Prior Heart Failure Hospitalization, Clinical Outcomes, and Response to Sacubitril/Valsartan Compared with Valsartan in HFpEF
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Author + information
- Muthiah Vaduganathan, MD MPH1,
- Brian L. Claggett, PhD1,
- Akshay S. Desai, MD MPH1,
- Stefan D. Anker, MD PhD2,3,4,
- Sergio V. Perrone, MD5,
- Stefan Janssens, MD6,
- Davor Milicic, MD7,
- Juan L. Arango, MD8,
- Milton Packer, MD9,
- Victor C. Shi, MD10,
- Martin P. Lefkowitz, MD10,
- John J.V. McMurray, MD11 and
- Scott D. Solomon, MD1,∗ (ssolomon{at}bwh.harvard.edu), @mvaduganathan@akshaydesaimd@svperrone@scottdsolomon
- 1Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- 2Division of Cardiology and Metabolism, Department of Cardiology (CVK) and Berlin-Brandenburg Center for Regenerative Therapies (BCRT)
- 3German Centre for Cardiovascular Research (Deutsches Zentrum für Herz-Kreislauf-Forschung), Berlin, Germany
- 4Charité Universitätsmedizin, Berlin, Germany
- 5Instituto FLENI, Buenos Aires, Argentina
- 6Department of Cardiology, University Hospitals Leuven, Belgium
- 7Department of Cardiovascular Diseases, University Hospital Center Zagreb, Croatia
- 8Guatemalan Heart Institute, Guatemala
- 9Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX and Imperial College, London, UK
- 10Novartis Pharmaceuticals, East Hanover, New Jersey
- 11British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
- ↵∗Address for Correspondence: Scott D. Solomon, MD Cardiovascular Division Brigham and Women’s Hospital 75 Francis Street Boston, MA 02115 Twitter: .
Abstract
Background The period shortly after hospitalization for heart failure (HF) represents a high-risk window for recurrent clinical events, including rehospitalization or death.
Objectives To determine whether the efficacy and safety of sacubitril/valsartan varies in relation to the proximity to HF hospitalization among patients with HF and preserved ejection fraction (HFpEF).
Methods In this post hoc analysis of PARAGON-HF, we assessed risk of clinical events and response to sacubitril/valsartan in relation to time from last HF hospitalization among patients with HFpEF (≥45%). Primary outcome was composite total HF hospitalizations and cardiovascular death, analyzed 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 31-90 days, 435 (9%) within 91-180 days, 694 (14%) after 180 days, and 2,490 (52%) were never previously hospitalized. Over median 35 months follow-up, risk of total HF hospitalizations and cardiovascular death was inversely and non-linearly 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 0.53-0.99) to patients never hospitalized (rate ratio 1.00; 95% confidence interval 0.80-1.24); trend in relative risk reduction Pinteraction=0.15. With valsartan alone, rate of total primary events was 26.7 (≤30 days), 24.2 (31-90 days), 20.7 (91-180 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% (31-90 days), 3.4% (91-180 days), while 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, 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 warrants prospective validation.
Footnotes
Disclosures: Dr. Vaduganathan is supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (NIH/NCATS 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 consulting fees and/or honoraria from Abbott, AstraZeneca, Alnylam, Boehringer-Ingelheim, Boston Scientific, Biofourmis, Corvidia, DalCor Pharma, Novartis, Relypsa, and Regeneron. Dr. Anker reports grants from Vifor International and Abbott Vascular. He also 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. 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 & 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 Pharmaceutics, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, Novartis, Sanofi Pasteur, Theracos, and has consulted for Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Corvia, Gilead, GlaxoSmithKline, Ironwood, Merck, Novartis, Pfizer, Takeda, and Theracos.
Funding: The PARAGON-HF trial is funded by Novartis.
Tweet: New #PARAGONHF data at #AHA19: HFpEF pts early after hospitalization face ↑ HF events & may respond favorably to sacubitril/valsartan
Presentation: Featured Science Late Breaking Presentation at the American Heart Association Scientific Sessions in Philadelphia, PA on November 16th, 2019 at 10AM EST
Clinical Trial Registration: PARAGON-HF: ClinicalTrials.gov Identifier NCT01920711
- Received October 22, 2019.
- Revision received November 5, 2019.
- Accepted November 5, 2019.
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