STOP-CAD
Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection: The STOP-CAD Study
Year of Publication: 2024
Authors: Shadi Yaghi, MD; Liqi Shu, MD; Daniel Mandel, ..., MD; et al*
Journal: Stroke
Citation: Stroke. 2024;55:908-918. DOI: 10.1161/STROKEAHA.123.045731
Link: https://www.ahajournals.org/doi/10.1161/STROKEAHA.123.045731
PDF: https://www.ahajournals.org/doi/epub/10....EAHA.123.045731
PDF: Clinical Question
To compare outcomes in patients with cervical artery dissection treated with antiplatelets versus anticoagulation regarding stroke prevention and major hemorrhage.
Study Overview
Objective
To compare anticoagulation versus antiplatelet therapy for secondary stroke prevention in patients with cervical artery dissection (CAD).
Study Summary
- No significant difference in ischemic stroke between anticoagulation and antiplatelet
- Ischemic stroke was numerically lower with anticoagulation (1.5% vs 3.3%), but major hemorrhage by day 180 was significantly higher with anticoagulation (adjusted HR 5.56, P=0.009).
- If you plan on anticoagulation, consider switching to antiplatlet after 90-days to avoid risk of major bleeding
- Subgroup analysis shows benefit with anticoagulation in patients with *occlusive dissection*
Intervention
Multinational observational study of 3636 CAD patients, with comparative analysis of exclusive anticoagulation (n=402) vs antiplatelet (n=2453) therapy over 180 days. Additional 781 received both during follow-up.
Patients per Arm
2453 antiplatelet, 402 anticoagulation, 781 mixed
Bottom Line
There was no statistically significant difference in ischemic stroke between antiplatelet and anticoagulation, though ischemic stroke was numerically lower with anticoagulation. However, anticoagulation was associated with a significantly higher risk of major hemorrhage by day 180 (adjusted HR 5.56, 95% CI 1.53–20.13, P=0.009). Subgroup analysis shows benefit with anticoagulation in patients with *occlusive dissection*. If anticoagulation is chosen, switching to antiplatelet therapy before 180 days may be reasonable to lower the risk of major bleeding. Large prospective studies are needed for validation.
Major Points
- The STOP-CAD study was a large multicenter observational retrospective international study involving 3636 patients with cervical artery dissection (CAD).
- It compared antiplatelet therapy (2453 patients) with anticoagulation (402 patients) for stroke prevention and major hemorrhage.
- By day 180, 162 new ischemic strokes (4.4%) and 28 major hemorrhages (0.8%) occurred.
- Anticoagulation was associated with a nonsignificantly lower risk of subsequent ischemic stroke at 30 days (HR 0.71; P=0.145) and 180 days (HR 0.80; P=0.670) compared to antiplatelet therapy.
- In patients with occlusive dissection, anticoagulation showed a significantly lower ischemic stroke risk (adjusted HR 0.40; P_interaction=0.009).
- Anticoagulation was associated with a significantly higher risk of major hemorrhage by day 180 (adjusted HR 5.56, 95% CI 1.53–20.13; P=0.009), but not by day 30 (adjusted HR 1.39; P=0.637).
- The majority of ischemic strokes occurred within the first 30 days (87.0%).
Design
Study Type: Observational Retrospective International Study
Randomization:
Blinding: Outcomes were abstracted from available medical records and reviewed by site principal investigators. Neurologists at the lead site reviewed imaging reports to confirm outcomes.
Follow-up Duration: Up to 180 days
Centers: 63
Countries: Countries not explicitly listed, stated as 16 countries
Sample Size: 3636
Analysis: Adjusted Cox regression models with clustered standard error, inverse probability of treatment weighting (IPTW), propensity-matched analyses with replacement (caliper of 0.05). As-treated crossover approach. STATA/SE version 18.0 and R version 4.3.0.
Inclusion Criteria
- Adult patients aged ≥18 years with cervical artery dissection (CAD).
- CAD without concomitant major trauma.
- Diagnosis based on International Classification of Diseases, Ninth Revision codes (443.21 and 443.24) or Tenth Revision codes (I77.71, I77.74, and I77.75) or institutional registries.
- Clinical suspicion for CAD and imaging confirmation (presence of crescent-shaped hyperintensity in vessel wall, double lumen sign, dissecting pseudoaneurysm, intimal flap, vessel irregularity, or flame-shaped/tapering stenosis/occlusion without atherosclerotic changes).
Exclusion Criteria
- Incidental chronic dissection.
- Major head or neck trauma within the previous 4 weeks (e.g., skull or cervical fractures or hemorrhage).
- Dissecting aneurysm causing primary subarachnoid hemorrhage.
- Iatrogenic dissection.
- Patients with stent placement at the site of dissection on day 0.
- Patients with no antithrombotic treatment.
- Patients treated with both antiplatelet and anticoagulation at the same time.
