Key Points
Question
Is dual antiplatelet therapy superior to aspirin alone in patients with acute mild to moderate ischemic stroke?
Findings
In this randomized clinical trial that included 3000 participants, early neurologic deterioration at 7 days occurred in significantly fewer participants randomized to dual antiplatelet therapy vs those randomized to receive aspirin alone.
Meaning
The findings indicate that dual antiplatelet therapy, compared with aspirin alone, may be a superior treatment option in patients with acute mild to moderate ischemic stroke.
This randomized clinical trial evaluates the use of dual vs single antiplatelet therapy in the treatment of patients with mild to moderate ischemic stroke.
Abstract
Importance
Dual antiplatelet therapy has been demonstrated to be superior to single antiplatelet in reducing recurrent stroke among patients with transient ischemic attack or minor stroke, but robust evidence for its effect in patients with mild to moderate ischemic stroke is lacking.
Objective
To evaluate whether dual antiplatelet therapy is superior to single antiplatelet among patients with mild to moderate ischemic stroke.
Design, Setting, and Participants
This was a multicenter, open-label, blinded end point, randomized clinical trial conducted at 66 hospitals in China from December 20, 2016, through August 9, 2022. The date of final follow-up was October 30, 2022. The analysis was reported on March 12, 2023. Of 3065 patients with ischemic stroke, 3000 patients with acute mild to moderate stroke within 48 hours of symptom onset were enrolled, after excluding 65 patients who did not meet eligibility criteria or had no randomization outcome.
Interventions
Within 48 hours after symptom onset, patients were randomly assigned to receive clopidogrel plus aspirin (n = 1541) or aspirin alone (n = 1459) in a 1:1 ratio.
Main Outcomes and Measures
The primary end point was early neurologic deterioration at 7 days, defined as an increase of 2 or more points in National Institutes of Health Stroke Scale (NIHSS) score, but not as a result of cerebral hemorrhage, compared with baseline. The superiority of clopidogrel plus aspirin to aspirin alone was assessed based on a modified intention-to-treat population, which included all randomized participants with at least 1 efficacy evaluation regardless of treatment allocation. Bleeding events were safety end points.
Results
Of the 3000 randomized patients, 1942 (64.6%) were men, the mean (SD) age was 65.9 (10.6) years, median (IQR) NIHSS score at admission was 5 (4-6), and 1830 (61.0%) had a stroke of undetermined cause. A total of 2915 patients were included in the modified intention-to-treat analysis. Early neurologic deterioration occurred in 72 of 1502 (4.8%) in the dual antiplatelet therapy group vs 95 of 1413 (6.7%) in the aspirin alone group (risk difference −1.9%; 95% CI, −3.6 to −0.2; P = .03). Similar bleeding events were found between 2 groups.
Conclusions and Relevance
Among Chinese patients with acute mild to moderate ischemic stroke, clopidogrel plus aspirin was superior to aspirin alone with regard to reducing early neurologic deterioration at 7 days with similar safety profile. These findings indicate that dual antiplatelet therapy may be a superior choice to aspirin alone in treating patients with acute mild to moderate stroke.
Trial Registration
ClinicalTrials.gov Identifier: NCT02869009
Introduction
Reperfusion and thrombolytic therapies are effective strategies in the treatment of acute ischemic stroke.1,2 However a subset of patients with acute ischemic stroke are not eligible for reperfusion therapies due to a limited therapeutic window and access to endovascular care.3 According to current guidelines, almost all patients with acute ischemic stroke receive an antithrombotic treatment, such as antiplatelet or anticoagulant, to prevent the progression and recurrence of stroke. Antiplatelet therapy with aspirin alone is recommended in patients with acute ischemic stroke who do not receive reperfusion therapy.1,4 Compared with aspirin alone, dual antiplatelet with clopidogrel and aspirin was reported to be more effective for some individuals.5 The Clopidogrel With Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE)6 and Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA (POINT)7 trials found that, in patients who were treated within 24 hours of symptom onset after transient ischemic attack or minor ischemic stroke (defined as National Institutes of Health Stroke Scale [NIHSS] score ≤3), dual antiplatelet with clopidogrel and aspirin reduced the risk of recurrent stroke compared with aspirin alone but did not improve clinical outcome. For patients with mild to moderate ischemic stroke, aspirin monotherapy is recommended by stroke guidelines1; however, early neurologic deterioration remains a challenge to overcome in this population, given the association of early neurologic deterioration with clinical outcome.8
Up to 50% of early neurologic deterioration occurs within 48 hours after transient ischemic attack or acute ischemic stroke onset.8 The Fast Assessment of Stroke and Transient Ischemic Attack to Prevent Early Recurrence (FASTER)9 trial suggested some evidence of benefit with early clopidogrel and aspirin in patients at high risk of recurrent stroke. Two previous studies10,11 found that in patients with acute mild to moderate ischemic stroke (NIHSS score ≤7 or 14) within 48 hours of symptom onset, dual antiplatelet with clopidogrel and aspirin may be superior to aspirin alone with comparable safety profile. In theory, intensive antithrombotic therapy, such as clopidogrel and aspirin, could reduce early neurologic deterioration and improve clinical outcome if the hemorrhagic risk can be contained. Nonetheless, there is a lack of robust evidence for dual antiplatelet in this patient population.
