ATAMIS
Clopidogrel Plus Aspirin vs Aspirin Alone in Patients With Acute Mild to Moderate Stroke: The ATAMIS Randomized Clinical Trial
Year of Publication: 2024
Authors: Hui-Sheng Chen, Yu Cui, Xin-Hong Wang, ..., for the ATAMIS investigators
Journal: JAMA Neurology
Citation: JAMA Neurol. 2024;81(5):450-460.
Link: https://jamanetwork.com/journals/jamaneu...article/2816997
PDF: Clinical Question
Does dual antiplatelet therapy with clopidogrel + aspirin reduce early neurologic deterioration at 7 days compared with aspirin alone in patients with acute mild to moderate ischemic stroke (NIHSS 4-10) not eligible for reperfusion therapy?
Bottom Line
DAPT reduced early neurologic deterioration at 7 days (4.8% vs 6.7%; RD -1.9%; RR 0.71; 95% CI 0.53-0.96; P=0.03) in NIHSS 4-10 stroke. No significant bleeding increase (0.7% vs 1.0%). However, no improvement in 90-day functional outcome (mRS 0-1: 76.9% vs 74.6%; P=0.14). Benefit was time-sensitive: significant only within <24 hours (P interaction=0.01).
Major Points
- Primary endpoint met: END at 7 days 4.8% (DAPT) vs 6.7% (aspirin); RD -1.9%; RR 0.71 (0.53-0.96; P=0.03).
- Fills evidence gap: CHANCE/POINT targeted NIHSS ≤3; ATAMIS specifically studied NIHSS 4-10.
- No 90-day functional benefit: mRS 0-1 76.9% vs 74.6% (RD 2.4%; P=0.14). Short 14-day DAPT duration may explain.
- Time-sensitive: benefit only within <24h (RD -3.6%; P=0.01 interaction). No benefit at ≥24h (RD +0.6%).
- No bleeding increase: any bleeding 0.7% vs 1.0% (P=0.35); sICH 0.1% vs 0.1%. Lower than CHANCE (2.3%).
- Predominantly undetermined etiology (61%) and small vessel (30%). Large artery only 7.5-7.9%.
- NIHSS ≥7 subgroup showed larger benefit (RD -4.6%) though interaction NS (P=0.21).
- Open-label PROBE design with blinded endpoints at 66 Chinese hospitals.
- 14-day DAPT then aspirin monotherapy through Day 90. 2,915 patients (mITT).
- Novel primary endpoint (END at 7 days) vs traditional stroke recurrence — clinically meaningful but different from CHANCE/POINT.
Design
Study Type: Multicenter, randomized, open-label, blinded endpoint (PROBE) trial
Randomization: 1
Blinding: Open-label; blinded endpoint assessors. Simple randomization via computer-generated sequence.
Enrollment Period: December 20, 2016 to August 9, 2022
Follow-up Duration: 90 days
Centers: 66
Countries: China
Sample Size: 2915
Analysis: Modified ITT. Generalized linear models (RD, RR). 80% power to detect 2.62% reduction (from 7.5% to 4.88%).
Inclusion Criteria
- Adults ≥18 years.
- Acute ischemic stroke at randomization.
- NIHSS score 4-10.
- Prestroke mRS ≤1.
- Within 48 hours of symptom onset.
- CT or MRI confirming ischemic stroke.
Exclusion Criteria
- Eligible for IV thrombolysis or endovascular therapy.
- Clear indication for anticoagulation.
- History of intracerebral hemorrhage.
- Planned carotid revascularization.
- GI or urinary bleeding in last 3 months.
- Allergy to clopidogrel or aspirin.
