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Selvaraj, S. et al. (2020) Serum uric acid, influence of sacubitril/valsartan,
and cardiovascular outcomes in heart failure with preserved ejection
fraction: PARAGON-HF. European Journal of Heart Failure, 22(11), pp.
2093-2101.
(doi: 10.1002/ejhf.1984)
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This is the peer reviewed version of the following article:
Selvaraj, S. et al. (2020) Serum uric acid, influence of sacubitril/valsartan,
and cardiovascular outcomes in heart failure with preserved ejection
fraction: PARAGON-HF. European Journal of Heart Failure, 22(11), pp.
2093-2101, which has been published in final form at: 10.1002/ejhf.1984
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https://eprints.gla.ac.uk/222726/
Deposited on: 1 September 2020
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Serum Uric Acid, Influence of Sacubitril/Valsartan, and Cardiovascular Outcomes in
Heart Failure with Preserved Ejection Fraction: PARAGON-HF
Senthil Selvaraj, MD, MA, Brian L. Claggett, PhD, Marc A. Pfeffer, MD, PhD, Akshay S. Desai,
MD, Finnian R. McCausland, MD, Martina M. McGrath, MD, Inder S. Anand, MD, Dirk J. van
van Veldhuisen, MD, Lars Kober, MD, DMSc, Stefan Janssens, MD, John G.F. Cleland, MD,
PhD, Burkert Pieske, MD, Jean L. Rouleau, MD, Michael R. Zile, MD, Victor C. Shi, MD,
Martin P. Lefkowitz, MD, John J. V. McMurray, MD, Scott D. Solomon, MD
From the Division of Cardiology, Department of Medicine, Hospital of the University of
Pennsylvania, Philadelphia, PA (S.S.); Division of Cardiology, Department of Medicine,
Brigham and Women’s Hospital, Boston, MA (B.C., M.A.P., A.S.D, S.D.S.); Renal Division,
Brigham and Women's Hospital, Harvard Medical School, Boston, MA (F.R.M., M.M.M.);
Department of Cardiovascular Medicine, University of Minnesota, Minneapolis, Minnesota
(I.S.A.); University of Groningen, Department of Cardiology, University Medical Centre
Groningen, RB Groningen, the Netherlands (D.J.V.V.); Rigshospitalet Copenhagen University
Hospital, Copenhagen, Denmark (L.K.); Department of Cardiology, University Hospitals,
Leuven, Belgium (S.J.); Robertson Institute of Biostatistics and Clinical Trials Unit, University
of Glasgow, Glasgow, UK (J.G.F.C.); Department of Internal Medicine and Cardiology, German
Center for Cardiovascular Research partner site Berlin, Germany (B.P.); Institut de Cardiologie
de Montreal, Université de Montreal, Canada (J. L. R.); Medical University of South Carolina
and RHJ Department of Veterans Administration Medical Center, Charleston, SC (M. R. Z.);
Novartis, East Hanover, NJ (V.C. S., M.P. L.); BHF Cardiovascular Research Centre, University
of Glasgow, Glasgow, UK (J.J.V.M.)
Running title: Uric Acid in HFpEF
Address for correspondence:
Scott D. Solomon, MD
Brigham and Women’s Hospital
75 Francis Street
Boston, MA 02115
Phone: 857.307.1954
Fax: 857.307.1944
E-mail: ssolomon@rics.bwh.harvard.edu
This article is protected by copyright. All rights reserved.
Accepted Article
This article has been accepted for publication and undergone full peer review but has
not been through the copyediting, typesetting, pagination and proofreading process
which may lead to differences between this version and the Version of Record. Please
cite this article as doi: 10.1002/ejhf.1984
Sponsor: Novartis
ClinicalTrials.gov Identifier: NCT01920711
ABSTRACT (word count = 244)
Aims: To determine the prognostic value of serum uric acid (SUA) on outcomes in heart failure
with preserved ejection fraction (HFpEF), and whether sacubitril/valsartan reduces SUA and
SUA-related therapies.
Methods and Results: We analyzed 4,795 participants from PARAGON-HF. We related
baseline hyperuricemia (using assay definitions) to the primary outcome (CV death and total HF
hospitalization). Between baseline and 4 months, we assessed the association between changes in
SUA and Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS) and
other cardiac biomarkers. We simultaneously adjusted for baseline and time-updated SUA to
determine whether lowering SUA was associated with clinical benefit. Average age was 73±8
years and 52% were women. After multivariable adjustment, hyperuricemia was associated with
increased risk for the primary outcome (rate ratio 1.61, 95%CI 1.37, 1.90). The treatment effect
of sacubitril/valsartan for the primary endpoint was not significantly modified by hyperuricemia
(p-interaction=0.14). Sacubitril/valsartan reduced SUA -0.38 mg/dL (95%CI: -0.45, -0.31)
compared with valsartan at 4 months, with greater effect in those with elevated SUA vs. normal
SUA (-0.51 vs. -0.32 mg/dL) (p-interaction=0.031). Sacubitril/valsartan reduced the odds of
initiating SUA-related treatments by 32% during follow-up (p<0.001). After multivariable
adjustment, change in SUA was inversely associated with change in KCCQ-OSS and directly
associated with high-sensitivity Troponin T (p<0.05). Time-updated SUA was a stronger
predictor of adverse outcomes than baseline SUA.
This article is protected by copyright. All rights reserved.
Accepted Article
Conclusions: SUA independently predicted adverse outcomes in HFpEF. Sacubitril/valsartan
reduced SUA and related therapy initiation compared to valsartan. Reducing SUA was
associated with improved outcomes.
Keywords: heart failure with preserved ejection fraction; heart failure hospitalization;
sacubitril/valsartan; uric acid
This article is protected by copyright. All rights reserved.
Accepted Article
ACRONYMS AND ABBREVIATIONS
eGFR, estimated glomerular filtration rate
HFpEF, heart failure with preserved ejection fraction
HFrEF, heart failure with reduced ejection fraction
KCCQ-OSS, Kansas City Cardiomyopathy Questionnaire overall summary score
NT-proBNP, N-terminal pro B-type natriuretic peptide
PARADIGM-HF, Prospective comparison of ARNI with ACEI to Determine Impact on Global
Mortality and morbidity in Heart Failure trial
PARAGON-HF, Prospective Comparison of Angiotensin receptor–neprilysin inhibitor with
Angiotensin-receptor blockers Global Outcomes in HF with Preserved Ejection Fraction
SUA, serum uric acid
This article is protected by copyright. All rights reserved.
Accepted Article
