Direct oral anticoagulants (DOACs) are considered advantageous compared to vitamin K antagonists in eligible atrial fibrillation patients.1 Increased body weight is associated with 30% lower exposure to standard doses of DOACs, raising concerns about adequate dosing in obese patients.2, 3 Due to lack of sufficient clinical data, use of DOACs in patients with a body mass index (BMI) > 40 kg/m² or a weight of >120 kg should be accompanied by measurement of trough and peak plasma concentrations.3
We report on a 48-year-old male patient (189 cm, 229.5 kg, BMI 64.4 kg/m²) with a history of bradycardia-tachycardia syndrome, arterial hypertension, and obstructive sleep apnea syndrome who was admitted to our clinic because of infection-triggered, non-valvular atrial fibrillation (CHA2DS2-VASc-Score 2) and cardiac decompensation. Physical examination showed massive leg edema with stasis dermatitis in the right leg and erysipelas of the left lower leg infected with streptococci (C-reactive protein, 56 mg/L). Renal and hepatic function tests were in the normal range. Transthoracic echocardiography showed mild left ventricular dysfunction. The patient lost 26 kg of body weight within 12 days of treatment with torasemide and furosemide. Subsequent to initial anticoagulation with enoxaparin, apixaban (5 mg bid) was started. Antibiotic treatment that commenced with piperacillin/tazobactam was switched to ampicillin/sulbactam. No potentially interacting concomitant drugs were used.
On days 1, 4, 6, and 12 of apixaban administration, venous blood samples were collected into tubes containing 10% sodium citrate (Sarstedt, Nümbrecht, Germany) before (all occasions) and 2 to 4 hours after apixaban intake (days 1, 4, and 6). Apixaban concentrations were quantified using a previously published liquid chromatography tandem-mass spectrometric method.4 Observed apixaban concentrations were initially found at the lower margin of the expected on-therapy range but increased over time, while body weight continuously decreased (Table).
A 2-compartment pharmacokinetic model (MwPharm++,Mediware, Prague, Czech Republic) was developed based on concentration data in healthy obese volunteers (≥120 kg).5 Pharmacokinetic parameters were fitted to observed apixaban plasma concentrations. The derived apixaban elimination half-life was 9.8 hours and thus was comparable to that reported by Upreti et al.5 in the high body weight group, which was shorter compared to lower body weight groups. Nonetheless, recent data indicate that the safety and effectiveness of DOACs are not impaired by obesity.6 Our patient’s hospitalization was uneventful, and he was discharged home with no signs of thrombotic complications.
This case illustrates that measured DOAC concentrations should be interpreted with caution in phases of acute illness such as cardiac decompensation and diuretic treatment, as steady-state pharmacokinetics may not be reached within several days. Our findings further demonstrate that in super obese patients, apixaban plasma concentrations may be found within expected on-therapy concentration ranges. Further studies are warranted to assess the safety and efficacy of standard doses of DOACs in these patients.
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-Cornelia Fietz, DMD, Guido Michels, MD, Carsten Müller, MD, Martin H.J. Wiesen, MD
This article originally appeared in the January issue of The American Journal of Medicine.