Baseline Characteristics
| Characteristic | Clopidogrel + Aspirin (N=1,502) | Aspirin Alone (N=1,413) |
|---|---|---|
| Age (mean±SD) | 65.7±10.3 | 66.1±10.8 |
| Male | 972 (64.7%) | 923 (65.3%) |
| Hypertension | 931 (62.0%) | 879 (62.2%) |
| Diabetes | 401 (26.7%) | 341 (24.1%) |
| Previous ischemic stroke | 482 (32.3%) | 457 (32.4%) |
| Current smoker | 503 (33.8%) | 464 (33.1%) |
| NIHSS median (IQR) | 5 (4-6) | 5 (4-6) |
| NIHSS <7 | 1,244 (82.8%) | 1,153 (81.6%) |
| NIHSS ≥7 | 258 (17.2%) | 260 (18.4%) |
| Time onset to randomization (mean±SD) | 19.1±13.1 h | 19.8±14.5 h |
| Time <24h | 902 (60.1%) | 855 (60.5%) |
| SBP (mean±SD) | 154.4±21.6 mmHg | 154.3±21.9 mmHg |
| Etiology — Undetermined | 917 (61.2%) | 855 (60.6%) |
| Etiology — Small vessel | 454 (30.3%) | 444 (31.5%) |
| Etiology — Large artery | 119 (7.9%) | 106 (7.5%) |
| Anterior circulation | 910/1,317 (69.1%) | 870/1,190 (73.1%) |
Arms
| Field | Clopidogrel + Aspirin | Control |
|---|---|---|
| Intervention | Day 1: clopidogrel 300 mg + aspirin 100 mg loading. Days 2-14: clopidogrel 75 mg/day + aspirin 75 mg/day. Days 15-90: aspirin 100 mg/day alone. | Days 1-14: aspirin 100-300 mg/day. Days 15-90: aspirin 100 mg/day. |
| Duration | 14 days DAPT, then aspirin monotherapy to Day 90 | 90 days |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Early neurologic deterioration at 7 days (NIHSS increase ≥2 points from baseline, excluding hemorrhage/metabolic causes) | Primary | 95/1,413 (6.7%) | 72/1,502 (4.8%) | 0.03 | |
| mRS 0-1 at 90 days | Secondary | 1,015/1,361 (74.6%) | 1,130/1,470 (76.9%) | RR 1.10 | 0.14 |
| mRS shift at 90 days | Secondary | — | — | OR 1.10 | 0.19 |
| New stroke within 90 days | Secondary | 13/1,361 (1.0%) | 12/1,470 (0.8%) | HR 0.86 | 0.70 |
| All-cause death within 90 days | Secondary | 12/1,361 (0.9%) | 16/1,471 (1.1%) | HR 1.24 | 0.58 |
| Any bleeding | Adverse | 14/1,442 (1.0%) | 10/1,521 (0.7%) | RR 0.68 | 0.35 |
| sICH | Adverse | 1/1,442 (0.1%) | 1/1,521 (0.1%) | 0.97 | |
| Intracranial hemorrhage | Adverse | 2/1,442 (0.1%) | 1/1,521 (0.1%) | 0.54 |
Subgroup Analysis
Significant interaction by time from onset (P=0.01): <24h RD -3.6% (95% CI -6.0 to -1.1); ≥24h RD +0.6% (-1.4 to 2.7). NIHSS ≥7: RD -4.6% (-8.8 to -0.3) vs <7: RD -1.3% (-3.2 to 0.5; P interaction=0.21). Anterior circulation: RD -2.4% (-4.8 to -0.1) vs posterior: RD -0.8% (-3.8 to 2.2; P=0.28).
Criticisms
- Sample size imbalance (1,541 vs 1,459) from simple randomization.
- Open-label PROBE design.
- 82.8% had NIHSS 4-5 (mild end) — limited power for moderate stroke subgroup.
- Excluded thrombolysis/EVT patients.
- 14-day DAPT only — shorter than CHANCE (21 days).
- Chinese population only.
- No 90-day functional benefit despite primary endpoint being met.
- Benefit only within <24h (P interaction=0.01).
Funding
Science and Technology Project Plan of Liao Ning Province (2014225008).
Based on: ATAMIS (JAMA Neurology, 2024)
Authors: Hui-Sheng Chen, Yu Cui, Xin-Hong Wang, ..., for the ATAMIS investigators
Citation: JAMA Neurol. 2024;81(5):450-460.
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