The 'obesity paradox' in atrial fibrillation: observations from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial

Sandhu RK, Ezekowitz J, Andersson U, et al.
Eur Heart J 2016;37:2869-2878

Background

BMI is an established risk factor for the development of atrial fibrillation (AF) and an independent predictor of progression from paroxysmal to sustained AF [1,2]. While some studies have shown that overweight status and obesity may be associated with a favourable prognosis in patients with CVD (the ‘obesity paradox’), other studies have come to the opposite conclusions [3,4].

In this study, the association between various measures of adiposity and clinical outcomes was evaluated in 18 107 participants that had been randomised to apixaban or warfarin (ARISTOTLE trial) for a median follow-up of 1.8 years. BMI was categorized as normal (18.5-25 kg/m²) in 22.6% of patients, as overweight (25-30 kg/m²) in 37.4% of patients and as obese (≥30 kg/m²) in 40% of patients.

Main results

• The unadjusted annualised rate of the efficacy and safety events death, stroke/systemic embolism [SE]/myocardial infarction[MI]/death and major bleeding was overall lower for patients with a higher BMI compared with those with a normal BMI. However in contrast to death and the composite endpoint stroke/SE/MI/death (P<0.001 for both), this was this association not significant for stroke/SE (P=0.18) and major bleedings (P=0.11).

• In models adjusting for randomised treatment only, overweight status and obesity were significantly associated with lower risk of efficacy and safety outcomes compared with normal weight (P < 0.0001).

• In multivariable analyses adjusting for additional covariates, higher BMI was associated with lower risk of death and the composite endpoint stroke/SE/MI/death, since the HR for death in the overweight was 0.67 (95% CI: 0.59–0.780) and in the obese was 0.63 (95% CI: 0.54–0.74; P < 0.0001). Moreover, the HR for the composite endpoint in overweight patients was 0.74 (95% CI: 0.65–0.84), which was 0.68 (95% CI: 0.60–0.78; P < 0.0001) for obese patients.

• Risk for stroke/SE was not associated to BMI in this multivariable analysis (P = 0.20).

• There was an 18% relative risk reduction in major bleeding events in patients who were overweight, but this was not statistically significant (P = 0.11).

• BMI was further categorised into stages I (≥30 to <35 kg/m²), II (35 to <40 kg/m²), and III (≥40 kg/m²) in sensitivity analysis. Only in adjusted models, the risk for stroke/SE was lower with a BMI of 35-40 kg/m² as the risk hazard for stroke/SE was 0.60 (95% CI: 0.39–0.92), for death was 0.57 (95% CI: 0.45–0.73) and for the composite endpoint was 0.61 (95% CI: 0.49–0.75).

• In women, high waist circumference (WC) was significantly associated with a lower risk of death (HR: 0.69; 95% CI: 0.55–0.86; P = 0.001) and the composite endpoint stroke/SE/MI/death (HR: 0.73; 95% CI: 0.61–0.89; P = 0.001) and a 28% risk reduction in stroke/SE (P = 0.048) compared with normal WC after adjusting for established risk factors.
  There was no association between high WC and outcomes in men.

Conclusion

In the ARISTOTLE study, higher BMI or WC were associated with a more favourable prognosis in AF patients treated with oral anticoagulants. These data provide further evidence that an obesity paradox is present in AF patients.

Editorial comment [5]

In their editorial article, the authors Lau, Middeldorp and Sanders, comment on the weaknesses of the study that include many residual confounding factors due to a high number of non-matched baseline characteristics among the normal and higher BMI patients. For example, medication use was significantly higher in the higher BMI patients, older age was more frequent in the normal BMI patients, and superior renal function was more common in the higher BMI subjects.
They conclude: ‘Taken together, the ‘obesity paradox’ in AF should be approached with caution and a new paradigm of care beyond rate and rhythm management of AF should be actively pursued in the form of aggressive lifestyle modification strategies to facilitate purposeful weight reduction, increased physical activity, and improved cardiorespiratory fitness in overweight and obese AF individuals.’


Find this article online at Eur Heart J

References

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2. Tsang TS, Barnes ME, Miyasaka Y, et al. Obesity as a risk factor for the progression of paroxysmal to permanent atrial fibrillation: a longitudinal cohort study of 21 years. Eur Heart J 2008;29:2227–2233.
3. Wang J, Yang YM, Zhu J, et al. Overweight is associated with improved survival and outcomes in patients with atrial fibrillation. Clin Res Cardiol 2014;103:533–542.
4. Overvad TF, Rasmussen LH, Skjoth F, et al. Body mass index and adverse events in patients with incident atrial fibrillation. Am J Med 2013;126:640.e9–640.e17.
5. Lau DH, Middeldorp ME, Sanders P. Obesity paradox in atrial fibrillation: a distracting reality or fictitious finding? Eur Heart J 2016 37: 2879-2881.