Complication of Atrial Fibrillation with Obesity and Its Management with Novel Oral Anticoagulants
Obesity is the most common chronic metabolic disease worldwide with an increasing prevalence. It has been reported that more than 1.9 billion adults were classified as overweight in 2016, of which 650 million were obese1. In Hong Kong, approximately 29.9% of local population aged 15-84 were obese (body mass index (BMI) ≥ 25kg/m2)2. Although the pathophysiological basis of the obesity-atrial fibrillation (AF) relationship is complex and multifactorial, AF risk appears to follow a linear pattern with increase in BMI3. While novel oral anticoagulants (NOACs) are now established as safe, effective, and more convenient alternatives to warfarin for preventing thromboembolic complications of non-valvular AF (NVAF), clinical data from randomised control trials (RCTs) on the efficacy and safety of the therapies in patients with obesity are limited. This article reviews the pathophysiological interactions between AF and obesity as well as clinical data on treatment outcomes of NOACs in managing AF with obesity.
Pathophysiology of Obesity and AF
Obesity has been identified as an independent modifiable risk factor for AF4. The ARIC (Atherosclerosis Risk In Communities) study, which involved 15,792 participants aged 45-64 in the United States, estimated that obesity and overweight explain 17.9% of all AF cases5. Essentially, a meta-analysis of 51 studies included more than 600,000 individuals demonstrated that every 5-unit increment in BMI was found to confer an additional 19% to 29% risk of incident AF, a 10% risk of post-operative AF, and a 13% risk of post-ablation AF6.
The pathophysiological mechanisms linking obesity and AF are still not fully understood, but include dysregulation in various domains such as haemodynamics, neurohumoral, inflammatory, metabolic, adipokines, and autonomics, as well as the impact of obesity to increase heart failure and coronary heart disease (Figure 1)7. It is likely that a combination of these contribute to the initiation and maintenance of AF in the obese atria. For instance, the changes in haemodynamics encompass elevation in left atrial and systolic blood pressure, and left ventricular diastolic dysfunction leading to atrial stretch and triggers for AF8.
Figure 1. Pathophysiological mechanism of increased risk of AF in obesity7
Besides, increased adipose tissue can result in a hypoxic state because of inadequate capillarisation, which is pro-inflammatory with cytokine release, such as tumour necrosis factor-α (TNFα). TNFα can increase the pulmonary vein arrhythmogenicity and induce an abnormal calcium homeostasis, thereby causing inflammation-related AF9. Notably, there has been an increasing interest in the relationship between the thickness of the epicardial adipose tissue (EAT) and AF. Former report indicated that pericardial fat volume predicts the occurrence of AF, independent of other anthropometric variables like BMI10.
On the other hand, abnormally activation of signaling pathways in obesity, such as the renin-angiotensin-aldosterone system (RAAS) and endothelin-1 can result in increased interstitial collagen deposition, which may disrupt atrial conduction leading to a substrate that favours re-entry and AF perpetuation11. Hence, with progressive obesity, there were changes in atrial size, conduction, histology, and expression of pro-fibrotic mediators. These changes were associated with spontaneous and more persistent AF.
The Obesity Paradox
The association between increasing BMI and AF risk, particularly in relation to the increased risk for incident and recurrent AF, has been extensively reported. However, recent reports have demonstrated the phenomenon of obesity paradox among patients with AF, in which the risk of all-cause mortality among overweight and obese patients was significantly lower on long-term follow-up as compared to those with normal BMI. For instance, a recent meta-analysis of 20 prospective studies, accounted for more than 160,000 individuals, indicated that underweight was associated with an increased risk of all-cause mortality (relative risk [RR]: 2.6), cardiovascular death (RR: 2.91), major bleeding (RR: 1.57), stroke or systemic embolism (SSE, RR: 1.62), and a composite endpoint (RR: 2.23), whereas the risk per every 5-unit increment in BMI was reduced for all-cause mortality (RR: 0.86, 95% confidence interval [CI]: 0.80-0.92), cardiovascular death (RR: 0.82, 95% CI: 0.71-0.95), SSE (RR: 0.89, 95% CI: 0.84-0.95) and a composite endpoint (RR: 0.78, 95% CI: 0.67-0.92)12.
