Initial Direct Oral Anticoagulants Versus Warfarin After Cerebral Venous Thrombosis: A Target Trial Emulation

Vitamin K antagonists have traditionally been used after cerebral venous thrombosis, whereas direct oral anticoagulants (DOACs) are increasingly prescribed. Whether DOACs are noninferior to warfarin for preventing 1-year symptomatic recurrent venous thromboembolism (VTE) remains uncertain.

We conducted a registry-based target trial emulation in a bidirectional multicenter Chinese cerebral venous thrombosis registry (retrospective phase, 2015-2022; prospective phase, 2023-2025). Eligible patients were adults with imaging-confirmed cerebral venous thrombosis who initiated either a DOAC or warfarin within 30 days after diagnosis. Time zero was the date of the first oral anticoagulant prescription. The primary efficacy outcome was symptomatic recurrent VTE within 1 year. Propensity score overlap weighting was used, and weighted Fine-Gray models treated death as a competing event. The clinically acceptable noninferiority margin was defined as an absolute increase of 1.5 percentage points in 1-year recurrent VTE risk, corresponding approximately to a relative margin of 1.50 for the primary Fine-Gray analysis.

Among 2476 eligible patients, 942 initiated a DOAC (rivaroxaban, n=701; dabigatran, n=121; apixaban, n=113; edoxaban, n=7) and 1534 initiated warfarin. Within 1 year, symptomatic recurrent VTE occurred in 36 and 73 patients, respectively. The overlap-weighted 1-year recurrence risks were 3.74% and 5.47%, corresponding to a risk difference of -1.73 percentage points (95% CI, -3.76 to 0.30). DOAC treatment was associated with a lower subdistribution hazard ratio of 0.67 compared with that of warfarin ([95% CI, 0.37-1.21]; P=0.184), meeting the prespecified noninferiority criterion (P for noninferiority=0.004). Major bleeding was rare within 1 year (0 versus 1 patient). Clinical nonmajor bleeding occurred in 18 versus 34 patients, and any bleeding occurred in 48 versus 75 patients.

Among patients with cerebral venous thrombosis selected for oral anticoagulation, initial treatment with a DOAC met the noninferiority criterion relative to warfarin for the prevention of symptomatic recurrent VTE at 1 year. Findings regarding bleeding outcomes were exploratory and do not permit conclusions regarding comparative safety or equivalence.