In this context, we conducted the Antiplatelet Therapy in Acute Mild to Moderate Ischemic Stroke (ATAMIS) trial to determine whether dual antiplatelet with clopidogrel and aspirin would be superior to aspirin alone in patients with acute mild to moderate ischemic stroke (NIHSS score 4-10) presenting within 48 hours of symptom onset.
Methods
Study Design
ATAMIS was a multicenter, open-label, blinded end point, randomized clinical trial to assess the efficacy and safety of clopidogrel plus aspirin in patients with mild to moderate ischemic stroke within 48 hours of symptom onset. The study protocol and the statistical analysis plan are in Supplement 1. The trial was conducted at 66 sites (eMethods in Supplement 2) in China. Details of the study design and rationale have been published.12 The trial protocol was approved by the regulatory and Ethics Committee of the General Hospital of Northern Theatre Command and other participating hospitals. An independent data monitoring committee monitored the progress of the trial every 6 months. Written informed consent was obtained from patients or their legally authorized representative. The ATAMIS trial was registered at ClinicalTrials.gov (NCT02869009). This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Participants
Eligible patients were adults 18 years and older with acute ischemic stroke at the time of randomization (baseline NIHSS score 4-10; range from 0 to 42, with higher scores indicating greater stroke severity) who had been functioning independently (modified Rankin Scale [mRS] scores ≤1; range from 0 [no symptoms] to 6 [death]) before a stroke and were enrolled up to 48 hours after the onset of stroke symptoms (time last seen well). Head computed tomography or magnetic resonance imaging was performed on admission to identify patients with ischemic stroke. If a patient met eligibility criteria for intravenous thrombolysis or endovascular therapy, then they received this as standard of care and were excluded from the trial. Other exclusion criteria were as follows: had a clear indication for anticoagulation, had a history of intracerebral hemorrhage, was planned for carotid revascularization, had gastrointestinal or urinary tract bleeding in the last 3 months, and had an allergy to clopidogrel or aspirin. A full list of inclusion and exclusion criteria is in the study protocol (Supplement 1).
Randomization and Masking
Eligible patients were randomly assigned to either the clopidogrel plus aspirin group or the aspirin alone group with the simple randomization (1:1) method, through a computer-generated random sequence that was centrally administered via a password-protected web-based program at http://atamis.medsci.cn (Shanghai Meisi Medical Technology Co). The study team members were unblinded to the treatment allocation.
Procedures
Patients were randomly assigned to the clopidogrel plus aspirin group (300-mg loading dose of clopidogrel plus aspirin, 100 mg; followed by clopidogrel, 75 mg/d, and aspirin, 100 mg/d, from day 2 to day 14 and clopidogrel, 75 mg/d, or aspirin, 100 mg/d, from day 15 to day 90) or the aspirin alone group (100 to 300 mg aspirin from day 1 to day 14, followed by aspirin, 100 mg/d, from day 15 to day 90).10 All patients received guideline-based stroke care for vascular risk factor control, including statins if eligible.1 Details of the study procedure are in the eMethods in Supplement 2.
