Obesity (defined as body mass index [BMI] ≥30 kg/m²) is steadily rising, with a prevalence of 39.8% of US adults and affecting over 90 million people.¹ This expanding epidemic is a significant contributor to the increase in cardiovascular diseases, including hypertension, stroke, and coronary artery disease. Obesity has also been linked to the expanding incidence of atrial fibrillation (AF), with a 49% increased risk in obese individuals compared with non-obese individuals.² Therapeutic interventions for AF typically involve antiarrhythmic drugs (AADs) and/or anticoagulation, of which direct oral anticoagulants (DOACs) are preferred due to rapid onset of action, fewer monitoring parameters, and standard dosing. However, considerable uncertainty exists regarding efficacy and safety of the use of both DOACs and AADs in obese individuals. Dosing recommendations are fixed and generally based on studies of normal-weight individuals with under-representation of the obese population, particularly those classified as morbidly obese (BMI ≥40 kg/m²).³ Significant disparities in pharmacokinetic (PD) and pharmacodynamic (PD) responses can occur among the extremes of body weight, which should be considered in selection of therapy and drug dosing. This review provides to the clinician a summary of the available literature regarding AF therapies, specifically AADs and DOACs, in the obese population.

DOACs in Obesity

Currently, four DOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) are approved by the US Food and Drug Administration for prevention of stroke in patients with nonvalvular atrial fibrillation (NVAF). Current guidelines recommend DOACs over warfarin in eligible patients with NVAF due to similar, if not superior, efficacy in prevention of stroke and thromboembolism combined with lower risks of serious bleeding.⁴ However, due to the concern of decreased drug exposure and risk of underdosing in the obese population, the International Society of Thrombosis and Haemostasis (ISTH) does not support the use of DOACs in patients with a BMI of >40 kg/m² or weight of >120 kg.⁵ Obtaining drug-specific peak and trough levels is suggested to assess therapeutic appropriateness in this population if DOACs are prescribed. Because availability of reliable coagulation assays is limited, testing of DOAC levels in the real-world setting remains to be widely implemented. In addition, therapeutic ranges have yet to be established or validated, making clinical utility challenging. Since the ISTH guidelines were released in 2016, several studies have been conducted to further evaluate the impact of body weight on the safety and effectiveness of DOACs. Of these, the analyses of the pivotal DOAC trials are crucial in evaluating the relationship between BMI and outcomes in patients with NVAF (Table 1).^6-11 Primary efficacy outcomes of the DOAC trials were measured by prevention of stroke and systemic embolism and mortality, and safety outcomes focused on major bleeding. The results indicate that DOACs provide consistent efficacy and safety compared with warfarin across all categories of BMI, but weight categories vary among trials, with small representations of the morbidly obese population.

Table 1: Representation of Stages of Obese BMI From the DOAC Phase III AF Clinical Trials

DOAC	NVAF Trial	Obese Weight Category (kg/m2)	N (%)
Dabigatran6,7	RE-LY: Randomized Evaluation of Long-Term Anticoagulant Therapy With Dabigatran Etexilate	BMI >36	1,787 (10)
Rivaroxaban8	ROCKET-AF: Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation	BMI 30-<35 BMI ≥35	3,308 (23.5) 1,898 (13.5)
Apixaban9,10	ARISTOTLE: Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation	BMI 30-<35 BMI 35-<40 BMI ≥40	4,379 (24.1) 1,774 (9.8) 1,006 (5.5)
Edoxaban11	ENGAGE AF-TIMI 48: Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48	BMI 30-<35 BMI 35-<40 BMI ≥40 BMI >50	5,209 (24.8) 2,099 (10.0) 1,149 (5.5) 148 (0.7)

Interestingly, an "obesity paradox" has been observed, in which increased BMI has been associated with better overall outcomes. A significantly reduced stroke risk was found in those with a BMI ≥35 kg/m² in ROCKET-AF.⁸ Similarly, obesity was associated with a lower risk of all-cause mortality, stroke, and systemic embolism in ARISTOTLE.¹⁰ However, there was a greater reduction in major bleeding with normal versus higher BMI.

Although higher BMI was independently associated with lower adjusted risk of stroke or systemic embolism and death in those treated with edoxaban or warfarin in the ENGAGE AF-TIMI 48 trial, this relationship differed by gender.¹¹ There was a lower risk of stroke or systemic embolism in men, and a significantly higher risk of bleeding was observed in women as BMI increased. Similar trough edoxaban plasma concentrations and anti-Factor Xa activity were demonstrated among normal and obese cohorts, indicating that obesity may not alter the pharmacokinetic or pharmacodynamic activity of edoxaban despite the observed clinical differences.

The impact of body weight on the pharmacokinetics and pharmacodynamics of a single 10-mg dose of rivaroxaban was analyzed in healthy volunteers (n = 48). No difference was found in peak concentration, exposure to the drug, or inhibition of Factor Xa activity in those weighing >120 kg compared with normal-weight subjects.¹² Comparable results were reported in a single-center study (n = 101), indicating that body weight alone had little effect on rivaroxaban pharmacokinetics, yet only 20 patients had a BMI ≥35 kg/m², and the majority were being treated for acute venous thromboembolism.¹³ Collectively, these results demonstrate that dose adjustment is likely not required for obese patients; however, study populations are small with low inclusion rates of morbidly obese patients.

