Author + information
- Received March 19, 2019
- Revision received May 22, 2019
- Accepted May 22, 2019
- Published online September 30, 2019.
- Alvin Chandra, MDa,
- Muthiah Vaduganathan, MD, MPHa,
- Eldrin F. Lewis, MD, MPHa,
- Brian L. Claggett, PhDa,
- Adel R. Rizkala, PharmDb,
- Wenyan Wang, PhDb,
- Martin P. Lefkowitz, MDb,
- Victor C. Shi, MDb,
- Inder S. Anand, MD, DPhilc,
- Junbo Ge, MDd,
- Carolyn S.P. Lam, MBBS, PhDe,f,
- Aldo P. Maggioni, MDg,
- Felipe Martinez, MDh,
- Milton Packer, MDi,j,
- Marc A. Pfeffer, MD, PhDa,
- Burkert Pieske, MDk,l,
- Margaret M. Redfield, MDm,
- Jean L. Rouleau, MDn,
- Dirk J. Van Veldhuisen, MDo,
- Faiez Zannad, MDp,
- Michael R. Zile, MDq,r,
- John J.V. McMurray, MDs,
- Scott D. Solomon, MDa,∗ (, )
- on behalf of the PARAGON-HF Investigators
- aCardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
- bNovartis Pharmaceutical Corporation, East Hanover, New Jersey
- cDepartment of Medicine, University of Minnesota, Minneapolis, Minnesota
- dDepartment of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
- eNational Heart Centre Singapore, Duke-National University of Singapore Medical School, Singapore
- fGeorge Institute for Global Health, University of New South Wales, Sydney, Australia
- gANMCO Research Center, Florence, Italy
- hUniversidad Nacional of Cordoba, Cordoba, Argentina
- iBaylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas
- jImperial College London, London, United Kingdom
- kDepartment of Internal Medicine, Cardiology Charité, Universitaetsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
- lGerman Heart Center, Berlin, Germany
- mDepartment of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
- nInstitut de Cardiologie de Montréal, Université de Montréal, Montreal, Canada
- oUniversity Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- pInserm CIC 1433, French Clinical Research Infrastructure Network, Investigation Network Initiative Cardiovascular and Renal Clinical Trialists, Centre Hospitalier Régionale Universitaire de Nancy, Université de Lorraine, Nancy, France
- qMedical University of South Carolina, Charleston, South Carolina
- rRalph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina
- sBritish Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland
- ↵∗Address for correspondence:
Dr. Scott Solomon, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115.
Objectives This study sought to describe baseline health-related quality of life (HRQL) in the PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF) trial, the largest heart failure with preserved ejection fraction (HFpEF) trial to date.
Background There are limited data characterizing HRQL in patients with HFpEF using validated metrics.
Methods The PARAGON-HF trial randomized symptomatic patients with HFpEF (≥45%) ≥50 years of age to either sacubitril/valsartan or valsartan. The study reports comprehensive baseline HRQL using Kansas City Cardiomyopathy Questionnaire (KCCQ) administered at randomization after active run-in period. The study then compares baseline HRQL with patients with heart failure with reduced ejection fraction (HFrEF) (≤40%) 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. Forward multivariable stepwise regression modeling was performed separately in both trials to identify independent clinical correlates of KCCQ-Overall Summary (KCCQ-OS) score. PARADIGM-HF trial patients <50 years of age were excluded to enable comparison.
Results In the PARAGON-HF trial, 4,735 of 4,822 patients (mean age 73 ± 8 years; 48% men) completed baseline KCCQ at randomization. Mean KCCQ-OS score was 71. Women had worse mean KCCQ-OS score than men did. Patients in the PARAGON-HF trial reported lower KCCQ scores in nearly all domains when compared with the PARADIGM-HF trial (KCCQ-OS score 71 ± 19 vs. 73 ± 19; p < 0.001). The strongest independent clinical correlates of adverse HRQL in both the PARAGON-HF and PARADIGM-HF trials were New York Heart Association functional class, female gender, lower extremity edema, body mass index, angina, dyspnea, and paroxysmal nocturnal dyspnea. After accounting for these clinical correlates of adverse HRQL that were common to both HFpEF and HFrEF patients, KCCQ-OS score did not differ significantly.