The NIHSS was used to assess the neurologic status at baseline, 7 days, and 14 days after randomization. A detailed flowchart of the assessment schedule is provided in the study protocol (Supplement 1). Data on demographic and clinical characteristics were obtained at randomization. Follow-up data were collected at 7 days, 14 days (or at hospital discharge if earlier), and 90 days after randomization. Remote and on-site quality control monitoring and data verification were conducted throughout the study.
Outcomes
The primary end point was the presence of early neurologic deterioration at 7 days, defined as an increase in the NIHSS score of 2 or more points (excluding cerebral hemorrhage, hypoglycemia, cardiac complications, fever, and infection) compared with baseline.11 The primary end point was modified from the original definition (≥1 increase in NIHSS compared with baseline at 14 days) and published definition (≥4 point increase in the NIHSS score in 48 hours)12 to the current definition prior to analysis. The modification rationale is explained in detail in Supplement 1.
The secondary end points were excellent functional outcome at 90 days, defined as a mRS score of 0 to 1; a shift in the distribution of the mRS score at 90 days; change in NIHSS score compared with baseline at 14 days; the occurrence of new ischemic or hemorrhagic stroke13 within 90 days; and the occurrence of other vascular events (pulmonary embolism, peripheral vascular, or cardiovascular event) or death within 90 days.
Any bleeding event or other adverse event that occurred during the study period was recorded. The prespecified adverse event outcomes were mucocutaneous hemorrhage, organ hemorrhage, or intracranial hemorrhage (per Heidelberg bleeding classification) within 14 days and severe adverse events.
Follow-up NIHSS scores were evaluated by a certified neurologist, who was blinded to the treatment allocation. The final follow-up was performed at 90 days in person or, if an in-person visit was not possible, a structured interview for telephone assessment (eMethods in Supplement 2) was performed by a trained and certified staff member in each center who was unaware of the randomized treatment assignment. A training course was held for all investigators at each center to ensure the validity and reproducibility of the evaluation. Only certified investigators were eligible to evaluate the NIHSS or mRS score. Central adjudication of clinical outcomes and adverse events was performed by assessors who were unaware of treatment allocation or patient clinical details. If there was disagreement between the local and central assessors, a consensus was reached by discussion. The local assessor retained control of the NIHSS and final mRS score following discussion.
Sample Size Calculation
Power calculations were based on the estimated treatment effects with a binary assessment of early neurologic deterioration at 7 days. Based on our previous study10 reporting 6% early neurologic deterioration (defined as an increase in ≥2 NIHSS points compared with baseline at 14 days) in patients receiving aspirin monotherapy with similar characteristics to this current trial, we assumed a 7.5% rate of early neurologic deterioration (defined as ≥2 NIHSS point increase compared with baseline at 7 days) in the aspirin alone group in this trial, and that clopidogrel plus aspirin would result in a 35% reduction of early neurologic deterioration compared with aspirin alone, namely to 4.88% in the clopidogrel plus aspirin group. A sample size of 2638 (1319 per group) was estimated to provide more than 80% power (using a 2-sided α = .05) to detect the 2.62% lower rate of early neurologic deterioration in the clopidogrel plus aspirin group. Assuming a 12% loss to follow-up, the total sample size was 2998. Therefore, this study was planned to include 3000 participants (1500 participants per group). The sample size calculation was also revised (Supplement 1).
Statistical Analysis
Statistical analyses were performed on the modified intention-to-treat population, which included all randomized participants with at least 1 valid postbaseline efficacy evaluation. Generalized linear models were performed for the analyses of the primary outcome of 7-day early neurologic deterioration and secondary outcomes of excellent functional outcome at 90 days. The treatment effects for the above outcomes were presented as risk differences (RDs) and risk ratios (RRs) with 95% CIs. In sensitivity analyses, missing values in the primary outcome were imputed using the last observation carried forward, worst-case scenario, and best-case scenario approaches. No interim analyses were performed in this study.
