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Original research article
Obesity paradox on outcome in atrial fibrillation maintained even considering the prognostic influence of biomarkers: insights from the ARISTOTLE trial
  1. Roopinder K Sandhu1,2,
  2. Justin A Ezekowitz1,2,
  3. Ziad Hijazi3,4,
  4. Johan Westerbergh3,
  5. Julia Aulin3,4,
  6. John H Alexander5,
  7. Christopher B Granger5,
  8. Sigrun Halvorsen6,
  9. Michael S Hanna7,
  10. Renato D Lopes5,
  11. Agneta Siegbahn3,8 and
  12. Lars Wallentin3,4
  1. 1 Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
  2. 2 Canadian VIGOUR Centre, University of Alberta, Edmonton, Alberta, Canada
  3. 3 Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
  4. 4 Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden
  5. 5 Duke Medicine, Duke Clinical Research Institute, Durham, North Carolina, USA
  6. 6 Department of Cardiology B, Oslo University Hospital Ulleval and University of Oslo, Oslo, Norway
  7. 7 Bristol-Myers Squibb (Former Employee), Princeton, New Jersey, USA
  8. 8 Department of Medical Sciences, Clinical Chemistry, University Hospital, Uppsala, Sweden
  1. Correspondence to Dr Roopinder K Sandhu; rsandhu2{at}ualberta.ca

Abstract

Objective We investigated the association between obesity and biomarkers indicating cardiac or renal dysfunction or inflammation and their interaction with obesity and outcomes.

Methods A total of 14 753 patients in the Apixaban for Reduction In STroke and Other ThromboemboLic Events in Atrial Fibrillation (ARISTOTLE) trial provided plasma samples at randomisation to apixaban or warfarin. Median follow-up was 1.9 years. Body Mass Index (BMI) was measured at baseline and categorised as normal, 18.5–25  kg/m2; overweight, >25 to <30 kg/m2; and obese, ≥30 kg/m2. We analysed the biomarkers high-sensitivity C reactive protein (hs-CRP), interleukin 6 (IL-6), growth differentiation factor-15 (GDF-15), troponin T and N-terminal B-type natriuretic peptide (NT-pro-BNP). Outcomes included stroke/systemic embolism (SE), myocardial infarction (MI), composite (stroke/SE, MI, or all-cause mortality), all-cause and cardiac mortality, and major bleeding.

Results Compared with normal BMI, obese patients had significantly higher levels of hs-CRP and IL-6 and lower levels of GDF-15, troponin T and NT-pro-BNP. In multivariable analyses, higher compared with normal BMI was associated with a lower risk of all-cause mortality (overweight: HR 0.73 (95% CI 0.63 to 0.86); obese: 0.67 (0.56 to 0.80), p<0.0001), cardiac death (overweight: HR 0.74 (95% CI 0.60 to 0.93); obese: 0.71 (0.56 to 0.92), p=0.01) and composite endpoint (overweight: 0.80 (0.70 to 0.92); obese: 0.72 (0.62 to 0.84), p<0.0001).

Conclusions Regardless of biomarkers indicating inflammation or cardiac or renal dysfunction, obesity was independently associated with an improved survival in anticoagulated patients with AF.

Trial registration number NCT00412984.

  • obesity
  • biomarkers
  • atrial fibrillation
  • atrial fibrillation
  • obesity

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Footnotes

  • Contributors All coauthors were involved in the planning and data interpretation of the analyses for this substudy. The statistical analyses in this substudy were performed at Uppsala Clinical Research Center, Uppsala University, Sweden (JW) using R V.3.3.2. All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The corresponding author (RKS) wrote the first draft of the manuscript and thereafter it was revised by all coauthors until agreement to submit was reached.

  • Funding This study was sponsored by Bristol-Myers Squibb and Pfizer.

  • Disclaimer The sponsor had no role in the analysis of the data, interpretation of the results or decision to submit the article for publication.

  • Competing interests JAE: other research support; modest; Astra Zeneca, Amgen, Abbott, Servier, Johnson & Johnson, Pfizer, BMS. Honoraria; modest; Astra Zeneca, Amgen, Abbott, Servier, Johnson & Johnson, Pfizer, BMS. Other; modest; Astra Zeneca, Amgen, Abbott, Servier, Johnson & Johnson, Pfizer, BMS. ZH: speaker’s bureau (modest) from Bristol-Myers Squibb/Pfizer, Roche Diagnostics; consultant/advisory board (modest) from Roche Diagnostics. JW: institutional research grant (significant) from Bristol-Myers Squibb/Pfizer. JA: institutional research grant (significant) from BMS/Pfizer. JHA: research grant (significant) from Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, FDA, NIH; research grant (modest) from CryoLife, Tenax Therapeutics, VoluMetrix; honoraria (significant) from Bristol-Myers Squibb; honoraria (modest) from CSL Behring, Janssen Pharmaceuticals, Merck, NovoNordisk Pharmaceuticals, Pfizer, VA Cooperative Studies Program, Zafgen; consultant/advisory board (significant) from Bristol-Myers Squibb, Portola Pharmaceuticals; consultant/advisory board (modest) from Abbvie, CSL Behring, Janssen Pharmaceuticals, Merck, NovoNordisk Pharmaceuticals, Pfizer, VA Cooperative Studies Program, Zafgen. CBG: research grant (significant) from Armetheon, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Duke Clinical Research Institute, FDA, GlaxoSmithKline, Janssen Pharmaceuticals, Medtronic Foundation, Novartis, Pfizer; consultant/advisory board (significant) from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Medscape, Novartis, Pfizer; consultant/advisory board (modest) from Abbvie, Armetheon, AstraZeneca, Bayer, Boston Scientific, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Medtronic, Merck, NIH, Rho Pharmaceuticals, Sirtex, Verseon. SH: honoraria (modest) from AstraZeneca, Bayer, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Merck, Sanofi. MSH: former employee of and has stock ownership in Bristol-Myers Squibb. RDL: research grant (significant) from Amgen, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Medtronic PLC, Sanofi-Aventis; consultant/advisory board (significant) from Bristol-Myers Squibb/Pfizer; consultant/advisory board (modest) from Bayer, Boehringer Ingelheim. AS: institutional research grant (modest) from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Roche Diagnostics; consultant/advisory board (modest) from Olink Proteomics. LW: institutional research grants (all significant): AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Roche Diagnostics, Merck & Co.

  • Patient consent Obtained.

  • Ethics approval Approval by the appropriate ethics committees was obtained at all sites.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement No additional data are available.

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