The underlying mechanisms of obesity paradox are unclear, and it remains doubtful whether this is a true biomedical phenomenon or related to residual confounding factors. For instance, previous opinions suggested that patients with normal BMI were significantly older than those with higher BMI in most observational studies, while the confounding effects of age may not be completely accounted for by statistical adjustment7. Of importance, age is a major predictor of all-cause mortality among patients with AF.
Of note, obese patients are frequently suffered from co-morbidities such as hypertension and diabetes mellitus, which are common risk factors for AF development resulting in the initiation of medication such as ACE inhibitors, beta-blockers, and lipid-lowering therapies13. The differences in management strategies across BMI categories would possibly alter the treatment outcomes and hence leading to obesity paradox.
Moreover, in observational studies, BMI is regularly used to define obesity. However, BMI is in fact not a direct measurement of body fat content and not an indicator of the potential harmful effects that adiposity can cause. For instance, athletes with high muscle mass and higher weights may be classified as overweight or even obese based on BMI though they have low body fat composition. Hence, there are many potential factors contributing to the observation of obesity paradox among AF patients (Figure 2)14. Essentially, the obesity paradox should not be taken as a rationale against aggressive lifestyle risk factor modification such as weight management for AF patients.
Figure 2. Potential factors contribute to obesity paradox14
Risk Factor Management in AF Patients with Obesity
The management of AF has focused on anticoagulation, rhythm control and ventricular rate control. Nonetheless, the importance of risk factor management has been recognised for controlling risk of AF. Traditionally, age, hypertension, heart failure, diabetes mellitus and valvular heart disease are well accepted as risk factors contributing to the development and progression of AF. However, a number of additional factors such as obesity, smoking, alcohol and physical inactivity are demonstrated to be associated with the development of AF. Importantly, many of these risk factors are modifiable, whereas patients with AF who comprehensively managed their risk factors demonstrate greater reduction in symptoms, AF burden, more successful ablations and improved outcomes with greater AF freedom15.
Previous prospective cohort study by Pathak et al (2014) evaluated the clinical benefits of risk factor and weight management on AF ablation outcomes. Among the 149 AF patients with BMI≥27 and at least 1 cardiac risk factor, 61 opted for risk factor management and the remaining 88 served as control. The results showed that risk factor management yielded greater reduction in weight and blood pressure, as well as better glycemic and lipid control. Essentially, at follow-up, AF frequency, duration, symptoms, and symptom severity decreased more in the risk factor management group compared with the control group. Moreover, both single-procedure drug-unassisted and multiple-procedure arrhythmia-free survival were significantly better in risk factor management patients compared with control subjects (Figure 3)16. Hence, the results indicated that risk factor management would improve long-term success of AF ablation. With the emerging evidence on the clinical benefits of risk factor management for AF patients, the treatment approach has been advocated by major clinical guidelines as a key component of AF management15.
Figure 3. Kaplan-Meier curves for single-procedure drug-free AF-free survival and for multiple-procedures with antiarrhythmic drugs AF-free survival16. RFMx: risk factor management
The Impact of Obesity on Efficacy and Safety of NOACs in AF
In addition to risk factor management, anticoagulation to minimise thromboembolic complications is another core component in the management of AF. Recent retrospective study evaluating warfarin requirements in hospitalised AF patients, stratified by BMI, demonstrated that the total weekly dose (TWD) of warfarin for morbidly obese patients (BMI≥40, 41.5 mg) was significantly higher than that for patients who were underweight (BMI<18, 25.6 mg), normal/overweight (BMI: 18-29.9, 28.8 mg) and obese patients (BMI: 30-39.9, 32.4 mg). This reflected that morbidly obese patients may require higher TWD of warfarin to obtain and maintain a therapeutic international normalised ratio17.