The 90-day mRS score was compared using ordinal logistic regression with treatment effect presented as odds ratio (OR) with 95% CI. The odds proportionality assumption for treatment was assessed by a likelihood ratio test. A generalized linear model was used to compare changes in log (NIHSS score +1) between admission and 14 days, and a geometric mean ratio with 95% CI was calculated between the 2 groups. Time-to-event outcomes of new ischemic or hemorrhagic stroke within 90 days and other vascular or death events were compared using Cox regression models, and the corresponding treatment effects were presented as hazard ratios (HRs) with 95% CIs. The hazard proportionality assumption was tested by introducing an interaction between time and treatment in the Cox model.
The primary analyses of the primary and secondary outcomes were unadjusted. Covariate adjusted generalized linear model analyses were performed for all outcomes, adjusting for 7 prespecified prognostic factors: age, sex, history of diabetes, history of hypertension, NIHSS score at randomization, time from symptom onset to antiplatelet treatment, and stroke etiology. The degree of responsible vessel stenosis and location of responsible vessel were planned in the covariate adjusted analyses but were excluded due to a skewed distribution or a large proportion of missing values. The missing values of baseline variables in the covariate adjusted analyses were imputed using simple imputation methods based on their sample distributions. For example, for a continuous variable, missing values were imputed from random values generated from a normal distribution with mean and standard deviation with a prespecified seed calculated from the available sample.
Subgroup analysis of the primary outcome was performed using generalized linear model on 9 prespecified subgroups (age [<65 years or ≥65 years], sex [female or male], history of diabetes, history of hypertension, NIHSS score at randomization [<7 or ≥7], time from symptom onset to antiplatelet therapy [<24 hours or ≥24 hours], stroke etiology, degree of responsible vessel stenosis [≤50% vs >50%] measured by computed tomography angiography or magnetic resonance angiography according to the Warfarin-Aspirin Symptomatic Intracranial Disease method of measurement,14 and location of responsible vessel [anterior circulation vs posterior circulation vs anterior and posterior circulation]). Assessment of the homogeneity of the treatment effect by a subgroup variable was conducted using a generalized linear model with the treatment, subgroup variable, and their interaction term as independent variables, and the P value for the interaction term was presented. In addition, per-protocol analyses for primary and secondary outcomes were performed on patients who received complete intervention as specified in the protocol. Detailed statistical analyses are described in the statistical analysis plan (Supplement 1).
A 2-sided P value less than .05 was considered statistically significant. Because of the potential for a type I error due to multiple comparisons, findings for secondary outcome analyses should be interpreted as exploratory. SPSS version 23 (IBM) and R version 4.1.0 (R Foundation) were used for the statistical analyses.
Results
Trial Population
Between December 20, 2016, and August 9, 2022, 3005 patients were enrolled, and 3000 (1942 [64.6%] were men and 1063 [35.4%] women; mean [SD] age, 65.9 [10.6] years; median [IQR] NIHSS score at admission, 5 [4-6]; 1830 [61.0%] with stroke of undetermined cause) were randomly assigned to the clopidogrel plus aspirin group (1541 patients) or the aspirin alone group (1459 patients) after excluding 5 patients due to randomization error. A total of 85 patients (2.8%) were further excluded (63 withdrew consent, 13 for duplicate randomization, and 9 were lost to follow-up). Finally, the modified intention-to-treat population included 2915 patients (1502 in the clopidogrel plus aspirin group and 1413 in the aspirin alone group) (Figure 1 and eFigure 1 in Supplement 2). The procedure was completed according to protocol for 2763 patients (1433 in the clopidogrel plus aspirin group and 1330 in the aspirin alone group), and the results were included in the per-protocol analysis. The reasons for the incomplete procedures are provided in Figure 1. The trial was completed in October 2022.
Figure 1. Flow Diagram.
IVT indicates intravenous thrombolysis; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; TIA, transient ischemic attack.
aThe baseline characteristics of patients who dropped out from the modified intention-to-treat population are shown in eTable 4 in Supplement 2.
There were 1964 of 2915 (67.4%) patients with mild neurologic deficit, 939 of 2900 (32.4%; 15 patients with missing data) with a history of ischemic stroke, 111 of 2915 (3.8%) patients with the use of prior antiplatelet therapy. The treatment groups were well balanced with respect to baseline patient characteristics in the modified intention-to-treat population (Table 115) and per-protocol analysis (eTable 1 in Supplement 2). In the clopidogrel plus aspirin group, 1433 of 1502 patients (95.4%) underwent the complete procedure of clopidogrel plus aspirin treatment at a mean (SD) of 19.1 (13.1) hours from symptom onset to antiplatelet treatment. The remaining 69 patients did not complete clopidogrel plus aspirin treatment. In the aspirin alone group, 1330 of 1413 patients (94.1%) underwent the complete procedure of aspirin treatment at a mean (SD) of 19.8 (14.4) hours from symptom onset to antiplatelet treatment. The remaining 83 patients did not complete aspirin treatment.