Due to minimal representation of morbidly obese patients in the pivotal DOAC trials, as well as limited pharmacokinetic and pharmacodynamic data in this population, several retrospective studies have been conducted to determine whether DOACs are a safe and effective alternative compared with warfarin in this population. Peterson et al. used healthcare claims data to identify patients with AF with a BMI >40 kg/m² or body weight >120 kg on rivaroxaban and warfarin.¹⁴ The study found no difference in risk of ischemic stroke or systemic embolism and major bleeding among the 3,563 matched pairs of morbidly obese patients with AF being treated with rivaroxaban (1.5% vs. 1.7%, p = 0.5) or warfarin (2.2% vs. 2.7%, p = 0.15). Furthermore, total healthcare costs were significantly lower in the rivaroxaban group. Although limited by retrospective healthcare claims data, which innately pose risk for inaccuracies, this study included a large population and supported the use of rivaroxaban in morbidly obese patients with AF.

A larger retrospective, single-center study analyzed the effect of apixaban and rivaroxaban versus warfarin in morbidly obese patients (BMI ≥40 kg/m²) with AF or venous thromboembolism.¹⁵ Of the patients with AF (n = 429), there was no statistically significant difference in the incidence of stroke or composite bleeding in the apixaban and rivaroxaban cohort compared with warfarin (p = 0.71 and p = 0.063, respectively).

Kido and Ngorsuraches also showed no difference in ischemic stroke or major bleeding in DOACs compared with warfarin in morbidly obese patients with AF.¹⁶ Patients on dabigatran (n = 20), rivaroxaban (n = 25), and apixaban (n = 19) were included. Although based on a small overall population, the authors concluded that apixaban and rivaroxaban may be considered as alternatives to warfarin in patients with weight >120 kg or BMI >40 kg/m² while cautioning against the use of dabigatran due to a numerically higher stroke rate among the DOACs.

AAD Dosing in Obesity

Although the pharmacokinetics and pharmacodynamics of AAD therapies can be quite complex and altered by body composition, there is limited guidance on dosing and management specific to the obese population. Amiodarone, one of the most commonly used AADs, is extremely lipophilic, with a very large volume of distribution (60 L/kg) accumulating mainly in adipose tissue and highly perfused organs.¹⁷ It has been shown that amiodarone clearance was significantly reduced in those with a BMI >25 kg/m², but there are no recommendations for dose adjustments in obesity.¹⁸ Careful attention must be taken once arrhythmia control is achieved because correct maintenance dose is partly determined by individual response and elimination rate. Alternatively, the volume of distribution and clearance of digoxin is not altered by changes in body composition associated with obesity, and standard loading doses may be used.¹⁹ If a weight-based dosing approach is chosen, it should be based on estimated lean body weight.

Proarrhythmia and sudden cardiac death are significant risks associated with use of select AADs and, in most cases, dose dependent. Particularly, Class III AADs, dofetilide and sotalol, require actual body weight to calculate creatinine clearance for determination of dosing, which may lead to overdosage in the obese population. Cao et al. retrospectively evaluated dofetilide dosing in overweight and obese patients and found no difference in initial dose reduction or discontinuation due to QT-interval prolongation in those who would have required a lower dose based on their ideal body weight versus those who qualified for the same dose based on both ideal body weight and actual body weight.²⁰ This supports the safety of the current dofetilide dosing recommendation in the overweight population, but the sample size was small with only 24 patients with a BMI >35 kg/m².

Obesity may cause cardiac electrical and structural remodeling, increasing the predisposition to AF; this is an underlying pathophysiology that is not well understood. Because AAD therapy modulates sodium or potassium channels to treat AF, the relationship among obesity, mechanism of AF, and optimal use of AAD must be elucidated. McCauley et al. found that obese patients treated with AADs were 2.5 times more likely to be switched to an alternative AAD versus non-obese patients (odds ratio 2.5; 95% confidence interval, 1.02-5.97; p = 0.04).²¹ Furthermore, obese patients were less likely to respond to Class I AADs than non-obese patients (33% vs. 7%, p < 0.02), indicating a disparity in response to sodium channel versus potassium channel blockers.

There is a clear lack of available data to guide prescribing of drug therapies in the obese patient with AF. With the increasing impact of obesity on the population and coinciding rise in AF, cardiovascular clinicians must be aware of the caveats in drug selection and dosing in patients with a BMI over 30 kg/m². Evidence from the pivotal trials of DOACs suggests that current dosing is safe and effective in obese patients, suggesting that an "obesity paradox" is present in patients with AF. However, due to small cohorts, further investigation is required for those weighing >120 kg or with a BMI ≥40 kg/m². If DOAC therapy is desired in these morbidly obese patients, peak and trough drug-specific levels should be drawn in accordance with ISTH guidelines until further evidence is available to support use. Clinicians must also be cautious in management of AAD therapy in the obese population because pharmacokinetic and pharmacodynamic alterations in extreme body size may result in significant risk and overdosage. Because current AF therapies will not correct the underlying pathophysiological electrical dysfunction caused by obesity, it is essential that providers encourage lifestyle strategies to improve cardiovascular disease outcomes such as increased physical activity and healthy dietary interventions.

