Association of Carbohydrate Antigen 125 on the Response to Dapagliflozin in Patients With Heart Failure.

BACKGROUND

Elevated circulating carbohydrate antigen 125 (CA125) is a marker of congestion and a predictor of outcomes in acute heart failure (HF). Less is known about CA125 in chronic ambulatory HF with reduced ejection fraction.

OBJECTIVES

This study examined the association between baseline CA125 (and changes in CA125) and outcomes in patients with HF with reduced ejection fraction in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; NCT03036124) trial and its relationship with the effect of dapagliflozin.

METHODS

The primary outcome was a composite of a first episode of worsening HF or cardiovascular death. CA125 was measured at baseline and 12 months following randomization.

RESULTS

Median baseline CA125 was 13.04 U/mL (IQR: 8.78-21.13 U/mL) in 3,123 of 4,774 patients with available data. Compared with CA125 ≤35 U/mL (upper limit of normal), patients with CA125 >35 U/mL were at a higher risk of the primary outcome (adjusted HR: 1.59; 95% CI: 1.29-1.96). The adjusted risks of the primary outcome relative to quartile 1 (Q1) (≤8.78 U/mL) were as follow: Q2, 8.79-13.04 U/mL (HR: 0.94; 95% CI: 0.71-1.24); Q3, 13.05-21.13 U/mL (HR: 1.22; 95% CI: 0.94-1.59); Q4, ≥21.14 U/mL (HR: 1.63; 95% CI: 1.28-2.09). The beneficial effect of dapagliflozin compared with placebo on the primary outcome was consistent whether CA125 was analyzed in quartiles (interaction P = 0.13) or as a continuous variable (interaction P = 0.75). The placebo-corrected relative change in CA125 at 12 months was -5.2% (95% CI: -10.6% to 0.5%; P = 0.07).

CONCLUSIONS

In DAPA-HF, elevated CA125 levels were an independent predictor of the risk of worsening HF or cardiovascular death. Dapagliflozin reduced the risk of worsening HF or cardiovascular death regardless of baseline CA125.

Informations de copyright

Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Funding Support and Author Disclosures The DAPA-HF trial was funded by AstraZeneca. Roche Diagnostics supported this study through provision of CA125 tests, free of charge. Dr Docherty’s employer, the University of Glasgow, has been remunerated by AstraZeneca for his work on the DAPA-HF and DELIVER trials; has received speaker fees from AstraZeneca and Radcliffe Cardiology; has served on Advisory Boards for Us2.ai and Bayer AG; has served on a Clinical Endpoint Committee for Bayer AG; and has received grant support from AstraZeneca, Roche, and Boehringer Ingelheim, outside the submitted work. Dr Welsh has received grant income from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics; and has received speaker fees from Novo Nordisk, outside the submitted work. Dr Annad has served as a consultant for Novartis, Amgen, Cyberonics, and Zensun. Dr de Boer has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals Inc, Novo Nordisk, and Roche; and has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, and Roche. Dr Køber has received speaker fees from Novo Nordisk, Novartis, Bayer, Boehringer Ingelheim, and AstraZeneca. Dr Kosiborod has received research grant support from AstraZeneca and Boehringer Ingelheim; has served as a consultant or on Advisory Boards for Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, Pharmacosmos, and Vifor Pharma; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Martinez has received consultation fees and research grants from AstraZeneca, Baliarda, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Gador, Milestone, Novartis, Pfizer, and St Lukes University. Dr O’Meara has received research funds (paid to her institution) for clinical trials from American Regent, Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, Novartis, and Pfizer; has received consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, and Janssen; and has received speaker fees from AstraZeneca, Bayer, and Boehringer Ingelheim. Dr Ponikowski has received personal fees from Boehringer Ingelheim, AstraZeneca, Servier, Bristol Myers Squibb, Amgen, Novartis, Merck, Pfizer, and Berlin Chemie; and has received grants and personal fees from Vifor Pharma. Dr Schou has received lecture fees from Novartis, AstraZeneca, Novo Nordisk, and Boehringer Ingelheim. Dr Berg has received support from Harvard Catalyst KL2/CMeRIT (National Institutes of Health/National Center for Advancing Translational Sciences grant UL 1TR002541); has received research grant support to his institution from AstraZeneca and Pfizer; has received consulting fees from AstraZeneca; and has served on a Clinical Endpoint Committee for a study sponsored by Kowa Pharmaceuticals. Dr Sabatine has received research grant support through Brigham and Women’s Hospital from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, Intarcia, Ionis, The Medicines Company, MedImmune, Merck, Novartis, Pfizer, and Quark Pharmaceuticals; has been a consultant for Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Bristol Myers Squibb, DalCor, Dr Reddy’s Laboratories, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk, and Silence Therapeutics; and is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from Abbott, ARCA Biopharma Inc, Janssen Research and Development LLC, Siemens Healthcare Diagnostics Inc, Softcell Medical Limited, Regeneron, Roche, and Zora Biosciences. Dr Morrow has received grants paid to the Brigham and Women’s Hospital from Abbott Laboratories, Amgen, Anthos Therapeutics, AstraZeneca, Eisai, The Medicines Company, Merck, Novartis, Pfizer, Roche Diagnostics, and Siemens; has received consultant fees from InCardia, Inflammatix, Merck and Co, Novartis, and Roche Diagnostics; and is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Roche, Siemens Healthcare Diagnostics, The Medicines Company, and Zora Biosciences. Dr Jarolim has received research support from Abbott Laboratories, Amgen Inc, AstraZeneca LP, Daiichi-Sankyo Inc, GlaxoSmithKline, Merck and Co Inc, Regeneron, Roche Diagnostics Corporation, and Siemens Healthineers. Drs Hammarstedt, Sjöstrand, and Langkilde are employees of AstraZeneca. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer 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, Sarepta, Lexicon, Anacardio, and Akros. Dr Sattar has received support from a British Heart Foundation Centre of Research Excellence grant RE/18/6/34217; has received consulting or speaker fees from Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp and Dohme, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi; and has received grant support paid to his university from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics, outside the submitted work. Dr Jhund has received support from a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217 and the Vera Melrose Heart Failure Research Fund; his employer has been remunerated for his work on the DELIVER and DAPA-HF trials by AstraZeneca; has received consulting and speaker fees from Novartis, AstraZeneca, and Boehringer Ingelheim; has received research funding from Boehringer Ingelheim; and has received remuneration for clinical trial work from Novo Nordisk and Bayer. Dr McMurray has received support from a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217 and the Vera Melrose Heart Failure Research Fund; has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline, KBP Biosciences, and Novartis; has received personal consulting fees from Alnylam Pharma, Bayer, Bristol Myers Squibb, George Clinical PTY Ltd, Ionis Pharma, Novartis, Regeneron Pharma, and River 2 Renal Corporation; has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharma, J.B. Chemicals and Pharma Ltd, Lupin Pharma, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, and Translational Medicine Academy; and is a director of Global Clinical Trial Partners Ltd. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.