment of Molecular and Clinical Medicine, University of Gothenburg, Sweden
- hNovartis, East Hanover, New Jersey
- iBritish Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland, United Kingdom
- ↵∗Address for correspondence:
Prof. Scott D. Solomon, Harvard Medical School, Brigham and Women's Hospital, Cardiovascular Division, Department of Medicine, 75 Francis Street, Boston, Massachusetts 02115.
Objectives The purpose of this study was to investigate the effect of sacubitril/valsartan therapy on sudden cardiac death (SCD) according to the use of and eligibility for an implantable cardioverter-defibrillator (ICD), stratified by heart failure cause.
Background SCD still accounts for a significant proportion of overall mortality in heart failure with reduced ejection fraction (HFrEF).
Methods Patients enrolled in the PARADIGM-HF (Prospective Comparison of ARNI with an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial (n = 8,399) were evaluated to assess patterns of ICD implantation and eligibility according to clinical guidelines. The impact of ICD (adjusted for propensity of ICD implantation) and sacubitril/valsartan therapy on SCD was evaluated by using cause-specific Cox models and competing risk analysis.
Results At baseline, of the 7,145 patients (85%) eligible for ICD implantation, only 1,243 (15%) had an ICD. Use of ICD varied by region with the highest rates in North America (56%) and lowest in Asia-Pacific (1.7%). In a propensity score-adjusted analysis, use of an ICD was associated with a 56% lower risk of SCD in ICD-eligible patients, in both patients with ischemic (p < 0.001) and nonischemic cardiomyopathy (p = 0.02). Sacubitril/valsartan reduced SCD risk in patients with an ICD (hazard ratio [HR]: 0.49; 95% confidence interval [CI]: 0.25 to 0.99) and in those who were eligible for but did not receive an ICD (HR: 0.81; 95% CI: 0.67 to 0.98). This effect was particularly evident in nonischemic cardiomyopathy (p < 0.05), although interaction with the cause of HF was not significant (p = 0.11 in subjects using an ICD and p = 0.25 in eligible nonusers).
Conclusions Use of an ICD was associated with lower rates of SCD, regardless of HF cause but was underused in most regions of the world in the PARADIGM-HF study. Sacubitril/valsartan reduced SCD risk regardless of use of an ICD or eligibility, particularly in ICD users and nonischemic cardiomyopathy.
The PARADIGM-HF trial was sponsored by Novartis. Dr. Rohde is partly supported by the “National Council for Scientific and Technological Development” (CNPq, Brazil, research fellowship 30833/2017-1) and by “Coordenação de Aperfeiçoamento de Pessoal de Nível Superior” (CAPES, senior fellowship). Dr. Vaduganathan is supported by KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (NIH/NCATS Award UL 1TR002541). Dr. McMurray is supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217. Dr. Rohde has been a consultant or served on advisory board for AstraZeneca, Amgen, and Novartis. Dr. Vaduganathan has been a consultant or served on advisory boards for Amgen, AstraZeneca, Baxter HealthCare, Bayer AG, Boehringer Ingelheim, Relypsa, and Cyto-kinetics. Dr. Claggett has been a consultant for Amgen, AO Biome, Biogen, Boehringer Ingelheim, Corvia, Gilead, Myokardia, and Novartis. Dr. Packer has received personal fees from Akcea Therapeutics, AstraZeneca, Amgen, Actavis, AbbVie, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance. Dr. Desai has received grants consulting fees from Novartis, Alnylam, and AstraZeneca and consulting fees from Abbott, Boehringer-Ingelheim, Regeneron, Biofourmis, Boston Scientific, Corvidia, DalCor Pharma, Relypsa. Dr. Zile has received research funding from Novartis; and has been a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronics, Ironwood, Merck, Medtronic, and Myokardia V Wave. Dr. Rouleau has received grants and consulting fees from Novartis and consulting fees from AstraZeneca. Dr. Swedberg has received consulting for Novartis and AstraZeneca. Dr. McMurray has received consulting payments through Glasgow University from Bayer, Alnylam, Cardurion, Cytokinetics, Amgen, DalCor Pharmaceuticals, Pfizer, Merck, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Vifor-Fresenius, Kidney Research UK, Novartis, and Theracos; all payments were made through a consultancy with Glasgow University and were not personal payments; and has received personal fees from the Corpus, Abbott, Hickma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, and Servier. Dr. Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, Respicardia, Sanofi Pasteur, Theracos; and has consulted for Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, and Moderna. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Heart Failure author instructions page.
- Received April 28, 2020.
- Revision received June 24, 2020.
- Accepted June 25, 2020.
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