Indefinite anticoagulation for VTE: reduced-dose vs full-dose DOAC

Background

In patients with deep vein thrombosis (DVT) or pulmonary embolism (PE) who are at high risk of disease recurrence, management options consist of indefinite anticoagulation, typically with a direct oral anticoagulant (DOAC), or reducing the DOAC dose by 50% after a 3- to 6-month course of full-dose therapy. This study assessed the efficacy and safety of reduced-dose versus full-dose DOAC therapy in patients with venous thromboembolism (VTE) receiving indefinite anticoagulation.

Methods

This study was a randomized controlled trial comparing a reduced-dose DOAC strategy (apixaban 2.5 mg twice daily or rivaroxaban 10 mg daily) versus a full-dose DOAC strategy (apixaban 5 mg twice daily or rivaroxaban 20 mg daily). It used open-label treatment allocation and blinded event adjudication.

Included patients were adults (aged ≥18 years) with acute symptomatic proximal DVT or PE who received from 6 to 24 months of full-dose anticoagulation and had one of the following:

• First episode of unprovoked VTE;
• Recurrent VTE;
• VTE with persistent risk factors;
• VTE with other factors associated with a high recurrence risk.

Excluded patients had ≥1 of the following:

• Required full-dose anticoagulation for reasons other than VTE;
• Idiopathic VTE associated with a low recurrence risk (eg, women with normal D-dimer levels post anticoagulation);
• High bleeding risk;
• Renal insufficiency (creatinine clearance [CrCl] <25 mL/min);
• Receiving dual antiplatelet therapy or aspirin >100 mg/d;
• Active cancer within 6 months;
• Pregnancy;
• Life expectancy <12 months.

This study was designed as a noninferiority trial so that it had 90% power to exclude a hazard ratio (HR) of 1.7 for the primary outcome of symptomatic fatal or nonfatal recurrent VTE between the reduced-dose and full-dose DOAC groups.

Results

The study included 2768 patients (65.0% male) who had a median (interquartile range [IQR]) follow-up of 37.1 (24.0-48.3) months. The 5-year incidence rates of recurrent VTE in the reduced-dose and full-dose groups were 2.2% (95% confidence interval [CI], 1.1-3.3]) and 1.8% (95% CI, 0.8-2.7), respectively, with an adjusted HR of 1.32 (95% CI, 0.67-2.60).

The 5-year incidence of major or clinically relevant bleeding was 9.9% (95% CI, 7.7-12.1) in the reduced-dose group and 15.2% (95% CI, 12.8-17.6) in the full-dose group, with an adjusted HR of 0.61 (95% CI, 0.48-0.79).

Mortality in the reduced-dose group was 4.3% (95% CI, 2.6-6.0) compared with 6.1% (95% CI, 4.3-8.0) in the full-dose group.

Conclusions

The authors concluded that although noninferiority for the outcome of recurrent VTE in the reduced-dose versus full-dose strategy was not met (the upper bound of the 95% CI for HR of recurrent VTE was 2.6, which exceeded the 1.7 limit), the low 5-year recurrence rates in both groups (2.2% vs 1.8%) and the significant reduction in clinically relevant bleeding supported using the reduced-dose DOAC strategy for indefinite anticoagulation in patients with VTE.

McMaster editors’ commentary

Previous trials comparing reduced-dose and full-dose DOAC therapy after VTE provided similar results, whereby a reduced-dose strategy was associated with similar rates of recurrent VTE and significantly less bleeding. However, as VTE is a heterogenous disease, estimating the risks of bleeding (if anticoagulation is continued) and the risks of recurrent VTE (if anticoagulation is stopped or dose-reduced), even with the help of clinical decision scores (eg, DASH, HERDOO2, Vienna, HAS-BLED), has its limitations. Ultimately, the decision about continuing or not continuing anticoagulation and dosing regimens is individualized and takes into account baseline risks for recurrent VTE and bleeding as well as “unmeasured factors,” such as the clinical impact of recurrent VTE, ongoing or emerging comorbidities, and patient preferences.