TREAT-CAD
Biomarkers and Antithrombotic Treatment in Cervical Artery Dissection Trial
Clinical Question
Is aspirin non-inferior to vitamin K antagonists for secondary prevention in patients with symptomatic cervical artery dissection, using a composite of clinical and MRI outcomes?
Study Overview
Objective
To test the non-inferiority of aspirin compared to vitamin K antagonists in patients with cervical artery dissection using a composite clinical and MRI endpoint
Study Summary
- Non-inferiority of aspirin to VKA was NOT demonstrated in cervical artery dissection (23% vs 15% composite endpoint, absolute difference 8%, p=0.55)
- All 7 ischemic strokes occurred in the aspirin group (8%) vs 0 in VKA group
- Evidence does not support replacing anticoagulation with aspirin as standard of care for cervical artery dissection
Intervention
Aspirin 300 mg daily vs Vitamin K antagonist (phenprocoumon, acenocoumarol, or warfarin; target INR 2.0-3.0) for 90 days
Patients per Arm
Per-protocol: Aspirin 91, VKA 82; Full analysis: Aspirin 100, VKA 94
Bottom Line
Non-inferiority of aspirin to vitamin K antagonists was not demonstrated. The primary composite endpoint occurred in 23% of aspirin-treated patients versus 15% of VKA-treated patients. All seven ischemic strokes occurred in the aspirin group. The evidence does not support replacing anticoagulation with aspirin as the standard of care in cervical artery dissection.
Major Points
- Multicenter, randomized, open-label, non-inferiority trial comparing aspirin 300 mg daily to vitamin K antagonists (INR 2.0-3.0) for 90 days in cervical artery dissection
- Primary composite endpoint (clinical + MRI outcomes) occurred in 23% of aspirin group vs 15% of VKA group (absolute difference 8%; 95% CI -4 to 21; non-inferiority p=0.55)
- Non-inferiority margin was 12%; upper CI limit of 21% exceeded margin, so non-inferiority was NOT shown
- All 7 ischemic strokes (8%) occurred in the aspirin group; none in VKA group; all strokes occurred on day 1 or day 7
- One major hemorrhage (upper GI bleed) occurred in VKA group; none in aspirin group; no deaths
- MRI outcomes: 22% aspirin vs 13% VKA had new ischemic or hemorrhagic brain lesions
- Sensitivity analyses including clinical-only and MRI-only outcomes were concordant with primary analysis
- Results do not support replacement of anticoagulation with aspirin as standard of care, though superiority of VKA was also not proven
Design
Study Type: Phase 3, multicenter, randomized, open-label, non-inferiority trial with blinded outcome assessment
Randomization: 1
Blinding: Open-label for treatment allocation; independent imaging core laboratory adjudicators were masked to treatment; clinical event adjudicators were aware of allocation
Enrollment Period: September 11, 2013 to December 21, 2018
Follow-up Duration: 90 days (mean 90.8 days aspirin, 90.5 days VKA)
Centers: 10
Countries: Switzerland, Germany, Denmark
Sample Size: 194
Analysis: Per-protocol population for primary analysis (n=173); absolute risk difference with 95% CI using Wilson's method; non-inferiority tested using Z statistics; sensitivity analyses including full analysis set with worst-case/best-case imputation and inverse probability weighting; R software version 3.6.3
Inclusion Criteria
- Age >18 years
- Acute ischemic symptoms (TIA or ischemic stroke) OR non-ischemic local signs of cervical artery dissection
- Symptom onset within 2 weeks before enrollment
- Cervical artery dissection confirmed by MRI according to accepted diagnostic criteria
- For patients with preceding IV thrombolysis or endovascular treatment, enrollment allowed only after 24-hour latency period
- Written informed consent obtained
Exclusion Criteria
- Pregnancy
- Contraindications to MRI
- Contraindications to aspirin use
- Contraindications to anticoagulation (vitamin K antagonists or heparin)
Arms
| Field | Aspirin | Control |
|---|---|---|
| Intervention | Oral aspirin 300 mg once daily; intravenous aspirin 250 mg once daily allowed for patients with dysphagia until swallowing function recovered; low-dose prophylactic heparin for DVT prevention allowed | Phenprocoumon, acenocoumarol, or warfarin according to local practice with target INR 2.0-3.0; bridging with IV heparin or low-molecular-weight heparin recommended until target INR reached (54% received bridging) |
