Obesity is an independent risk factor for the acquisition of VTE. Extremely high BMI has been shown to be correlated with an increased incidence of VTE; this correlation is more apparent with a BMI of 30 kg/m2 or more [33, 34]. The increased risk of VTE in this cohort is likely due to the increased abdominal pressure and the mechanical effect it exerts on the veins [35, 36]. Furthermore, the associated molecular hypercoagulable status; this status is postulated to be due to the associated elated levels of tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β) [35, 36]. Moreover, the increased levels of Von Willebrand factor, and clotting factors, such as factor VII, factor VIIIc, and fibrinogen [37,38,39].
The clinical implications (efficacy and safety) of such observations remain uncertain. Subgroup analysis of randomized controlled trials of DOACs in VTE treatment have shown that their efficacy in obese patients (> 100 kg) had no difference compared to average weight [17, 40,41,42]. However, morbidly obese (bodyweight of > 120 kg or BMI > 40 kg/m2) patients were significantly under-represented in these trials. These inconsistencies were the driving factor behind the broad statement of the ISTH recommending against the use of DOACs in extremely high body weight (body weight of > 120 kg or BMI > 40 kg/m2) .
Our meta-analysis, aimed at settling this uncertainty, demonstrated that DOAC analogs are non-inferior to warfarin in terms of effectiveness (VTE events) in morbidly obese patients. Additionally, it showed a propensity towards lower major bleeding events. To the best of our knowledge, our meta-analysis is the first to address the uncertainty regarding the efficacy and safety of DOACs in patients with VTE and extremely high body weight [40,41,42]. The low I2 and the results of the sensitivity analysis indicated the homogeneity of our data. All the studies included in our review are relatively recent (2019 and 2020). Hence, these were not available to previous reviewers attempting to resolve this uncertainty.
The registry-based study by Spyropoulos et al. 2019 makes up to 88% of patients included in our review. They retrospectively studied rivaroxaban compared to warfarin in an adjusted comparison of 5780 patients. From this real-world analysis, they concluded a similar efficacy (rates of VTE events) and safety (major bleeding events). One major limitation of this study was the use of a claims-coded database. Besides, it did not report the International Normalized Ration (INR), and the time in therapeutic (TTR) for patients on warfarin, thus, bias may have been introduced . Kushiner et al. 2019 investigated the use of rivaroxaban and Apixaban vs. warfarin in morbidly obese patients (BMI of ≥ 40 kg/m2) with atrial fibrillation and DVT. This study included 366 patients and also concluded that the incidence of recurrent VTE and major bleeding did not differ across the three cohorts . This study was limited by missing data for patients’ history of thrombotic risk factors and by the presence of malignancy and bariatric surgery, which might independently contribute to a higher risk of thromboembolism. Additionally, a high proportion of the population was of African American and Hispanic origin, which questions the generalizability of the findings to other racial groups of morbidly obese patients .
In early 2020, Coons et al. retrospectively evaluated VTE recurrence and bleeding outcomes in 1840 cases of acute VTE, which were treated with either DOACs or warfarin. Included patients had bodyweight that ranged between 100 and 300 kg. This study did not detect any significant difference in the rate of VTE recurrence between DOACs and warfarin (6.5% vs. 6.4%; p = 0.93). Bleeding occurred in 1.7% and 1.2% of patients on DOACs and warfarin, respectively (p = 0.31). However, 50–55% of the patients in this study had a BMI of less than 40 kg/m2. Although their results support our conclusion, they did not report the outcomes for morbidly obese patients exclusively; hence, their study was excluded from our review .
Our meta-analysis is the first meta-analysis that demonstrated the non-inferior effectiveness and safety of DOAC analogs in morbidly obese patients and resolved this uncertainty. It has a good number of patients, out of which the biggest is a registry-based study examining the effect of these agents in real-world settings. Our review is not without limitations. It comprised of observational studies only; it is known that these studies have an inherently higher risk of bias. Secondly, we did not adjust for potential confounders (age, gender, and history of-or active malignancy). Additionally, the major DOAC used in the included studies was rivaroxaban, followed by Apixaban. This limits the generalizability of our findings to other DOAC analogs. Lastly, DOACs dosing information including drug interactions were not reported except for Quan et al. .
Acknowledging these limitations, a multicenter randomized controlled trial testing DOAC analogs vs. warfarin in morbidly obese patients is needed to settle this uncertainty once and for all. We think that the use of DOAC analogs as an intervention in this study will be ethically justifiable by the results of our review and the primary studies included in it.