Obesity paradox on outcome in atrial fibrillation maintained even considering the prognostic influence of biomarkers: insights from the ARISTOTLE trial

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.

Keywords: atrial fibrillation; biomarkers; obesity.

Conflict of interest statement

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.

Figures

Figure 1

Multivariable-adjusted HRs and 95% CIs of outcomes according to categories of BMI adjusting for established risk factors, study treatment and cardiac, renal and inflammatory biomarkers. Multivariable models adjusted for age, sex, region, glomerular filtration rate, smoking, systolic blood pressure, heart rate, atrial fibrillation type, diabetes, heart failure, previous stroke or systemic embolism or transient ischaemic attack, hypertension, previous myocardial infarction, previous peripheral artery disease/coronary artery bypass graft/percutaneous coronary intervention, alcohol, baseline medications, prior warfarin/vitamin K antagonist treatment, randomised treatment, hs-CRP, IL-6, GDF-15, troponin T, NT-pro-BNP and cystatin C. For bleeding endpoints: haematocrit, chronic liver disease, history of anaemia, use of non-steroidal inflammatory agents and history of spontaneous or clinical relevant bleeding, randomised treatment and hs-CRP, IL-6, GDF-15, troponin T, NT-pro-BNP and cystatin C. BMI, Body Mass Index; GDF-15, growth differentiation factor-15; hs-CRP, high-sensitivity C reactive protein; IL-6, interleukin 6; MI, myocardial infarction; NT-pro-BNP, N-terminal pro-brain natriutetic peptide.

Figure 2

Multivariable-adjusted HRs and 95% CIs for outcomes for waist circumference. Waist circumference for men

Figure 3

Multivariable-adjusted HRs and 95% CIs for outcomes for waist circumference according to sex. Waist circumference men