Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Trial.

Objectives: In this study, the authors sought to assess the relationship between AFF and outcomes, the treatment response to sacubitril/valsartan and first-detected AFF in patients with HFpEF enrolled in the PARAGON-HF trial.
Background: Atrial fibrillation and flutter (AFF) are common in heart failure with preserved ejection fraction (HFpEF) and increase the risk of adverse outcomes.
Methods: A total of 4,776 patients formed 3 groups: those with AFF according to electrocardiography (ECG) at enrollment (n = 1,552; 33%), those with history of AFF but without AFF on ECG at enrollment (n = 1,005; 21%), and those without history of AFF or AFF on ECG at enrollment (n = 2,219, 46%). We assessed outcomes, treatment response to sacubitril/valsartan in each group, and the risk associated with first-detected AFF in patients without any known AFF. The primary outcome was a composite of total heart failure hospitalizations and cardiovascular death.
Results: History of AFF and AFF at enrollment were associated with higher risk of the primary outcome (risk ratio [RR]: 1.36 [95% CI: 1.12-1.65] and RR: 1.31 [1.11-1.54], respectively), than no AFF. Neither history of AFF nor AFF at enrollment modified the treatment effect of sacubitril/valsartan. Post randomization AFF occurred in 12% of patients without previous AFF and was associated with 2.8-fold higher risk of the primary outcome, but it was not influenced by sacubitril/valsartan.
Conclusions: History of AFF and AFF on ECG at enrollment were associated with a higher risk of the primary outcome. First-detected AFF was not influenced by sacubitril/valsartan, yet it was associated with increased risk of all subsequent outcomes and may represent a potential target for future HFpEF trials. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).
Competing Interests: Funding Support and Author Disclosures The PARAGON-HF study was sponsored by Novartis; no additional funding was provided for this analysis. Dr Cikes has received institutional grants or contracts from Novartis, Abbott, and Corvia; payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Novartis, GE Healthcare, Pfizer, Bayer, Boehringer Ingelheim, AstraZeneca, Teva Pharmaceutical Industries, Sanofi, and LivaNova; and participation on advisory boards for Pfizer, Boehringer Ingelheim, Bayer, and Novartis. Dr Planinc has received an educational grant from Boehringer Ingelheim; has received payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Sanofi Aventis, Pfizer, Bayer, Teva Pharmaceuticals, Krka-Farma, Servier-Pharma, Sandoz, Mylan, and AstraZeneca; has received support for attending meetings and/or travel from Pfizer, Bayer, and Abbott; and has participated on advisory boards for Novartis and Boehringer Ingelheim. Dr Claggett has received consulting fees from Amgen, Boehringer Ingelheim, Corvia, Myokardia, and Novartis. Dr Cunningham has received grant support from the United States National Heart Lung and Blood Institute (T32HL094301). Dr Sweitzer has received salary support from Novartis for work as PARAGON-HF national leader, Merck for work as national leader, and the American Heart Association for work as journal editorship; and has received research support from the National Institutes of Health. Dr Shah has received institutional grants from Actelion, AstraZeneca, Corvia, Pfizer, and Novartis; has received royalties or licenses from UpToDate; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Axon Therapies, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardiora, CVRx, Cytokinetics, Eidos, Eisai, GlaxoSmithKline, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Sanofi, Shifamed, Tenax, and United Therapeutics. Dr Packer has received consulting fees from Abbvie, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Casana, CSL Behring, Cytokinetics, Johnson & Johnson, Lilly, Moderna, Novartis, ParatusRx, Pfizer, Relypsa, Salamandra, Synthetic Biologics, and Theravance; has received payment for expert testimony from Actavis; and has received support for attending meetings and/or travel from Boehringer Ingelheim. Dr Pfeffer has received institutional research grant support from Novartis for serving on the PARAGON-HF Steering Committee and as Study Chair of PARADISE-MI; has received personal consulting fees from AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, CinCor, Corvidia, DalCor, GlaxoSmithKline, Innovative Science Solutions, Jazz, Lexicon, MyoKardia, National Heart, Lung, and Blood Institute CONNECTs (Master Protocol Committee), Novartis, Novo Nordisk, Peerbridge, Pfizer, Pharmascience, Roche, Sanofi, Servier, and Takeda; has received support for attending meetings and/or travel from Novartis, Novo Nordisk, and A+ (third party to AstraZeneca); and has received stock options from DalCor and Peerbridge. Dr Zile has received grants, consulting fees and participation on a data safety monitoring board or advisory board as part of the committees for the PARAGON-HF and PARADIGM trials. Dr Anand has received consulting fees from Novartis, Amgen, ARCA, Boehringer Ingelheim, AstraZeneca, and LivaNova; and has participated on a data safety monitoring board or advisory board for Boston Scientific. Dr Chiang is a Novartis employee receiving wages and stocks from Novartis as part of an annual wage package. Dr Lam has received research grants from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has received consulting fees from Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, Janssen R & D, Medscape/WebMD Global, Merck, Novartis, Novo Nordisk, Roche Diagnostics, Sanofi, St Luke, and Us2.ai; has received payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Medscape/WebMD Global, Novartis, Radcliffe, and Roche Diagnostics; has a patent pending PCT/SG2016/050217; has a patent application number 16/216,929; has participated on a data safety monitoring board or advisory board for Amgen, AstraZeneca, Bayer, Boston Scientific, Novartis, Novo Nordisk, and Roche Diagnostics; and has nonexecutive director role and stock or stock options for Us2.ai. Dr Redfield has received steering committee membership for PARAGON-HF without personal compensation. Dr Desai has received institutional research grant support from Abbott, AstraZeneca, Alnylam, Bayer, and Novartis; and has received personal consulting fees from Abbott, Alnylam, Amgen, AstraZeneca, Biofourmis, Boehringer Ingelheim, Boston Scientific, Cytokinetics, DalCor Pharma, Lupin Pharma, Lexicon, Merck, Novartis, Relypsa, Regeneron, and Sun Pharma. Dr McMurray has received institutional support from Novartis; has received payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Servier, and The Corpus; and has received other institutional funding from Cytokinetics, KBP Biosciences, AstraZeneca, Amgen, Bayer, AstraZeneca, Theracos, Ionis Pharmaceuticals, DalCor, Glaxo Smith Kline, Bristol Myers Squibb, Boehringer Ingelheim, Cardurion, and Alnylam. Dr Solomon has received an institutional grant from Novartis for conduct of the PARAGON trial; has received institutional grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, the National Heart, Lung, and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, and Theracos; and has received consulting fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
(Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)