Conclusions HRQL was largely worse in women and was similar in HFpEF and HFrEF after accounting for variation in demographics, functional status, and symptom burden. (Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF [PARAGON-HF] NCT01920711; Prospective Comparison of ARNI with an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255)
- gender disparity
- health-related quality of life
- heart failure with preserved ejection fraction
- heart failure with reduced ejection fraction
- regional variation
The study was supported by Novartis. Novartis participated in the design and conduct of the PARAGON-HF trial; collection, management, and interpretation of the data; and reviewed and commented on the manuscript before submission for publication. The sponsor otherwise had no role in the analysis of the data, preparation of this manuscript or the decision to submit this manuscript for publication. Dr. Chandra is supported by a National Heart, Lung, and Blood Institute T32 postdoctoral training grant (5T32HL094301-09). Dr. Vaduganathan is supported by a KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (National Institutes of Health/National Center for Advancing Translational Sciences Award UL 1TR002541). Dr. Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore. Dr. Zannad is supported by the European Commission under the Health Cooperation Work Programme of the 7th Framework Programme, under the Grant Agreement nos. 6029047 and 305507, and the Agence Nationale de la Recherche Action RHU 15-RHUS-0004. Dr. Vaduganathan has served on the advisory board for Amgen, AstraZeneca, Bayer AG, and Baxter Healthcare. Dr. Lewis has served as a consultant for and received research support from Novartis and Merck. Dr. Claggett has received consulting fees from Boehringer Ingelheim, Gilead, AOBiome, and Corvia. Drs. Rizkala, Wang, Lefkowitz, and Shi are employees of Novartis. Drs. Anand, Ge, Martinez, Redfield, Van Veldhuisen, and Zile have served as consultants to Novartis as members of PARAGON-HF Executive Steering Committee. Dr. Lam has received research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; and has served on the advisory board/steering committee/executive committee for Novartis, Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, Vifor Pharma, Amgen, Merck, Janssen Research & Development, Menarini, Boehringer Ingelheim, Novo Nordisk, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, JanaCare, Biofourmis, and Darma. Dr. Maggioni has received honoraria for participation in study committees sponsored by Novartis, Bayer, and Fresenius, outside the present work. Dr. Packer has served as a consultant for Abbott, Actavis, Akcea, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance. Dr. Pfeffer has received research support from Novartis; has served as a consultant for AstraZeneca, Corvidia, DalCor, GlaxoSmithKline, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Servier, and Takeda; and owns equity in DalCor. Dr. Pieske has served as a consultant for or as a speaker or steering committee member for Novartis, Bayer Healthcare, AstraZeneca, Bristol-Myers Squibb, Sanofi, Merck, and Stealth Peptides. Dr. Rouleau has served as a consultant for Novartis and AstraZeneca. Dr. Van Veldhuisen has received travel honoraria from Novartis and Corvia Medical; and membership fees from Novartis. Dr. Zannad has served on the advisory board/steering committee/executive committee for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, CEVA, CVRx, GE Healthcare, Janssen, KBP biosciences, LivaNova, Novartis, Novo Nordisk, Merck, Mundipharma, Quantum Genomics, Relypsa, Roche, Vifor Fresenius; and is co-founder of CardioRenal, CVCT, and Eshmoun. Dr. McMurray’s employer (Glasgow University) has been paid by Novartis for his time spent on the Executive Committee and as a co-principal investigator of the ATMOSPHERE trial, as a co-principal investigator of the PARADIGM-HF and PARAGON-HF trials, on the executive/steering committee for the PARADISE-MI and PERSPECTIVE trials (with sacubitril/valsartan), and meetings/presentations related to these trials and aliskiren and sacubitril/valsartan; he has also received travel and accommodation fees for some of these meetings from Novartis, with these payments made through a consultancy with Glasgow University, and he had not received personal payments in relation to these trials/drugs; his employer (Glasgow University) has also been paid by Novartis for his participation in a company advisory board which meets twice per year and covers the cardiometabolic field. Dr. Solomon has received research grant support from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, Theracos; and has served as a consultant for 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.
- Received March 19, 2019.
- Revision received May 22, 2019.
- Accepted May 22, 2019.
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