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TREAT-CAD

Biomarkers and Antithrombotic Treatment in Cervical Artery Dissection Trial

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Year of Publication: 2021

Authors: Stefan T Engelter, Christopher Traenka, Henrik Gensicke, ..., and TREAT-CAD Investigators

Journal: The Lancet Neurology

Citation: Lancet Neurol 2021;20:341-350

Link: https://doi.org/10.1016/S1474-4422(21)00044-2

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?

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

FieldAspirinControl
InterventionOral 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 allowedPhenprocoumon, 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 (51% received bridging)
Duration90 days or until occurrence of primary endpoint90 days or until occurrence of primary endpoint

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-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)Primary12/82 (15%)21/91 (23%)0.55 (non-inferiority)
Clinical outcomes only (per-protocol)Secondary1/82 (1%)7/91 (8%)
Ischemic strokeSecondary0/82 (0%)7/91 (8%)
Major extracranial hemorrhageSecondary1/82 (1%)0/91 (0%)
Symptomatic intracranial hemorrhageSecondary0/82 (0%)0/91 (0%)
DeathSecondary0/82 (0%)0/91 (0%)
MRI outcomes (all new lesions)Secondary11/82 (13%)20/91 (22%)
New acute ischemic brain lesion on MRISecondary6/82 (7%)9/91 (10%)
New hemorrhagic brain lesion on MRISecondary4/82 (5%)9/91 (10%)
New acute ischemic AND hemorrhagic lesion on MRISecondary1/82 (1%)2/91 (2%)
MRI outcomes without clinical symptomsSecondary11/82 (13%)14/91 (15%)
Recurrent dissectionSecondary2/82 (2%)3/91 (3%)
Increase of vessel wall haematomaSecondary1/82 (1%)1/91 (1%)
Transient ischemic attackSecondary2/82 (2%)0/91 (0%)
Excellent functional outcome (mRS 0-1 at 3 months)Secondary62/82 (77%)70/91 (77%)
Independence in ADL (mRS 0-2 at 3 months)Secondary80/82 (99%)88/91 (97%)
Total adverse eventsAdverse26 events19 events
Serious adverse eventsAdverse6 events1 event
Treatment discontinuation due to adverse eventsAdverse3 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 in aspirin group (15% vs 8% in patients with stroke) could confound results despite 24-hour enrollment delay
  • Bridging therapy with heparin/LMWH in VKA group (51%) 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

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