Author + information
- Received October 22, 2019
- Revision received November 5, 2019
- Accepted November 5, 2019
- Published online January 20, 2020.
- Muthiah Vaduganathan, MD, MPHa@mvaduganathan,
- Brian L. Claggett, PhDa,
- Akshay S. Desai, MD, MPHa@akshaydesaimd,
- Stefan D. Anker, MD, PhDb,c,d,
- Sergio V. Perrone, MDe@svperrone,
- Stefan Janssens, MDf,
- Davor Milicic, MDg,
- Juan L. Arango, MDh,
- Milton Packer, MDi,j,
- Victor C. Shi, MDk,
- Martin P. Lefkowitz, MDk,
- John J.V. McMurray, MDl and
- Scott D. Solomon, MDa,∗ (, )@scottdsolomon
- aCardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- bDivision of Cardiology and Metabolism, Department of Cardiology and Berlin-Brandenburg Center for Regenerative Therapies
- cGerman Centre for Cardiovascular Research (Deutsches Zentrum für Herz-Kreislauf-Forschung), Berlin, Germany
- dCharité Universitätsmedizin, Berlin, Germany
- eInstituto Fleni, Buenos Aires, Argentina
- fDepartment of Cardiology, University Hospitals Leuven, Leuven, Belgium
- gDepartment of Cardiovascular Diseases, University Hospital Center Zagreb, Zagreb, Croatia
- hGuatemalan Heart Institute, Guatemala City, Guatemala
- iBaylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas
- jImperial College, London, United Kingdom
- kNovartis Pharmaceuticals, East Hanover, New Jersey
- lBritish Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
- ↵∗Address for correspondence:
Dr. Scott D. Solomon, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115.
Background The period shortly after hospitalization for heart failure (HF) represents a high-risk window for recurrent clinical events, including rehospitalization or death.
Objectives This study sought to determine whether the efficacy and safety of sacubitril/valsartan varies in relation to the proximity to hospitalization for HF among patients with HF with preserved ejection fraction (HFpEF).
Methods In this post hoc analysis of PARAGON-HF (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ARB [Angiotensin Receptor Blocker] Global Outcomes in HFpEF), we assessed the risk of clinical events and response to sacubitril/valsartan in relation to time from last HF hospitalization among patients with HFpEF (≥45%). The primary outcome was composite total HF hospitalizations and cardiovascular death, analyzed by using a semiparametric proportional rates method, stratified by geographic region.
Results Of 4,796 validly randomized patients in PARAGON-HF, 622 (13%) were screened during hospitalization or within 30 days of prior hospitalization, 555 (12%) within 31 to 90 days, 435 (9%) within 91 to 180 days, and 694 (14%) after 180 days; 2,490 (52%) were never previously hospitalized. Over a median follow-up of 35 months, risk of total HF hospitalizations and cardiovascular death was inversely and nonlinearly associated with timing from prior HF hospitalization (p < 0.001). There was a gradient in relative risk reduction in primary events with sacubitril/valsartan from patients hospitalized within 30 days (rate ratio: 0.73; 95% confidence interval: 0.53 to 0.99) to patients never hospitalized (rate ratio: 1.00; 95% confidence interval: 0.80 to 1.24; trend in relative risk reduction: pinteraction = 0.15). With valsartan alone, the rate of total primary events was 26.7 (≤30 days), 24.2 (31 to 90 days), 20.7 (91 to 180 days), 15.7 (>180 days), and 7.9 (not previously hospitalized) per 100 patient-years. Compared with valsartan, absolute risk reductions with sacubitril/valsartan were more prominent in patients enrolled early after hospitalization: 6.4% (≤30 days), 4.6% (31 to 90 days), and 3.4% (91 to 180 days), whereas no risk reduction was observed in patients screened >180 days or who were never hospitalized (trend in absolute risk reduction: pinteraction = 0.050).
Conclusions Recent hospitalization for HFpEF identifies patients at high risk for near-term clinical progression. In the PARAGON-HF trial, the relative and absolute benefits of sacubitril/valsartan compared with valsartan in HFpEF appear to be amplified when initiated in the high-risk window after hospitalization and warrant prospective validation. (PARAGON-HF; NCT01920711)
The PARAGON-HF trial is funded by Novartis. Dr. Vaduganathan is supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (National Institutes of Health/National Center for Advancing Translational Sciences Award UL 1TR002541); and serves on advisory boards for Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, and Relypsa. Dr. Claggett has received consultancy fees from Boehringer Ingelheim, Gilead, AOBiome, and Corvia. Dr. Desai has received research grant support from AstraZeneca, Alnylam, and Novartis; and has received consulting fees and/or honoraria from Abbott, AstraZeneca, Alnylam, Boehringer Ingelheim, Boston Scientific, Biofourmis, Corvidia, DalCor Pharma, Novartis, Relypsa, and Regeneron. Dr. Anker has received grants from Vifor International and Abbott Vascular; and has received personal fees from Bayer, Boehringer Ingelheim, Brahms GmbH, Impulse Dynamics, Novartis, Servier, St. Jude Medical, and Vifor International. Dr. Perrone has received fees from Novartis for conferences, clinical research programs, and to integrate an advisory group; and has also received consulting fees from Servier, Abbott, United Pharmaceuticals, and Janssen-Cilag Pharmaceuticals. Dr. Janssens has received research grants from Novartis; and has a consultancy agreement with Novartis through the University of Leuven, Belgium. Dr. Milicic has lectured and consulted for Novartis. Dr. Arango has received funds for clinical studies and has consulted for Novartis. Dr. Packer has received personal fees from Akcea, AstraZeneca, Amgen, Actavis, AbbVie, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi-Sankyo, Johnson & Johnson, Novo Nordisk, Pfizer, Sanofi, Synthetic Biologics, and Theravance. Drs. Shi and Lefkowitz are employees of Novartis. Dr. McMurray has served as an executive committee member and coprincipal investigator of ATMOSPHERE and coprincipal investigator of the PARADIGM-HF and PARAGON-HF trials and his employer, Glasgow University, has been paid by Novartis for his time spent in these roles. Dr. Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Celladon, Gilead, GlaxoSmithKline, Ionis Pharmaceuticals, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and has consulted for Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Corvia, Gilead, GlaxoSmithKline, Ironwood, Merck, Novartis, Pfizer, Takeda, and Theracos. This paper was presented at the American Heart Association Scientific Sessions, Philadelphia, Pennsylvania, November 16, 2019.
- Received October 22, 2019.
- Revision received November 5, 2019.
- Accepted November 5, 2019.
- 2020 American College of Cardiology Foundation
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