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Direct Oral Anticoagulant Use for Venous Thromboembolism Treatment in Morbidly Obese Patients

03 Aug 2021 11:51 AM | Anonymous

By: Jaynika Patel, PharmD Candidate 2023; University of Health Sciences and Pharmacy at St. Louis College of Pharmacy, Saint Louis, Missouri

Mentor: Priyam Patel, PharmD; Aurora St. Luke’s Medical Center, Milwaukee, Wisconsin

Background
Obesity is a prevalent condition in the United States (U.S.) with nearly one in every three adults being affected.1 The body mass index (BMI) is utilized to determine the weight classification of an individual and can be calculated by dividing the weight in kilograms by the height in meters squared. Obesity is defined as a BMI of 30.0 kg/m2 or above and is further classified into three subcategories: class I (BMI 30-34.9 kg/m2), class II (35-39.9 kg/m2), and class III (≥ 40 kg/m2). Morbidly obese patients are considered Class III based on their BMI.

Obesity presents as a risk factor for venous thromboembolism (VTE).2 Venous thromboembolism is a serious, yet preventable medical condition which refers to blood clots in the veins and could lead to a serious illness or death.3 It is estimated that the annual incidence of VTE in the U.S is 1 to 2 per 1000 of the population.3 Due to the high morbidity and mortality risk, the prevention and treatment of VTE have become a growing concern.

Per the American College of Chest Physicians (CHEST) guidelines, the favorable treatment option for patients with VTE and no cancer diagnosis are direct oral anticoagulants (DOACs) over vitamin K antagonist (VKA) therapy.4 However, the guideline by the Scientific and Standardization Subcommittee of International Society on Thrombosis and Haemostasis (ISTH) advises that DOACs should not be administered for BMI greater than 40 kg/m2 or weight greater than 120 kg due to inadequate drug exposure, short half-lives, and lower peak concentrations in this patient population.5 The remainder of this article will evaluate landmark trials and recent studies followed by the key takeaways.

Landmark Trials and Recent Studies
Each DOAC, supported by its landmark trial(s), has been evaluated for its efficacy and safety in the treatment of VTE. The outcomes measured in these trials include, but are not limited to, recurrence of VTE and major bleeding. The results of these studies concluded that DOACs in VTE are as effective for anticoagulation as VKA, such as warfarin.


One limitation, as it pertains to this article, is that these landmark trials were conducted in a general population, which had a low enrollment of morbidly obese patients. The enrollment for the highest weight/BMI categories reported in these trials is summarized in Table 1. Recent studies aim to determine the efficacy and safety of DOAC use in morbidly obese patients.  

Elshafei et al. performed a systematic review followed by a meta-analysis of trials that compared efficacy and safety of DOAC use to warfarin for acute VTE in morbidly obese patients.12 Four observational studies assessed the efficacy and safety outcomes. The primary efficacy outcome of VTE recurrence rate in morbidly obese patients determined that DOAC use compared to warfarin was non-inferior (OR 1.07, 95% CI 0.93 to 1.23, Q=1.45, I2=0%) with a low I2, indicating the results were homogenous. In regard to major bleeding events, the analysis identified a non-significant risk reduction by 20% in the DOAC group (OR 0.80, 95% CI 0.54 to 1.17, Q=0.16, I2=0%). This study provided evidence that DOAC use as an alternative to warfarin in morbidly obese patients is effective and safe.

Spyropoulos et al. conducted a retrospective 1:1 propensity score-matched cohort study that analyzed morbidly obese patients diagnosed with a VTE who received rivaroxaban or warfarin.13 Two analyses were conducted in this study to observe continual anticoagulant use: intent-to-treat (ITT) and on-treatment (OT). In the ITT analysis, the risk of recurrent VTE in the rivaroxaban group (16.8%) versus the warfarin group (15.9%) was not significantly different (OR 0.99, 95% CI 0.85 to 1.14, P=0.8443). However, major bleeding events in the treatment group (1.8%) in comparison to the warfarin group (2.5%) were significant lower (OR 0.66, 95% CI 0.45 to 0.98, P = 0.0388). In the OT analysis, the risk of recurrent VTE for rivaroxaban (14.8%) versus warfarin (13.4%) was not statistically significant (OR 1.02, 95% CI, 0.87 to 1.20, P=0.8343). Major bleeding events for rivaroxaban (1.4%) and warfarin (1.8%) also did not occur at a statistically different rate (OT: OR 0.75, 95% CI 0.47 to 1.19, P=0.2266). The two analyses provided consistent results in concluding that rivaroxaban has comparable efficacy to warfarin in this study population.

