There are numerous anticoagulant options for the treatment of acute venous thromboembolism (VTE), with four direct oral anticoagulants (DOACs) approved by the U.S. Food and Drug Administration (FDA) in addition to traditional anticoagulants. Draft recommendations from ASH on the treatment of VTE1 do not recommend one DOAC in favor of another. Two recent observational studies have directly compared apixaban to rivaroxaban for the initial treatment of VTE.
The first study by Dr. Ghadeer Dawwas and colleagues is a retrospective cohort study using claims databases from the United States between 2014 and 2016. Propensity score matching was used to compare 3,091 apixaban users with 12,163 rivaroxaban users for initial treatment of acute VTE (initiated drug within 30 days of VTE diagnosis). Outcomes of recurrent VTE (positive predictive value of International Classification of Diseases (ICD) 9/10 codes for VTE, 73-83%) and major or minor bleeding were defined by ICD-9/10 codes (positive predictive value of ICD 9/10 codes for major or minor bleeding, to our knowledge, do not exist). Recurrent VTE (adjusted hazard ratio [aHR], 0.37; 95% CI, 0.24-0.55), major bleeding (aHR, 0.54; 95% CI, 0.37-0.82), and minor bleeding (aHR, 0.57; 95% CI, 0.48-0.67) were all lower with apixaban than with rivaroxaban.
The second study by Dr. Dalene M. Bott-Kitslaar and colleagues is a single-center prospective observational study from the Mayo Clinic comparing 302 apixaban-treated patients to 298 rivaroxaban-treated patients from 2013 to 2018.2 Patients were included if they had started the medication within 14 days of a diagnosis of acute VTE. Outcomes of VTE recurrence, major bleeding (MB), clinically relevant nonmajor bleeding (CRNMB), and composite of CRNMB and MB were adjudicated by nonblinded investigators using standard International Society on Thrombosis and Haemostasis (ISTH) definitions. Outcomes were analyzed at three months by total person-time of exposure for patients receiving longer treatment. At three months, recurrent VTE occurred in three apixaban-treated patients (1%) and in two rivaroxaban-treated patients (0.7%; p=0.66). Major bleeding occurred in six apixaban-treated patients (2%) and six rivaroxaban-treated patients (2%; p=0.98). A propensity score was generated and used in a Cox proportional hazard model evaluating total follow-up duration; after adjustment no differences were observed between apixaban and rivaroxaban in VTE recurrence (aHR, 1.4; 95% CI, 0.5-3.8) or MB (aHR, 1.2; 95% CI, 0.5-3.2). A lower rate of CRMB was demonstrated with apixaban (aHR, 0.4; 95% CI, 0.2-0.9), but the composite (CRNMB and MB) safety outcome was not different (aHR, 0.6; 95% CI, 0.3-1.2). The authors concluded that the safety and efficacy of apixaban and rivaroxaban were similar in clinical practice.
Patient populations and methodologies differed between studies; both are limited by their observational, nonrandomized design (Table). Interestingly, active cancer was more prevalent in the second study but did not seem to increase overall adverse event rates. Weight was not addressed in the study by Dr. Dawwas and colleagues but was similar in the two groups from the Mayo study by Dr. Bott-Kitslaar and colleagues. Concerns about the efficacy of DOACs in the morbidly obese remain,2,3 and it is unknown whether one drug is better than another. The first study has a very large sample size that allows for identification of small differences in outcomes between the two drugs but is limited by potentially imprecise outcome definitions based on ICD 9/10 codes, whereas the second study had prospective follow up and adjudicated outcomes based on standard ISTH definitions of bleeding.
These two new studies with conflicting conclusions do not provide enough evidence to suggest the superiority of one medication over another for the treatment of acute VTE. Data directly comparing other DOACs are also needed. Choice of anticoagulation should remain based on pertinent clinical conditions and package labeling, availability, cost, patient preferences, and physician familiarity with the drugs. A randomized comparison of apixaban versus rivaroxaban for the treatment of acute VTE (COVET trial) is currently enrolling, with a goal of 2,760 participants and estimated study completion in 2022 (NCT03266783). This will provide a high-quality comparison between two of the most commonly used DOACs within the confines of the more stringent and restricted clinical trial population. Additional observational data will continue to be useful to assess the real-world efficacy of these drugs.
Comparison Between Studies of Baseline Characteristics and Crude Adverse Events for Apixaban and Rivaroxaban in the Treatment of Acute Venous Thromboembolism
| ||Dawwas GK et al||Bott-Kislaar DM et al||Dawwas GK et al||Bott-Kislaar DM et al|
|Baseline Characteristics|| || || || |
|Mean age (years)||61.5||62.4||56.5||58.5|
|Indication for anticoagulation: PE (%)||30||39||28||35|
|Indication for anticoagulation: Provoked VTE (%)||51||83||49||80|
|Mean weight (kg)||Not reported||88||Not reported||91|
|Active cancer (%)||14||47||17||40|
|ASA or NSAIDs (%)||25||23||23||21|
|Chronic kidney disease (%)||17a||2.3b||9a||0b|
|Adverse Outcomes (No. of events/100 person-years)|| |
|Recurrent VTE events||3||4||7||2|
|Major bleeding events||3||6||6||3|
|Nonmajor bleeding events||20c||4.0d||34c||6.8d|
Abbreviations: ASA, aspirin; NSAIDs, nonsteroidal anti-inflammatory drug; PE, pulmonary embolism; VTE, venous thromboembolism.
a Unknown definition of CKD.
b Creatinine clearance < 30 mL/min.
c Minor bleeding.
d Clinically relevant nonmajor bleeding (CRNMB).
Ortel TL, et al. ASH draft recommendations for treatment of acute venous thromboembolism. In development.
Martin K, Beyer-Westendorf J, Davidson BL, et al. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost. 2016;14:1308-1313.
Moll S, Crona DJ, Martin K. Direct oral anticoagulants in extremely obese patients OK to use?. Res and Prac in Thromb and Haem. 2018; doi: 10.1002/rth2.12178.
Conflict of Interests
Dr. Moll has been a consultant for Janssen Pharmaceuticals. Dr. Houghton has no financial disclosures; he is a coauthor of the 2019 publication by Bott-Kitslaar et al.
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