Paper: Chen HS et al. Dual Antiplatelet Therapy vs Alteplase for Patients With Minor Nondisabling Acute Ischemic Stroke: the ARAMIS Randomized Clinical Trial. JAMA 2023. PMID: 37367978
Clinical Question: Is dual antiplatelet therapy (DAPT) noninferior to intravenous thrombolysis in patients with minor nondisabling acute ischemic stroke?
What They Did:
- Multicenter, open-label, blinded end point, noninferiority randomized clinical trial
- Antiplatelet vs R-tPA for Acute Mild Ischemic Stroke (ARAMIS)
- 38 hospitals in China from October 2018 to April 2022
- Patients randomized within 4.5 hours of symptom onset to:
- DAPT: 300mg clopidogrel/100mg aspirin day one, followed by 75mg clopidogrel/100mg aspirin for 12 (+/- 2days); followed by guideline-based antiplatelet treatment for 90 days
- Alteplase:9mg/kg; Max dose 90mg; followed by guideline-based antiplatelet treatment beginning 24 hours after receipt of alteplase
Outcomes:
- Primary: Excellent functional outcome (mRs 0 or 1) at 90d
- Noninferiority of DAPT to alteplase was defined on basis of lower boundary of 1-sided 97.5% CI of -4.5%
- Secondary: Favorable functional outcome (mRS 0 to 2) at 90d
- Safety: Symptomatic ICH up to 90d
Inclusion:
- Adult (≥18 years of age) patients
- Acute ischemic stroke with NIHSS ≤5 (with ≤1 point on single-item scores, such as vision, language, neglect, or single limb weakness, and a score of 0 in the consciousness item at the time of randomization)
- Had CT or MRI performed on admission to identify ischemic stroke
- Could start receiving study treatment within 4.5 hours of stroke symptoms
Exclusion:
- Prestroke disability (mRS ≥2)
- History of ICH
- Definite indication for anticoagulation
Results:
- 760 patients with acute, minor, non-disabling stroke (NIHSS ≤5, with ≤1 point on the NIHSS in several key single-time scores) of which 719 patients were in the full analysis
- Median time from onset of symptoms to assigned treatment was 181min
- Median NIHSS score at randomization was 2
- Location of responsible vessel was anterior circulation in 78% of patients
- Excellent Functional Outcome (Primary Outcome):
- DAPT: 93.8%
- Alteplase: 91.4%
- Risk Diff: 2.3%; 95% CI -1.5 to 6.2%
- DAPT statistically noninferior to alteplase
- The finding was consistent in the per-protocol and as-treated groups as well
- Symptomatic ICH at 90d
- DAPT: 0.3%
- Alteplase: 0.9%
- Any Bleeding Events:
- DAPT: 1.6%
- Alteplase 5.4%
- There was no difference in secondary outcomes including mRS score of 0 to 2 at 90d, early neurological improvement within 24hrs, median change in NIHSS score at 24hrs from baseline, and death at 90d
- There was one difference in the secondary outcomes: Less patients had early neurological deterioration at 24 hours in the DAPT group than the alteplase group (4.6% vs 9.1%; -4.5%; 95% CI -8.2 to -0.8%)
Strengths:
- Assessors determining 90d outcomes were unaware of treatment group assignments
- Baseline characteristics were similar between groups with no significant imbalances
- Large sample size, multicenter recruitment, and randomized trial design enhance generalizability of results
- Primary outcome results were confirmed in various sensitivity analyses which provides more trust in the results
Limitations:
- Study team members were unblinded to treatment randomization
- High crossover rate (20.4%) between groups in this trial which could dilute results
- Lack of vessel imaging data in some patients makes subgroup analysis on etiology (large artery vs small artery occlusion) less powerful
- For secondary end points, the neurologist who was unblinded to the treatment assessment conducted early neurological assessment, which may have led to assessment bias for early neurological outcomes
- Patients with possible cardioembolism were excluded and a lower percentage of women than men were enrolled in this trial which could affect the generalizability of these findings to these cohorts
- High rates of the primary endpoint in the DAPT and alteplase groups could have created a celling effect that limited the opportunity for either agent
Discussion:
- Choice of noninferiority margin of -4.5% was based on the Third International Stroke Trial (IST-3), in which subgroup analysis showed a 9% absolute difference in proportion of favorable outcome in patients with minor stroke who were treated with IV alteplase compared with standard medical treatment
- One subgroup did numerically better with alteplase from an excellent neurologic outcome at 90d which was patients with NIHSS score of 4 to 5 at admission; this benefit was lost in patients with NIHSS ≤3 at admission. This result however was statistically not significant (P = 0.33). As this is a subgroup analysis this is a hypothesis generating finding
- Noninferiority design of trial could be deemed as a limitation, however with inconclusive evidence of IV alteplase, increasing number of patients receiving alteplase, and the uncertain benefit of DAPT on 90d mRS score in patients with nondisabling strokes this was the most appropriate trial design. DAPT therapy is cheaper with less potential to harm than standard care (i.e. alteplase).
- The high crossover rate in this trial may dilute results as stated in the limitations. This high crossover rate would actually make DAPT look better in efficacy than it actually is
Author Conclusion: “Among patients with minor nondisabling acute ischemic stroke presenting within 4.5 hours of symptom onset, DAPT was noninferior to intravenous alteplase with regard to excellent functional outcome at 90 days.”
Clinical Take Home Point: In patients presenting with minor nondisabling acute ischemic stroke within 4.5hours of symptom onset, DAPT treatment is noninferior to IV alteplase in regard to excellent functional outcomes at 90d with significantly less risk of hemorrhage. DAPT therapy should be considered as a replacement to standard care with alteplase in this select subgroup of patients with minor nondisabling acute ischemic strokes within 4.5hrs of symptom onset.
References:
- Chen HS et al. Dual Antiplatelet Therapy vs Alteplase for Patients With Minor Nondisabling Acute Ischemic Stroke: the ARAMIS Randomized Clinical Trial. JAMA 2023. PMID: 37367978
Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)