Coons et al. also performed a retrospective matched cohort study analyzing the effectiveness and safety of DOACs for acute VTE treatment in morbidly obese patients in comparison to warfarin.14 The primary outcome was the recurrence of VTE within 12 months after the index admission date. Of the patients with a diagnosis of acute VTE and weight threshold of 100 kg to 300 kg, 632 patients had received a DOAC, while 1208 patients had received warfarin. Rivaroxaban was the primary DOAC administered, representing 91.8% of the patient population. The recurrence of VTE occurred in 6.5% of patients in the DOAC group versus the 6.4% of patients in the warfarin group, which was not a statistically significant difference (P=0.93). The incidence of the primary outcome in the apixaban, rivaroxaban, and warfarin groups were 2.1%, 2%, and 1.2%, respectively (P=0.74). Bleeding events in the DOAC group (1.7%) and warfarin group (1.2%) were also not statistically significant (P=0.31). Based on the data, the authors of the study support the treatment of acute VTE in morbidly obese patients with DOACs.

A retrospective single-center cohort study by Patil et al. analyzed the efficacy and safety of DOACs versus warfarin in the morbidly obese Veteran patient population.15 In the DOAC group, apixaban was administered to 61.68% of the patients, rivaroxaban to 32.71%, and dabigatran to 5.61%. The primary outcome measure was a composite of VTE and stroke/transient ischemic attack. The results of the annual incidence rate of the primary outcome were not statistically significant between the DOAC group (1.61%) and warfarin group (3.91%) (RR 2.436, 95% CI 0.776 to 10.08, P=0.1543). The secondary outcome measuring major bleeding based on the ISTH guidelines had similar annual incidence rates between the two groups (warfarin: 3.13% vs. DOACs: 3.21%, RR 0.97, 95% CI 0.36 to 2.75, P=0.9438). Overall, the study results demonstrated that the administration of DOACs in comparison to warfarin is a viable alternative in morbidly obese patients. 

Conclusion 
The recent studies discussed above suggest that DOAC use in the treatment of VTE in morbidly obese patients may be efficacious in preventing recurrent VTE. The non-inferiority studies still hold warfarin to be a viable treatment option for patients. Regarding safety, DOACs demonstrated similar or slight variations in the rates of bleeding events compared to warfarin which may be contributed from patient-specific factors or inconsistent monitoring. The results of these studies were strengthened by the study design which included a diverse population, relevant subgroup of patients, and large databases for research. 

One major limitation found amongst the retrospective studies was that they relied on accurate documentation that may not have considered other factors at that time, such as specific comorbidities or concomitant use of other high bleeding risk medications. Additionally, the predominance of one DOAC in a study analyzing all DOACs does not provide a balanced comparison. Thus, prospective clinical trials studying the effects of all DOACs for the treatment of VTE in morbidly obese patients are needed to determine which DOAC is superior and most appropriate to recommend. 

References

  1. Defining adult overweight & obesity. Centers for Disease Control and Prevention. https://www.cdc.gov/obesity/adult/defining.html. Updated June 7, 2021. Accessed June 9, 2021.
  2. Overweight and obesity. National Heart, Lung, and Blood Institute. https://www.nhlbi.nih.gov/health-topics/overweight-and-obesity. Accessed June 3, 2021.
  3. What is venous thromboembolism? Centers for Disease Control and Prevention. https://www.cdc.gov/ncbddd/dvt/facts.html. Updated February 7, 2020. Accessed June 1, 2021.
  4. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):314-352.
  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(6):1308-1313.
  6. Schulman S, Kearon C, Kakkar AK, et al.; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-52.
  7. Schulman S, Kakkar AK, Goldhaber SZ, et al.; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764-72. 
  8. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-510. 
  9. EINSTEIN–PE Investigators, Büller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-97.
  10. Agnelli G, Buller HR, Cohen A, et al.; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799-808.
  11. Hokusai-VTE Investigators, Büller HR, Décousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406-15.
  12. Elshafei MN, Mohamed MFH, El-Bardissy A, et al. Comparative effectiveness and safety of direct oral anticoagulants compared to warfarin in morbidly obese patients with acute venous thromboembolism: systematic review and a meta-analysis. J Thromb Thrombolysis. 2021;51(2):388-396.
  13. Spyropoulos AC, Ashton V, Chen YW, et al. Rivaroxaban versus warfarin treatment among morbidly obese patients with venous thromboembolism: Comparative effectiveness, safety, and costs. Thromb Res. 2019;183:159-166.
  14. Coons JC, Albert L, Bejjani A, Iasella CJ. Effectiveness and safety of direct oral anticoagulants versus warfarin in obese patients with acute venous thromboembolism. Pharmacotherapy. 2020;40(3):204-210.
  15. Patil T, Lebrecht M. A single center retrospective cohort study evaluating use of direct oral anticoagulants (DOACs) in morbidly obese veteran population. Thromb Res. 2020;192:124-130. 

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