← Back

ACTION-CVT

Year of Publication: 2022

Journal: Stroke

Link: https://doi.org/10.1161/STROKEAHA.121.037541

PDF: https://www.ahajournals.org/doi/10.1161/STROKEAHA.121.037541

Clinical Question

In patients with cerebral venous thrombosis, are DOACs as effective as warfarin for preventing recurrent venous thrombosis and do they have a favorable safety profile?

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 viable 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
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
Secondary safety 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
Recanalization (partial/complete): aOR 0.92; p=0.79 — similar (525 patients analyzed)
Propensity score matching with replacement confirmed findings: similar VTE, lower major hemorrhage
Sensitivity analyses (excluding deep CVT, baseline hemorrhage, APS-positive patients, COVID patients) all consistent
Consistent with earlier studies (RE-SPECT CVT, meta-analyses) on efficacy; first study to show significantly LOWER hemorrhage with DOACs in CVT
Limitations: retrospective, non-blinded outcome ascertainment, unequal group sizes, heterogeneous imaging follow-up

      

Design

Study Type: Multicenter international retrospective observational cohort study

Randomization:

Blinding: Unblinded (non-central outcome adjudication)

Follow-up Duration: Median 345 days (IQR 140-720)

Sample Size: 1025

Analyzed: 845

Analysis: Inverse probability of treatment weighted Cox regression (primary); propensity score matching with/without replacement (sensitivity); multiple adjusted models

Inclusion Criteria

Adult patients with imaging-confirmed CVT (MRV or CTV)
Admitted between January 1, 2015 and December 31, 2020
Treated with oral anticoagulation (warfarin or DOAC)
Available clinical outcomes
Identified via ICD-9/10 codes with chart and imaging confirmation

Exclusion Criteria

Antiphospholipid antibody syndrome (warfarin typically preferred)
Active cancer (DOACs typically preferred)
Pregnancy (oral anticoagulation contraindicated)
Not treated with oral anticoagulation
For recanalization analysis: endovascular treatment or use of both drug classes before follow-up imaging

Baseline Characteristics

Characteristic	Control	Active
N	438	279
Age	44.3 ± 16.1	46.1 ± 17.4
Female	63.0%	67.4%
History of VTE	6.6%	15.4%
Antiphospholipid antibody (incidental)	12.1%	6.8%
Intracranial hemorrhage at baseline	36.4%	37.8%
LMWH use	77.9%	33.3%

Arms

Field	Control	DOAC only
N	438	279
Intervention	Warfarin dosed to INR 2-3 with INR monitoring per standard of care	Direct oral anticoagulant (dabigatran, rivaroxaban, apixaban, or edoxaban) at clinician discretion
Duration	Median 202.5 days	Median 194 days

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Recurrent cerebral or systemic venous thrombosis on oral anticoagulation	Primary	Rate 5.68 / 100 patient-years overall	Similar rate on DOACs		p=0.84
Major hemorrhage (intracranial or extracranial)	Secondary	Rate 4.70 per 100 PY	Rate 2.44 per 100 PY	aHR 0.35 (95% CI 0.15-0.82)	p=0.02 (LOWER with DOACs)
All-cause death	Secondary	Rate 1.84 per 100 PY overall	Similar	aHR 0.78 (95% CI 0.22-2.76)	p=0.70
Partial or complete recanalization (n=525)	Secondary	291/346 (84.1%)	154/179 (86.0%)	aOR 0.92 (95% CI 0.48-1.73)	p=0.79
Unadjusted major hemorrhage	Secondary	Reference	Lower	HR 0.47 (95% CI 0.21-1.04)	p=0.06 (trend, adjusted analyses stronger)
Propensity score matched major hemorrhage (N=720)	Secondary	Reference	Lower	aHR 0.42 (95% CI 0.16-1.06)	p=0.07 (consistent direction)
Propensity matched without replacement major hemorrhage (N=534)	Secondary	Reference	Lower	aHR 0.34 (95% CI 0.12-0.95)	p=0.04
Recurrent CVT within 90 days	Secondary	Reference	Similar	aHR 1.13 (95% CI 0.44-2.87)	p=0.80
Excluding COVID-19 patients (n=6) - sensitivity	Secondary	Reference	Findings unchanged	All HRs unchanged	Robust
Major hemorrhage rate per 100 PY	Adverse	4.70	2.44	aHR 0.35 (95% CI 0.15-0.82)	p=0.02
Recurrent venous thrombosis rate per 100 PY	Adverse	Similar	Similar	aHR 0.94	p=0.84
Death rate per 100 PY	Adverse	Similar	Similar	aHR 0.78	p=0.70
Symptomatic intracranial hemorrhage	Adverse	Subset of major hemorrhage	Lower proportion		Descriptive
Major extracranial hemorrhage	Adverse	Subset	Subset		Descriptive
Asymptomatic hemorrhage on imaging	Adverse	Low (ascertainment bias)	Low		Underreported by design
VTE-related death	Adverse	Rare	Rare		Low overall
Progression of CVT (captured in recurrence outcome)	Adverse	Captured	Captured		No difference

