Treatment Versus Prophylactic Apixaban or Rivaroxaban for Extended Venous Thromboembolic Disease Management

Introduction:

Apixaban and rivaroxaban are the most commonly used direct oral anticoagulants (DOACs) for the management of venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). For patients at clinical equipoise for continued anticoagulation after six months of standard anticoagulation treatment, prophylactic dose apixaban (2.5 mg twice daily) was associated with a reduced risk of recurrent VTE compared to placebo, achieving similar outcomes to full dose apixaban (5 mg twice daily). Similarly, rivaroxaban (10 mg daily) has been shown to significantly reduce the risk of recurrent VTE compared to aspirin, achieving similar thrombotic outcomes to full dose rivaroxaban (20 mg daily).

The 2021 American College of Chest Physician Guidelines suggest reduced-dose apixaban or rivaroxaban for extended-phase VTE management, providing a weak recommendation with very low-certainty evidence. We sought to determine if clinical outcomes differ for patients treated with full compared to prophylactic anticoagulation for extended therapy of VTE.

Methods:

We conducted a registry-based cohort study of adults on DOAC therapy for VTE followed at four health systems in Michigan between January 2012 to December 2023, recruited through the Michigan Anticoagulation Quality Improvement Initiative (MAQI²). Included patients had to be anticoagulated for DVT and/or PE, treated with apixaban or rivaroxaban, and have at least 9 months of follow-up. We required 9 months of follow-up to ensure that at least 3 months of follow-up occurred after the initial 6 months of anticoagulation. Patients with mechanical heart valves, on dual antiplatelet therapy, and with cirrhosis were excluded.

Two propensity score-matched cohorts of patients were compared based on anticoagulant dose using full matching, allowing one prophylactic dose patient to match to up to six therapeutically treated patients. Patients were matched on factors anticipated to influence anticoagulant treatment. Recurrent VTE was the primary outcome. Secondary outcomes included new episodes of any thrombosis, bleeding, emergency department visits, hospitalizations, and death. Random chart audits were done to confirm data accuracy. Event rates were compared using Poisson regression.

Results:

A total of 978 patients met the study inclusion criteria, 200 (20.4%) were on prophylactic dose anticoagulation. Unadjusted rates of thrombosis, bleeding, and healthcare utilization were higher among patients on therapeutic dosing. After propensity matching, we compared two groups: 662 patients with therapeutic dosing to 189 patients on prophylactic dosing. Mean (standard deviation [SD]) age was 66.4 years old (15.4), with 47.7% identified as male sex, 51.9% had a body mass index >30 kg/m², and the average follow-up was 21.1 months (SD 22.0). Of the matched cohort, 18.8% had provoked VTE, 32.4% had cancer, and 7.9% were receiving chemotherapy.

After matching, patients on therapeutic dose anticoagulation had a similar rate of recurrent VTE (1.8 versus 0.3 PE/100 patient years, 95% confidence interval [CI] 1.1-2.8 versus 0.0-1.4, p=0.21 for PE; 1.1 versus 0.3 DVTs/100 patient years, 95% CI 0.6-1.9 versus 0.0-1.4, p=0.22 for DVT) and rate of any thrombosis compared to patients on prophylactic dosing (4.1 versus 1.3 events/100 patient years; 95% CI 3.0-5.5 versus 0.4-3.0, p=0.055). Patients on therapeutic anticoagulation had a higher bleeding event rate (45.6 versus 40.0 events/100 patient years; 95% CI 41.7-49.8 versus 34.0-46.8, p=0.039) but a similar major bleeding rate compared to prophylactic anticoagulation (3.6 versus 1.8 events/100 patient years; 95% CI 2.6-4.9 versus 0.7-3.7, p=0.067). Patients on therapeutic anticoagulation had more bleed or thrombosis related emergency department (ED) visits (17.2 versus 9.1 ED visits/100 patient years, 95% CI 14.8-19.8 versus 6.4-12.6, p=0.002) and hospitalizations (9.0 versus 5.1 hospitalizations/100 patient years, 95% CI 7.3-10.9 versus 3.1-7.8, p=0.011). Mortality was similar between groups.

Conclusions:

Compared to prophylactic dosing, therapeutic dosing was associated with a similar rate of recurrent VTE, an increased bleeding rate, and a higher rate of healthcare utilization for extended secondary prevention of VTE in a real-world cohort. These findings support current guideline recommendations but should be confirmed in randomized trials.