Obesity Paradox in Atrial Fibrillation: Implications for Outcomes and Relationship With Oral Anticoagulant Drugs

Marco Proietti; Giuseppe Boriani


Am J Cardiovasc Drugs. 2020;20(2):125-137. 

In This Article

Obesity Paradox for the Outcomes of Patients With AF

To date, several studies have investigated the relationship between obesity or overweight and occurrence of major adverse events in patients with AF (Table 1).[20–35]

In 2010, Badheka et al.[20] published the first study to postulate the existence of an obesity paradox in patients with AF. In this subgroup analysis derived from the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) trial, a randomized controlled trial (RCT) testing the difference between rate and rhythm control in preventing the occurrence of death in patients with AF, both overweight and obesity were associated with a reduced risk for both cardiovascular and all-cause death and for a composite endpoint of all the major adverse events, with a reduced risk ranging between 30 and 60% according to the outcomes. Moreover, a multivariate regression analysis including BMI as a continuous variable found that the risk for all-cause death progressively decreased for each 1 kg/m2 (hazard ratio (HR) 0.95; 95% CI 0.93–0.98).[20]

In 2013, Overvad et al.[33] investigated the issue of the obesity paradox for patients with AF in the Danish Diet, Cancer and Health observational study. In this study, 3135 patients with AF were observed, focusing on the occurrence of ischemic stroke, thromboembolic event (TE) and all-cause death. After a median follow-up of 4.9 years, the authors clearly showed that, after full adjustments, overweight and obesity were associated with a higher risk of all-cause death occurrence and the composite outcome of the three events, whereas no difference was found in terms of stroke/TE occurrence.[33]

Since then, evidence regarding research into the obesity paradox in patients with AF has been noticeably conflicting (Table 1).[36] Indeed, most studies deriving from RCT subgroup analyses have shown an independent association, with a reduced risk of stroke, cardiovascular death, and all-cause death for overweight and obese patients. However, results from observational and population-based cohort studies testing the obesity paradox hypothesis have been controversial, sometimes showing no difference in the reported outcomes and other times reporting a substantial association with an increased risk for overweight and obese patients with AF (Table 1).

Very recently, in a subgroup analysis derived from the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48) study, overweight and obesity was associated with a lower risk of stroke/systemic embolism (SE) and all-cause death, including in severe and very severe obesity.[32] Furthermore, an independent association was found between increased BMI (for each 5 kg/m2 increase) and a reduced risk of the same events, included in a composite net outcome[32] (Table 1).

Conversely, an analysis derived from the EORP-AF (EURObservational Research Programme in AF) pilot study, a European Society of Cardiology observational study of patients with AF, found no difference in the occurrence of all-cause death in overweight and obese patients compared with normal-weight patients, with only a progressively lower rate of all-cause death outcome in female patients, albeit this was not confirmed in the regression analysis.[27]

In a systematic review and meta-analysis investigating the obesity paradox in patients with AF,[37] despite some small reductions in relative risk for stroke/SE (in obese patients) and all-cause death (in overweight patients), the authors concluded that the risk for adverse outcomes in overweight and obese patients with AF was substantially similar to that in healthy-weight patients with AF.[37] These conclusions were challenged by a second meta-analysis by Proietti et al.[36] and by a third recent meta-analysis by Zhou et al.,[38] performed mostly by pooling data from RCTs, that consistently showed that patients with higher BMI had a lower risk of stroke occurrence.

Regarding the relationship between underweight and outcomes in patients with AF, despite the relative lack of available evidence (since only a few studies have investigated this), current data appear to be quite concordant in indicating an increased risk for adverse outcomes, particularly for mortality (Table 1). Even the data in the meta-analysis by Zhu et al.[37] clearly indicated that underweight patients had a substantially higher risk of all outcomes.

Lastly, in terms of bleeding outcomes, although analyzed in few studies, the evidence does not seem to suggest a differential risk according to BMI groups. However, the recent ENGAGE AF-TIMI 48 analysis found an independent increase in risk for all the bleeding outcomes investigated for each 5 kg/m2 BMI increase.[32]