| Duration | 90 days or until occurrence of primary endpoint | 90 days or until occurrence of primary endpoint |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Composite of clinical outcomes (ischemic stroke, major extracranial or intracranial hemorrhage, or death) and MRI outcomes (new ischemic or hemorrhagic brain lesions) at 14 days (clinical and MRI) and 90 days (clinical only) | Primary | 12/82 (15%) | 21/91 (23%) | 0.55 (non-inferiority) | |
| Clinical outcomes only (per-protocol) | Secondary | 1/82 (1%) | 7/91 (8%) | ||
| Ischemic stroke | Secondary | 0/82 (0%) | 7/91 (8%) | ||
| Major extracranial hemorrhage | Secondary | 1/82 (1%) | 0/91 (0%) | ||
| Symptomatic intracranial hemorrhage | Secondary | 0/82 (0%) | 0/91 (0%) | ||
| Death | Secondary | 0/82 (0%) | 0/91 (0%) | ||
| MRI outcomes (all new lesions) | Secondary | 11/82 (13%) | 20/91 (22%) | ||
| New acute ischemic brain lesion on MRI | Secondary | 6/82 (7%) | 9/91 (10%) | ||
| New hemorrhagic brain lesion on MRI | Secondary | 4/82 (5%) | 9/91 (10%) | ||
| New acute ischemic AND hemorrhagic lesion on MRI | Secondary | 1/82 (1%) | 2/91 (2%) | ||
| MRI outcomes without clinical symptoms | Secondary | 11/82 (13%) | 14/91 (15%) | ||
| Recurrent dissection | Secondary | 2/82 (2%) | 3/91 (3%) | ||
| Increase of vessel wall haematoma | Secondary | 1/82 (1%) | 1/91 (1%) | ||
| Transient ischemic attack | Secondary | 2/82 (2%) | 0/91 (0%) | ||
| Excellent functional outcome (mRS 0-1 at 3 months) | Secondary | 62/81 (77%) | 70/91 (77%) | ||
| Independence in ADL (mRS 0-2 at 3 months) | Secondary | 80/81 (99%) | 88/91 (97%) | ||
| Total adverse events | Adverse | 26 events | 19 events | ||
| Serious adverse events | Adverse | 6 events | 1 event | ||
| Treatment discontinuation due to adverse events | Adverse | 3 patients (crossover to aspirin) | 2 patients (1 discontinuation, 1 dose reduction) |
Subgroup Analysis
Post-hoc sensitivity analyses: (1) As-treated population including crossovers showed absolute difference 7% (95% CI -5 to 19), consistent with primary analysis; (2) Excluding new subclinical hemorrhagic brain lesions showed difference 3% (95% CI -7 to 14); (3) Excluding patients with acute recanalisation procedures before enrollment showed difference 5% (95% CI -8 to 18). Clinical outcomes only analysis showed 7% difference (95% CI -1 to 14). MRI outcomes only analysis showed 9% difference (95% CI -4 to 21). Study-level meta-analysis combining CADISS and TREAT-CAD clinical outcomes showed aspirin 5% vs VKA 2% (absolute difference 3%, 95% CI -1 to 8, p=0.12).
Criticisms
- Large non-inferiority margin of 12% was not statistically guided due to absence of reliable data at trial design; the margin reflected clinical judgment rather than calculated estimates
- Large 95% CI for primary endpoint (-4 to 21%) indicates poor precision for observed treatment effect difference
- Open-label design with clinical event adjudicators aware of treatment allocation introduces potential bias
- Composite primary endpoint combining clinical and MRI outcomes may not weight all components equally or reflect same treatment response
- Non-inferiority design cannot demonstrate that aspirin is inferior or that VKA is superior
- Numerically higher frequency of acute recanalisation procedures before enrolment in aspirin group (15 aspirin vs 8 VKA patients; overall 23 [26%] of 90 patients presenting with stroke) could confound results despite 24-hour enrollment delay
- Bridging therapy with heparin/LMWH in VKA group (54%) may have provided better early protection against day 1 strokes compared to aspirin alone
- Trial excluded direct oral anticoagulants due to regulatory constraints at time of study design
- Relatively small sample size (173 per-protocol) limits power for subgroup analyses
- Most participants had minor-to-moderate strokes, TIAs, or non-ischemic symptoms; applicability to major/disabling stroke unclear
- MRI outcomes without clinical symptoms have uncertain clinical significance
Funding
Swiss National Science Foundation (grant 140340), Swiss Heart Foundation, Stroke Funds Basel, University Hospital Basel, University of Basel, Academic Society Basel
Based on: TREAT-CAD (The Lancet Neurology, 2021)
Authors: Stefan T Engelter, Christopher Traenka, Henrik Gensicke, ..., and TREAT-CAD Investigators
Citation: Lancet Neurol 2021;20:341-350
Content summarized and formatted by NeuroTrials.ai.