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(2023)Objective
Rivaroxaban 20 mg daily vs standard-of-care anticoagulation (warfarin INR 2-3 or LMWH) — to assess feasibility of recruitment, safety, and functional outcomes in a Canadian phase II CVT trial.
Study Summary
• Primary composite safety outcome (mortality/sICH/major extracranial bleeding) occurred in 1 rivaroxaban vs 0 control patients.
• All participants achieved partial or complete recanalization by day 180.
• At enrollment, both arms showed impaired quality of life, mood, headache impact, fatigue, and cognition; all improved by day 180.
• Mean mRS improved for 81% rivaroxaban vs 67% control; by day 365, 83-84% were mRS 0-1.
• Recruitment feasibility demonstrated, but low event rates suggest a large international phase 3 would be required.
Intervention
Rivaroxaban 20 mg daily (or 15 mg if creatinine clearance <50 mL/min) vs standard-of-care anticoagulation (warfarin INR 2-3 with bridging parenteral anticoagulation until target, or low-molecular-weight heparin), for 180 days with optional extension to 365 days.
Inclusion Criteria
Adults ≥18, within 14 days of imaging-confirmed CVT, suitable for oral anticoagulation, parenchymal brain scan within 72 hours. No lead-in parenteral anticoagulation required. Exclusions: antiphospholipid antibody syndrome, pregnancy/breastfeeding, anticipated invasive procedure, CrCl <30 mL/min, strong CYP3A4 inhibitors, contraindication to anticoagulation.
Study Design
Arms: Rivaroxaban 20 mg daily vs Standard-of-care (warfarin INR 2-3 or LMWH)
Patients per Arm: Rivaroxaban 26; Standard-of-care 27
Outcome
• Primary composite safety (death/sICH/major extracranial hemorrhage) 180 d: 1 rivaroxaban (sICH at 3.5 mo) vs 0 standard (3.8% vs 0%; diff 3.8%)
• Any intracranial hemorrhage 180 d: 2 (7.7%) rivaroxaban vs 0 standard; clinically relevant nonmajor bleeding: 2 (7.7%) vs 0
• All 53 analyzed achieved partial or complete recanalization; 37.5% rivaroxaban vs 50% control achieved complete recanalization
• At day 180: mRS 0-1 in 70.8% rivaroxaban vs 80.8% control; by day 365: 82.6% vs 84.0%
Clinical Question
In patients with recent symptomatic cerebral venous thrombosis, is a randomized trial of rivaroxaban 20 mg daily versus standard-of-care anticoagulation (warfarin or LMWH) feasible, and what is the comparative safety profile and trajectory of functional and patient-reported outcomes over 180-365 days?
Bottom Line
In 55 patients with symptomatic CVT at 12 Canadian centers randomized 1:1 to rivaroxaban 20 mg daily or standard-of-care (warfarin or LMWH), recruitment target was met (21.3 patients/year; 57% consent rate) with no major safety concerns. Numerically more bleeding with rivaroxaban (1 sICH, 2 CRNMB) but rates within prior CVT literature. All participants had partial or complete recanalization by day 180; patient-reported outcomes (quality of life, mood, headache, fatigue, cognition) all improved over time. Feasibility confirmed but larger trials needed.
Major Points
- Multicenter Canadian phase 2 feasibility trial at 12 comprehensive stroke centers (Field 2023)
- N=55 randomized (26 rivaroxaban, 27 standard-of-care, 2 remained unrandomized)
- Recruitment: 21.3 participants/year (feasibility met); 57% of eligible candidates consented
- Inclusion within 14 days of CVT diagnosis; no lead-in parenteral anticoagulation required (distinct from RE-SPECT CVT and EINSTEIN-Jr)
- 62.2% randomized within 1-4 days of diagnosis; 41.5% within 2 days
- Rivaroxaban started at 20 mg daily (no 15 mg BID loading typical for acute DVT/PE) — safety signal still favorable
- Primary composite safety outcome (mortality/sICH/major extracranial hemorrhage) at 180 d: 1 rivaroxaban (sICH) vs 0 standard
- Any intracranial hemorrhage and CRNMB numerically more frequent with rivaroxaban (consistent with ACTION-CVT and RE-SPECT signals)
- All 53 analyzed participants achieved partial or complete recanalization by day 180 (De Sousa grade 1B or better)
- Patient-reported outcomes: reduced QoL (EQ-5D), low mood (PHQ-9), high headache impact (HIT-6), fatigue (FAS), impaired cognition (MoCA) at baseline; all markedly improved by day 180
- By day 365, 82.6% (rivaroxaban) and 84.0% (control) achieved mRS 0-1
- Conclusion: feasibility established; larger trial impractical due to growing DOAC preference in practice; hierarchical composite win-ratio design suggested for future CVT trials
Study Design
- Study Type
- Phase 2 multicenter prospective open-label blinded-endpoint 1:1 parallel-group randomized feasibility trial (NCT03178864)
- Randomization
- Yes
- Blinding
- Open-label; blinded central adjudication of primary endpoints
- Sample Size
- 55
- Follow-up
- 180 days primary; 365 days optional extension
Primary Outcome
Definition: Primary feasibility: annual recruitment rate; primary safety: composite of all-cause mortality, symptomatic intracranial hemorrhage, or major extracranial hemorrhage at 180 days
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 0/27 (0%, 95% CI 0-12.8) | 1/26 (3.8%, 95% CI 0.1-19.6) - one spontaneous subdural hemorrhage at 3.5 months | - (95% CI -3.5 to 11.2) | Descriptive (not powered for significance) |
Limitations & Criticisms
- Small sample size (n=55) precludes superiority/noninferiority conclusions; powered only for feasibility
- Rivaroxaban 20 mg once daily (vs 15 mg BID standard for DVT/PE) — pharmacokinetic modeling supports this but direct comparison lacking
- High rate of missing cognitive data on follow-up limits MoCA trajectories
- Numerically higher bleeding with rivaroxaban (1 sICH, 2 CRNMB) warrants attention but confidence intervals are very wide
- Baseline characteristics unbalanced (52% vs 31% intracranial hemorrhage in rivaroxaban vs control) reflects small sample and may influence outcomes
- Open-label design with blinded endpoint adjudication partially mitigates bias but does not fully eliminate it
- Canadian single-country enrollment; generalizability limited; funded by Bayer (rivaroxaban manufacturer)