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

Summary and Relevance

We summarized much of the evidence relating to obesity and AF in the literature. It clearly indicates that obesity and AF are strongly associated, with existing data indicating a causative link between obesity and AF; it is also clear that specific interventions to reduce BMI can also be helpful in reducing the risk of incident and/or recurrent AF.

Epidemiological data suggest that a possible obesity paradox for outcomes could exist in patients with AF. However, these data also appear controversial. In particular, a clear difference emerges according to the type of studies testing the obesity paradox hypothesis. Data from RCT subgroup analyses appear to show an obesity paradox for stroke/SE, cardiovascular death, and all-cause death. This evidence was strengthened by two meta-analyses[36,38] that both highlighted how overweight and obese patients have a reduced risk of stroke, with the latter also showing that a higher BMI was associated with a lower stroke risk. However, both meta-analyses included almost exclusively data and studies from RCTs conducted in AF that were not specifically designed or powered to detect differences in BMI subgroups. Conversely, the meta-analysis by Zhu et al.,[37] which also included data from observational/population-based cohort studies, seemed to refute the obesity paradox, since no significant differences in risk emerged across the BMI classes.

When investigating the differential effects of OACs in conditioning outcomes according to BMI, the evidence consistently indicates that patients with healthy weights experience more beneficial impacts from NOACs than form VKAs[36,38] and that underweight patients experience a strong beneficial effect in terms of stroke and major bleeding reduction using NOACs rather than VKAs.[38]

These data lead us to several reflections related to the phenomenon of the obesity paradox. In general, in most studies, patient age was progressively lower according to increasing BMI class. Furthermore, overweight and obese patients generally had more comorbidities than healthy weight patients. Overweight and obese patients also more frequently received prescriptions for pharmacological treatments, particularly related to the control of cardiac and cardiovascular conditions and prevention of associated risks. Given this, we hypothesize that overweight and obese patients are usually treated earlier and with a more intensive pharmacological approach and usually have stricter and more continuous follow- up than healthy-weight patients. These reasons, among others, are considered possible explanations for the obesity paradox, both in general and among patients with AF[6,42] (Figure 2), and it should be considered that, even in multivariate analyses, it is not easy to account for all potential factors influencing outcomes.

Figure 2.

Main possible factors relating to/influencing the obesity paradox in atrial fibrillation. BMI body mass index

These factors can easily be attributed to the unreported confounders and bias sources that can possibly explain the obesity paradox in patients with AF. Other factors also possibly influence the better outcomes observed in obese patients, such as the unavoidable underpowering of subgroup analysis and possible selection bias. In particular, selection bias could be responsible for the differences we highlighted between RCTs and observational studies. Indeed, although affected by obesity, patients enrolled in RCTs tend to be fitter and less ill than obese patients in real-life scenarios enrolled in observational studies.

In this complex interplay of factors, the relationship between obesity and cardiorespiratory fitness may have important influence.[37] Cardiorespiratory fitness has been proven to have a significant impact on major adverse events in AF beyond obesity itself,[19] and improved cardiorespiratory fitness has been claimed to be a crucial step, even more important than weight reduction, in improving health.[43]

Lastly, another possible mediating mechanism for the obesity paradox has been the concept of "metabolically healthy obese" (MHO) patients.[43] This term relates to subjects who, despite being obese, have a positive metabolic profile and are substantially fit.[43] Several studies have shown that MHO patients have a significantly lower (and nonsignificant) risk of adverse outcomes.[43] Such a clinical phenotype has also been associated with a specific and peculiar adipose tissue biology that appears to be protective in terms of the risk of major adverse events.[44]

The evidence related to the advantage of NOACs versus VKAs in underweight and healthy weight patients can reflect a more predictable distribution volume for the drugs, also associated with more favorable organ function, particularly kidney and liver function. This is also supported by the evidence showing the favorable performance of NOACs, even in patients with extreme weights.[45,46]

Despite all the evidence, it is our opinion that the controversies regarding the obesity paradox are no reason to reduce efforts aimed at encouraging appropriate strategies for weight loss and increasing physical activity and exercise. These remain fully justified by the general unhealthy implications of overweight and obesity[9,18] and are to be advocated for both patients with AF and the general population, as claimed by international experts on health, weight and obesity.[47] The European Society of Cardiology AF management guidelines recommend appropriate education and patient empowerment; in obese patients, weight loss together with management of other risk factors constitute essential goals for reducing the burden and symptoms of AF and for improving outcomes.[48] Notwithstanding all these considerations, additional data are still needed to further elucidate the mechanisms underlying the obesity paradox, which may simply reflect a lack of understanding of the complex pathophysiology of obesity and of the multiform associations between adiposity and cardiovascular diseases, including AF.