PDF: ACTION-CVT
(2022)Objective
Direct oral anticoagulants vs warfarin — to compare effectiveness and safety in a real-world multicenter cohort of patients with cerebral venous thrombosis across 27 centers in 4 countries.
Study Summary
• Rate of recurrent venous thrombosis (5.68/100 patient-years overall) was similar with DOACs vs warfarin (aHR 0.94; p=0.84).
• Major hemorrhage was lower with DOACs (aHR 0.35; 95% CI 0.15-0.82; p=0.02) — the main clinical advantage.
• Recanalization rates (partial or complete) were similar: 86.0% DOAC vs 84.1% warfarin (p=0.56).
• Propensity score matching and multiple sensitivity analyses were directionally consistent.
• Largest real-world CVT study to date — supports DOACs as a reasonable alternative to warfarin.
Intervention
Observational comparison of oral anticoagulation strategies in CVT: direct oral anticoagulants (dabigatran, rivaroxaban, apixaban) vs warfarin (INR monitoring per standard of care; no target INR range specified in paper). Treatment chosen by treating clinicians; no randomization.
Inclusion Criteria
Adults with imaging-confirmed CVT admitted January 2015 - December 2020, treated with oral anticoagulation. Excluded: antiphospholipid syndrome (warfarin typically indicated), active cancer (DOACs typically indicated), pregnancy (neither drug class suitable), patients not treated with oral anticoagulation.
Study Design
Arms: DOAC only vs Warfarin only (observational, non-randomized; patients on both at different times analyzed as-treated crossovers)
Patients per Arm: DOAC only 279; Warfarin only 438; Both at different times 128 (analyzed as as-treated crossovers, not excluded). Full cohort N=845 used for clinical outcomes.
Outcome
• Major hemorrhage: aHR 0.35 (95% CI 0.15-0.82); p=0.02 — LOWER with DOACs
• Death: aHR 0.78 (95% CI 0.22-2.76); p=0.70 — similar (all-cause)
• Partial/complete recanalization: aOR 0.92 (95% CI 0.48-1.73); p=0.79 — similar
• Overall absolute event rates: 5.68 recurrent venous thromboses (17 VTE, 27 recurrent CVT, 2 both), 3.77 major hemorrhage, 1.84 deaths per 100 patient-years
Clinical Question
In adult patients with cerebral venous thrombosis requiring oral anticoagulation, are direct oral anticoagulants (DOACs) associated with similar rates of recurrent venous thrombosis, death, and recanalization, and with a different major hemorrhage rate, compared with warfarin?
Bottom Line
In 845 patients with CVT across 27 international centers, DOACs were associated with similar rates of recurrent venous thrombosis (aHR 0.94; p=0.84), death (aHR 0.78; p=0.70), and recanalization (aOR 0.92; p=0.79) as warfarin but with significantly lower major hemorrhage risk (aHR 0.35; 95% CI 0.15-0.82; p=0.02). Provides the largest real-world dataset supporting DOACs as a reasonable alternative to warfarin for CVT.
Major Points
- Retrospective multicenter international observational study at 27 centers in US, Italy, Switzerland, New Zealand (Yaghi 2022)
- N=1025 CVT patients screened; 845 met inclusion (CVT treated with oral anticoagulation, excluding APS, active cancer, pregnancy)
- 33.0% DOAC only, 51.8% warfarin only, 15.1% both at different times (crossovers analyzed as-treated; full N=845 used for clinical outcomes)
- Median follow-up 345 days (IQR 140-720); primary analysis via inverse probability of treatment weighted Cox regression
- Primary outcome: recurrent venous thrombosis — aHR 0.94 (95% CI 0.51-1.73); p=0.84 — SIMILAR (5.26 DOAC vs 5.87/100 PY warfarin)
- Secondary safety outcome: major hemorrhage — aHR 0.35 (95% CI 0.15-0.82); p=0.02 — LOWER with DOACs (2.44 DOAC vs 4.70/100 PY warfarin)
- All-cause death: aHR 0.78 (95% CI 0.22-2.76); p=0.70 — similar (1.81 DOAC vs 1.90/100 PY warfarin)
- Recanalization (partial/complete): aOR 0.92 (95% CI 0.48-1.73); p=0.79 — similar (adjusted model N=448; the full recanalization analysis cohort of 525 had unadjusted OR 1.16, p=0.56)
- Propensity score matching with replacement (N=720) was directionally consistent but non-significant for major hemorrhage (aHR 0.42; 95% CI 0.16-1.06; p=0.07); matching without replacement (N=532) was significant (aHR 0.34; 95% CI 0.12-0.95; p=0.04)
- Sensitivity analyses excluding deep CVT, baseline hemorrhage, or the antiphospholipid-antibody variable from the models, and separately excluding COVID-19 patients (n=6), all showed consistent findings
- Consistent with earlier studies (RE-SPECT CVT, meta-analyses) on efficacy; in contrast to prior work, showed a significantly LOWER major hemorrhage risk with DOACs in CVT
- Limitations: retrospective, non-blinded outcome ascertainment, unequal group sizes, heterogeneous imaging follow-up
Study Design
- Study Type
- Multicenter international retrospective observational cohort study
- Randomization
- No
- Blinding
- Unblinded (non-central outcome adjudication)
- Sample Size
- 845
- Follow-up
- Median 345 days (IQR 140-720)
Primary Outcome
Definition: Recurrent cerebral or systemic venous thrombosis on oral anticoagulation
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 5.87 per 100 patient-years (warfarin) | 5.26 per 100 patient-years (DOAC); unadjusted P=0.61 | - (0.51-1.73) | p=0.84 |
Limitations & Criticisms
- Retrospective observational design — residual confounding cannot be excluded despite IPTW and propensity matching
- Non-central, non-blinded outcome ascertainment — imaging and event adjudication varied by center
- DOAC subtype heterogeneity (dabigatran, rivaroxaban, apixaban) — outcomes not stratified by agent
- Unequal group sizes (279 DOAC vs 438 warfarin) reflect practice patterns and may introduce selection bias
- Follow-up imaging timing was heterogeneous, limiting precision of recanalization analysis
- Asymptomatic hemorrhage likely underdetected due to ascertainment bias (routine follow-up imaging not standardized)
- Part of the study period overlapped the COVID-19 pandemic; only 6 CVT-with-COVID patients were included and excluding them left findings unchanged