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Age, y; median (IQR) | 46 (37-56) | 45 (37-54) |
| Female sex | 1111/2453 (45.3%) | 205/402 (51.0%) |
| White race | 1795/2453 (73.2%) | 325/402 (80.8%) |
| Black race | 139/2453 (5.7%) | 21/402 (5.2%) |
| Asian race | 99/2453 (4.0%) | 7/402 (1.7%) |
| Non-Hispanic ethnicity | 1993/2197 (90.7%) | 345/389 (88.7%) |
| Migraine | 408/2453 (16.6%) | 80/402 (19.9%) |
| Hypertension | 865/2453 (35.3%) | 137/402 (34.1%) |
| Diabetes | 207/2453 (8.4%) | 26/402 (6.5%) |
| Hyperlipidemia | 544/2453 (22.2%) | 89/402 (22.1%) |
| Active smoking | 486/2453 (19.8%) | 80/402 (19.9%) |
| Recent COVID-19 infection | 30/2453 (1.2%) | 4/402 (1.0%) |
| Recent upper respiratory infection | 157/2453 (6.4%) | 21/402 (5.2%) |
| Ischemic stroke presentation | 1492/2452 (60.8%) | 239/401 (59.6%) |
| NIHSS score on admission, median (IQR) | 1 (0-5) | 0 (0-3) |
| Acute infarct on imaging | 1349/2453 (55.0%) | 205/402 (51.0%) |
| Baseline hemorrhagic conversion | 94/2453 (3.8%) | 12/402 (3.0%) |
| Occlusive dissection | 816/2425 (33.6%) | 116/399 (29.1%) |
| Partially occlusive thrombus | 159/2453 (6.5%) | 66/402 (16.4%) |
| Intracranial extension | 219/2453 (8.9%) | 38/402 (9.5%) |
| Intracranial dissection | 152/2453 (6.2%) | 11/402 (2.7%) |
| Vertebral dissection | 1220/2453 (49.7%) | 198/402 (49.3%) |
| Intravenous thrombolysis | 321/2453 (13.1%) | 48/402 (11.9%) |
| Endovascular treatment | 381/2453 (15.5%) | 40/402 (10.0%) |
| Days from diagnosis to treatment, median (IQR) | 0 (0-1) | 0 (0-1) |
Arms
| Field | Control | Anticoagulation Group |
|---|---|---|
| Intervention | Patients received exclusively antiplatelet therapy. Dual antiplatelet therapy was defined as a combination of aspirin ≥81 mg and clopidogrel (300 or 600 mg loading dose), ticagrelor, cilostazol, cangrelor, prasugrel, dipiridamole, or triflusal started within 2 days from dissection diagnosis and continued for at least 21 days, potentially followed by a single antiplatelet agent. | Patients received exclusively anticoagulation (parenteral anticoagulation with heparin or low-molecular-weight heparin, or oral anticoagulation with either vitamin K antagonist [VKA] or direct oral anticoagulant [DOAC]). |
| Duration | Up to 180 days (or until censoring) | Up to 180 days (or until censoring) |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Subsequent ischemic stroke during follow-up, defined as new or worsening neurological symptoms lasting for at least 24 hours or <24 hours but with imaging evidence of new or enlarging acute infarction and referable to the territory of the affected artery. | Primary | Ischemic stroke rate 3.3% (P=0.059 vs anticoagulation). Of the 162 subsequent strokes, 130 occurred on antiplatelet therapy. | Ischemic stroke rate 1.5% (P=0.059 vs antiplatelet). Of the 162 subsequent strokes, 32 occurred on anticoagulation. | 0.8 | 0.670 |
| Major Hemorrhage | Adverse | Major hemorrhagic events 0.5% (P=0.484 vs anticoagulation). Of the 28 major hemorrhages, 16 occurred on antiplatelet therapy. | Major hemorrhagic events 0.7% (P=0.484 vs antiplatelet). Of the 28 major hemorrhages, 12 occurred on anticoagulation. | 5.56 (95% CI, 1.53–20.13); adjusted HR by day 180 | 0.009 |
Subgroup Analysis
Anticoagulation was associated with reduced ischemic stroke risk in patients with occlusive dissection (adjusted HR 0.40 [95% CI, 0.18-0.88]; Pinteraction=0.009) but not with nonocclusive dissection (HR 1.34 [95% CI, 0.83-2.14]). No interactions were found for the major hemorrhage outcome.
Criticisms
- Retrospective and observational study design, potentially leading to confounding by indication and residual confounding.
- Lack of central and blinded outcome adjudication.
- Approximately 10% of patients were lost to follow-up after 30 days.
- Findings may not be generalizable to patients in community hospitals or moderate-/low-income countries due to a predominance of tertiary care centers in the study.
- Low number of major hemorrhagic events prevented reliable propensity score matching for this outcome.
- Heterogeneity in the dual antiplatelet therapy group, limiting generalizability to nonclopidogrel-based dual antiplatelet therapy.
- As-treated and crossover approach may have favored treatments started at a later time point.
- Did not analyze imaging data in detail or capture reasons for crossover for patients who switched treatment.
Funding
None
Based on: STOP-CAD (Stroke, 2024)
Authors: Shadi Yaghi, MD; Liqi Shu, MD; Daniel Mandel, ..., MD; et al*
Citation: Stroke. 2024;55:908-918. DOI: 10.1161/STROKEAHA.123.045731
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