References

1. Hales CM, Carroll MD, Fryar CD, Ogden CL. Prevalence of Obesity Among Adults and Youth: United States, 2015-2016. NCHS Data Brief 2017;288:1-8.
2. Aromolaran AS, Boutjdir M. Cardiac Ion Channel Regulation in Obesity and the Metabolic Syndrome: Relevance to Long QT Syndrome and Atrial Fibrillation. Front Physiol 2017;8:431.
3. Barras M, Legg A. Drug dosing in obese adults. Aust Prescr 2017;40:189-93.
4. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019;Jan 21:[Epub ahead of print].
5. Martin K, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost 2016;14:1308-13.
6. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.
7. Ezekowitz ME, Parise H, Connolly SJ, et al. The use of dabigatran according to body mass index: the RE-LY experience. Eur Heart J 2014;35:1111.
8. Balla SR, Cyr DD, Lokhnygina Y, et al. Relation of Risk of Stroke in Patients With Atrial Fibrillation to Body Mass Index (from Patients Treated With Rivaroxaban and Warfarin in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation Trial). Am J Cardiol 2017;119:1989-96.
9. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92.
10. Sandhu RK, Ezekowitz J, Andersson U, et al. The 'obesity paradox' in atrial fibrillation: observations from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Eur Heart J 2016;37:2869-78.
11. Boriani G, Ruff CT, Kuder JF, et al. Relationship between body mass index and outcomes in patients with atrial fibrillation treated with edoxaban or warfarin in the ENGAGE AF-TIMI 48 trial. Eur Heart J 2019;40:1541-50.
12. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects. J Clin Pharmacol 2007;47:218-26.
13. Barsam SJ, Patel JP, Roberts LN, et al. The impact of body weight on rivaroxaban pharmacokinetics. Res Pract Thromb Haemost 2017;1:180-7.
14. Peterson ED, Ashton V, Chen YW, Wu B, Spyropoulos AC. Comparative effectiveness, safety, and costs of rivaroxaban and warfarin among morbidly obese patients with atrial fibrillation. Am Heart J 2019;212:113-9.
15. Kushnir M, Choi Y, Eisenberg R, et al. Efficacy and safety of direct oral factor Xa inhibitors compared with warfarin in patients with morbid obesity: a single-centre, retrospective analysis of chart data. Lancet Haemotol 2019;6:e359-e365.
16. Kido K, Ngorsuraches S. Comparing the Efficacy and Safety of Direct Oral Anticoagulants With Warfarin in the Morbidly Obese Population With Atrial Fibrillation. Ann Pharmacother 2019;53:165-70.
17. Cordarone (amiodarone) Prescribing Information (Pfizer, Inc., website). 2018. Available at: http://labeling.pfizer.com/showlabeling.aspx?format=PDF&id=93. Accessed May 28, 2019.
18. Fukuchi H, Nakashima M, Araki R, et al. Effect of obesity on serum amiodarone concentration in Japanese patients: population pharmacokinetic investigation by multiple trough screen analysis. J Clin Pharm Ther 2009;34:329-36.
19. Albernethy DR, Greenblatt DJ. Drug disposition in obese humans. An update. Clin Pharmacokinet 1986;11:199-213.
20. Cao DX, Kohatsu A, Eng L, et al. Evaluation of initial dofetilide dosing recommendation based on actual body weight in overweight and obese patients. J Clin Pharm Ther 2015;40:635-9.
21. McCauley M, Kany S, Hong L, et al. Elucidating the underlying mechanisms for the differential response to sodium channel blocker antiarrhythmic drugs in obese patients with atrial fibrillation. Eur Heart J 2018;39:ehy566.5073.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Atherosclerotic Disease (CAD/PAD), Anticoagulation Management and Atrial Fibrillation, Anticoagulation Management and Venothromboembolism, Implantable Devices, EP Basic Science, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Novel Agents, Statins, Exercise, Hypertension

Keywords: Arrhythmias, Cardiac, Adipose Tissue, Anticoagulants, Atrial Fibrillation, Anti-Arrhythmia Agents, Amiodarone, Body Mass Index, Brain Ischemia, Body Composition, Coronary Artery Disease, Creatinine, Death, Sudden, Cardiac, Confidence Intervals, Cohort Studies, Embolism, Digoxin, Exercise, Health Care Costs, Healthy Volunteers, Factor Xa, Hemostasis, Hypertension, Ideal Body Weight, Life Style, Obesity, Morbid, Odds Ratio, Phenethylamines, Overweight, Potassium Channel Blockers, Potassium Channels, Incidence, Prevalence, Pyridines, Pyrazoles, Pyridones, Retrospective Studies, Sample Size, Sotalol, Sodium Channels, Stroke, Sulfonamides, Sodium, Thrombosis, United States Food and Drug Administration, Venous Thromboembolism, Warfarin, Thiazoles

< Back to Listings