Background: In patients with venous thromboembolism (VTE), warfarin had been considered standard of care until the new direct oral anticoagulants (DOACs) were developed. Studies in patients with acute VTE and non-valvular atrial fibrillation (AF) have shown comparable therapeutic efficacy and a similar or lower bleeding risk for DOACs when compared to warfarin. However, low representation of obese patients in these studies and the unknown effect of obesity on pharmacokinetics and pharmacodynamics of these drugs have raised questions about efficacy, adequacy of fixed dosing, and safety of DOACs in patients with BMI ≥30 kg/m2. We investigated clinical outcomes of VTE recurrence, stroke and bleeding in morbidly obese patients on apixaban.
Method: All adult (age ≥18 years) patients at Montefiore Medical Center with BMI ≥40 who were initiated on anticoagulation with apixaban or warfarin, between March 1, 2013 and March 1, 2017, were identified from electronic medical records using institutional data-mining software. All patients on apixaban were included. Patients on warfarin were selected using a random number generator to match the sample size of the apixaban cohort. Patients with indications for anticoagulation other than AF and prior VTE were excluded. Charts were reviewed to document demographic information and recurrent thrombotic and bleeding events while on anticoagulation during the follow-up period (from the prescription date to the earliest of an event, death or June 30, 2017). Initiation date of anticoagulation was based on the first prescription of warfarin or apixaban. VTE and CVA episodes were confirmed by imaging (compression sonography, ventilation/perfusion scans, CT scans, and MRIs). Bleeding events were classified according to criteria from the Control of Anticoagulation Subcommittee of the International Society on Thrombosis and Haemostasis. Data were analyzed according to anticoagulation indication. Summary statistics and chi-square tests were used to assess statistical significance of the differences in the VTE, CVA and bleeding rates between apixaban and warfarin groups.
Results: Data on 390 patients, with a mean age of 61.7 years and a mean BMI of 46.24, were collected. Characteristics of the study population are listed in the table. In the apixaban group, 124 (68.5%) of the patients were on anticoagulation for AF and 58 (32.0%) for VTE; in the warfarin group, the indication for AC was AF in 124 (59.3%) and VTE in 88 (42.1%) of the patients. In patients who were on anticoagulation because of prior VTE, we could not demonstrate a statistically significant difference in the rate of recurrent VTE in apixaban group compared to warfarin group (1.7% vs. 1.1%, OR 1.53, p=0.76). At these recurrence rates, at 80% power with a p<0.05, 6016 morbidly obese patients with VTE and BMIs ≥40 would have been necessary to acquire significance for these data, should they have been significant. Similarly, for patients on anticoagulation for AF, we could not demonstrate a statistically significant difference in the rate of stroke in the apixaban cohort compared to warfarin (0.8% vs. 2.4%, OR 0.33, p=0.31). At these stroke occurrence rates, at 80% power with a p<0.05, 962 morbidly obese patients with AF and BMIs ≥40 would be required to show a decreased rate of stroke in the apixaban group. There was no statistically significant difference in the bleeding rate in the apixaban group (8.3%) vs. those on warfarin (12.0%, OR 0.67, p=0.23), however major bleeding was significantly less common in patients on apixaban (0.6% vs. 4.3%, OR 0.12, p=0.02). Among the 37 patients on apixaban with BMI ≥50 (25 AF, 11 VTE, and 1 with dual indications), one patient with AF had a CVA (4%) and none had recurrent VTE. Among the 46 patients on warfarin with BMI ≥50 (30 AF, 16 VTE), one had a CVA (3.3%) and none had recurrent VTE.
Conclusion: This study provides further evidence of comparable efficacy and safety of apixaban and warfarin in patients with AF and VTE. Although not powered to detect statistical differences between thrombotic events, the overall low recurrence rate in morbidly obese patients is reassuring. Our study also suggests that there may be a decreased risk of major bleeding with apixaban, even in this population. A randomized controlled trial is needed to confirm these findings in a larger patient population.
Kushnir: Janssen Pharmaceutical: Research Funding. Billett: Janssen Pharmaceutical: Research Funding.
Asterisk with author names denotes non-ASH members.