Subgroup Analysis

Sensitivity analyses excluding deep CVT and baseline hemorrhage (not established predictors of recanalization/hemorrhage) confirmed similar recanalization and persistently lower major hemorrhage with DOACs (aHR 0.35; p=0.02). Excluding antiphospholipid antibody-positive patients, COVID-19 patients, and those lost to follow-up before 90 days all produced consistent findings. Time-of-recurrence subgroups (<90 days vs >90 days from anticoagulation initiation, and 2-week and 4-week cutoffs) showed similar DOAC vs warfarin effect, suggesting no differential risk window. The younger age of the cohort (mean 45 years) aligns with CVT epidemiology and with the age group showing greatest DOAC safety advantage over warfarin in other contexts.

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, edoxaban) — 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)
COVID-19 pandemic overlapped the study period, altering referral patterns and anticoagulation preferences

Funding

No direct funding (investigator-initiated); individual author support from various sources (NIH, AHA)

Based on: ACTION-CVT (Stroke, 2022)

Content summarized and formatted by NeuroTrials.ai.

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

• Retrospective multicenter cohort of 845 CVT patients at 27 centers in US, Europe, New Zealand (2015-2020).
• Rate of recurrent venous thrombosis (5.68/100 patient-years) 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 confirmed the findings.
• Largest real-world CVT study to date — supports DOACs as a safe alternative to warfarin.

Intervention

Observational comparison of oral anticoagulation strategies in CVT: direct oral anticoagulants (dabigatran, rivaroxaban, apixaban, edoxaban) vs warfarin (INR 2-3). 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 per Arm: DOAC only 279; Warfarin only 438; Both (excluded from primary analyses) 128

Outcome

• Primary: Recurrent venous thrombosis aHR 0.94 (95% CI 0.51-1.73); p=0.84 — similar efficacy
• 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
• Partial/complete recanalization: aOR 0.92 (95% CI 0.48-1.73); p=0.79 — similar
• Absolute event rates: 5.68 recurrent VTE, 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

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
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
Secondary safety 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
Recanalization (partial/complete): aOR 0.92; p=0.79 — similar (525 patients analyzed)
Propensity score matching with replacement confirmed findings: similar VTE, lower major hemorrhage
Sensitivity analyses (excluding deep CVT, baseline hemorrhage, APS-positive patients, COVID patients) all consistent
Consistent with earlier studies (RE-SPECT CVT, meta-analyses) on efficacy; first study to show significantly LOWER hemorrhage 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: 1025
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
Rate 5.68 / 100 patient-years overall	Similar rate on DOACs	- (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, edoxaban) — 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)
COVID-19 pandemic overlapped the study period, altering referral patterns and anticoagulation preferences

Citation

View Original Publication →

ACTION-CVT

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

Ask about ACTION-CVT