Prevention of Cardioembolic Stroke in Obese Patients With Nonvalvular Atrial Fibrillation
Ms. X is a 70-year-old female with new onset non-valvular atrial fibrillation. She has a past medical history of hypertension, diabetes, hyperlipidemia and morbid obesity. BMI 43.7 kg/m2, 123 kg, 66 inches. CrCl 45 mL/min. There are no pertinent drug interactions.
According to the 2016 International Society on Thrombosis and Haemostasis guidance document, which anticoagulant is most appropriate for stroke prevention in this patient?
The correct answer is: D. Warfarin 7.5 mg by mouth once daily, Target INR 2-3.
Given the patient's nonvalvular atrial fibrillation and CHA2DS2-VASc of four (female, age, hypertension and diabetes), anticoagulation for ischemic stroke prevention is warranted.1 Warfarin is the correct answer, since direct acting oral anticoagulant (DOAC) use in extremely obese patients remains controversial.
The four DOACS have an FDA approved indication for systemic embolism and ischemic stroke prevention in patients with nonvalvular atrial fibrillation. However, there is no guidance regarding dose adjustment in obese (BMI 30-40 kg/m2) and extremely obese (BMI >40 kg/m2) patients. There are no large randomized controlled trials specifically evaluating the efficacy and safety of DOACs in this patient population. The only evidence comes from subgroup analyses of the phase III clinical trials and pharmacokinetic/pharmacodynamics data (PK/PD). None of the phase III clinical trials reported data for patients with a BMI >40 kg/m2. Two of the four phase III clinical trials for non-valvular AF stroke prevention included subgroups by weight or BMI; 17.1% of patients in RE-LY (dabigatran) weighed ≥100kg1 and 13.6% of patients in ROCKET-AF (Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation) had a BMI>35 kg/m2.2-3
In the phase III clinical trials that included subgroups by weight or BMI, there was no difference in efficacy between DOACs and vitamin k antagonists (VKA) in the prevention of stroke or recurrent venous thromboembolism (VTE) in the higher weight categories. However, in a pooled analysis, dabigatran use for acute VTE in patients >100 kg was associated with a higher risk of recurrent VTE as compared to patients with normal weights.4 There were no direct analysis in patients with atrial fibrillation, limiting the applicability of this pooled analysis outside of patients with VTE. This data may not be directly applied to patients with atrial fibrillation as it looked at VTE patients. Two other weight based analyses have reported no difference in the rate of 1-year stroke/systemic embolism or recurrent VTE with use of DOACs in obese patients.5,6 In addition, multiple case reports have been published describing the occurrence of stroke and acute pulmonary embolism in obese patients with non-valvular AF taking dabigatran.7-9
There is less safety information for using a DOAC in an obese patient with non-valvular AF. Half of the DOAC clinical trials included weight based subgroups for safety outcomes; however, ROCKET-AF was the only nonvalvular AF trial to do this. From the available subgroup analyses, there was no increase in bleeding events in the obese population.4 Available PK/PD data indicated moderately reduced peak and trough concentrations for apixaban and dabigatran,10-11 respectively, while no meaningful difference was observed with rivaroxaban.12 Overall, pharmacokinetic data suggest lower DOAC exposure, reduced peak concentrations, and shorter half-lives with increasing weight; however, the clinical implications are unknown.4
Based on the lack of quality evidence and the available PK/PD data regarding the use of DOACs in obese patients, the 2016 International Society on Thrombosis and Haemostasis (ISTH) guidance document suggests that DOACs not be used in patients with a BMI >40 kg/m2 or a weight of >120 kg.4 In the event that DOACs are used, the guidance document suggests monitoring with drug specific peak and trough levels to better evaluate efficacy, which may be problematic for the clinician in terms of logistics and interpreting results.3
- January CT, Wann LS, Alpert JS, et al. 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 practice guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1-76.
- Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.
- Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.
- 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 Hemost 2016;14:1308-13.
- 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.
- Prins MH, Nisio MD, Vedovati MC, et al. Fixed-dose rivaroxaban is not associated with increased recurrent venous thromboembolism or major bleeding in patients with a high or low body weight. J Thromb Haemost 2015;13:35-6.
- Guler E, Babur Guler G, Demir GG, Hatipoglu S. A review of the fixed dose use of new oral anticoagulants in obese patients: is it really enough? Anatol J Cardiol 2015;15:1020-9.
- Breuer L, Ringwald J, Schwab S, Kohrmann M. Ischemic stroke in an obese patient receiving dabigatran. N Engl J Med 2013;368:2440-2.
- Safouris A, Demulder A, Triantafyllou N, Tsivgoulis G. Rivaroxaban presents a better pharmacokinetic profile than dabigatran in an obese non-diabetic stroke patient. J Neurol Sci 2014;346:366-7.
- Upreti VV, Wang J, Barrett YC, et al. Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects. Br J Clin Pharmacol 2013;76:908-16.
- Reilly PA, Lehr T, Haertter S, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014;63:321-8.
- 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.