Recently, NOACs have increasingly supplanted warfarin use due to the perceived convenience of a fixed dose and minimal monitoring requirements compared with those for warfarin. Essentially, there has been consistent evidence for an overall superior benefit-risk profile of NOACs compared with warfarin based on the four landmark randomised trials. However, the International Society on Thrombosis and Haemostasis (ISTH) published guidelines advising caution when using NOACs in patients with morbid obesity due to limited clinical efficacy and safety data supporting their use in obese AF patients18. Yet underutilisation of NOACs would possibly exclude a large number of patients who may benefit from the medications.
In order to evaluate the efficacy and safety of NOACs in overweight and obese populations for primary prophylaxis of AF and for treatment of venous thromboembolisms, a retrospective cohort study involved 398 patients was conducted. The patients were stratified into various weight groups according to BMI values. The results suggested that apixaban and rivaroxaban have similar efficacy in stroke prevention in all weight groups. Particularly, the bleeding rates were similar across all BMIs for rivaroxaban, whereas the sample sizes for apixaban and dabigatran were too small for statistical analysis19. Although the sample sizes were small and the retrospective design of the study, the results demonstrated the safety and efficacy of rivaroxaban in the obese patients.
Currently, evidence on efficacy and safety of NOACs in AF comorbid with obesity from RCTs is limited. A recent meta-analysis of 18 randomised trials or their sub-studies in this topic indicated that NOACs are better or similarly effective in controlling risk of stroke or systemic embolisation and major bleeding across all BMI classes as compared to warfarin (Figure 4). Notably, there was no impact on mortality in all the BMI classes. However, the results further demonstrated that the effect size advantages of NOACs compared with warfarin in terms of safety and efficacy gradually attenuated with increasing weight20. Hence, weight-based dosage adjustment may be necessary to achieve optimal benefits of NOACs for thromboembolic prevention in obese patients with NVAF.
Figure 4. Efficacy and safety of NOACs versus warfarin, (A) Stroke or systemic embolisation and (B) Major bleeding20.
CI: confidence interval; SE: standard error; TE: treatment effects
Since their approval, NOACs have been preferred over warfarin due to the convenience of fewer routine monitoring visits, no requirements for dose adjustment, and limited dietary interactions. Nonetheless, the use of NOACs in patients with obesity has not been as well-documented or established, whereas NOAC-specific pharmacokinetic variations have been observed. Hence, continued caution is recommended when considering NOAC use in the morbidly obese, particularly for those requiring anticoagulation for venous thromboembolism treatment. Essentially, higher-quality evidence on efficacy and safety of NOACs in AF with obesity from randomised trials is urgently required.
References
1 .World Health Organization. Obesity and overweight. 2020 2 .Centre for Health Protection. Obesity. 2019 3 .Tedrow et al. J Am Coll Cardiol 2010; 55: 2319-27. 4 .Wang et al. J Am Med Assoc 2004; 292: 2471-7. 5 .Huxley et al. Circulation 2011; 123: 1501-8. 6 .Wong et al. JACC Clin Electrophysiol 2015; 1: 139-52. 7 .Lavie et al J. Am. Coll. Cardiol. 2017; 70: 2022-35. 8 .Thanigaimani et al. Prog. Biophys. Mol. Biol. 2017; 130: 376-86. 9 .Lee et al. Life Sci 2007; 80: 1806-15. 10 .Thanassoulis et al. Circ Arrhythmia Electrophysiol 2010; 3: 345-50. 11 .Abed et al. Hear Rhythm 2013; 10: 90-100. 12 .Liu et al. Obes Rev 2020; 21. DOI:10.1111/obr.12970. 13 .Sandhu et al. Eur Heart J 2016; 37: 2869-2878. 14 .Vyas et al. Arrhythmia Electrophysiol Rev 2019; 8: 28-36. 15 .Middeldorp et al. Heart. 2019; 106. DOI:10.1136/heartjnl-2019-315327. 16 .Pathak et al. J Am Coll Cardiol 2014; 64: 2222-31. 17 .Tellor et al. Ther Adv Cardiovasc Dis 2018; 12: 207-16. 18 .Kido et al. Pharmacotherapy. 2020; 40: 72-83. 19 .Doucette et al. Adv Hematol 2020; 2020. DOI:10.1155/2020/3890706. 20 .Malik et al. Europace 2020; 22: 361-7.