Table 1. Baseline Characteristics of Patients.
| Characteristic | No. (%) | |
|---|---|---|
| Clopidogrel plus aspirin group (n = 1502) | Aspirin alone group (n = 1413) | |
| Age, y | ||
| Mean (SD) | 65.7 (10.3) | 66.1 (10.8) |
| <65 | 669 (44.5) | 622 (44.0) |
| ≥65 | 833 (55.5) | 791 (56.0) |
| Sex | ||
| Male | 972 (64.7) | 923 (65.3) |
| Female | 530 (35.3) | 490 (34.7) |
| Body mass indexa | ||
| Mean (SD) | 23.7 (2.6) | 23.9 (2.7) |
| <30 | 1478/1501 (98.5) | 1382/1412 (97.9) |
| ≥30 | 23/1501 (1.5) | 30/1412 (2.1) |
| Current smoking, No./total No. (%) | 503/1489 (33.8) | 464/1403 (33.1) |
| Current alcohol use, No./total No. (%)b | 301/1489 (20.2) | 289/1402 (20.6) |
| Comorbidities, No./total No. (%)c | ||
| Hypertension | 931 (62.0) | 879 (62.2) |
| Diabetes | 401 (26.7) | 341 (24.1) |
| Previous ischemic stroked | 482/1491 (32.3) | 457/1409 (32.4) |
| Myocardial infarction | 242/1487 (16.3) | 201/1402 (14.3) |
| Atrial fibrillation | 19/1486 (1.3) | 16/1398 (1.1) |
| Hyperlipidemia | 19/1464 (1.3) | 19/1387 (1.4) |
| Previous transient ischemic attack | 7/1493 (0.5) | 5/1401 (0.4) |
| Time from onset to randomization, h | ||
| Mean (SD) | 19.1 (13.1) | 19.8 (14.5) |
| <24 h | 902 (60.1) | 855 (60.5) |
| ≥24 h | 600 (39.9) | 558 (39.5) |
| Blood pressure at randomization | ||
| Systolic blood pressure, mean (SD), mm Hg | 154.4 (21.6) | 154.3 (21.9) |
| Systolic blood pressure >140 mm Hg | 1006 (67.0) | 959 (67.9) |
| Diastolic blood pressure, mean (SD), mm Hg | 89.6 (12.6) | 89.4 (12.5 |
| Diastolic blood pressure >90 mm Hg | 561 (37.4) | 486 (34.4) |
| Blood glucose, mg/dL | ||
| Mean (SD) | 130.7 (59.3) | 129.8 (59.8) |
| Blood glucose >126 mg/dL | 444/1329 (33.4) | 416/1247 (33.4) |
| NIHSS score at randomization, de | ||
| Median (IQR) | 5 (4-6) | 5 (4-6) |
| <7 | 1244 (82.8) | 1153 (81.6) |
| ≥7 | 258 (17.2) | 260 (18.4) |
| Estimated premorbid function (mRS)f | ||
| No symptoms (score 0) | 1056 (70.3) | 1016 (71.9) |
| Symptoms without any disability (score 1) | 443 (29.5) | 396 (28.0) |
| Mild disability (score 2) | 3 (0.2) | 1 (0.1) |
| Presumed stroke cause, No./total No. (%)g | ||
| Undetermined | 917/1499 (61.2) | 855/1410 (60.6) |
| Small artery occlusion | 454/1499 (30.3) | 444/1410 (31.5) |
| Large artery atherosclerosis | 119/1499 (7.9) | 106/1410 (7.5) |
| Other determined causeh | 7/1499 (0.5) | 4/1410 (0.3) |
| Cardioembolic | 2/1499 (0.1) | 2/1410 (0.1) |
| Location of responsible vessel, No./total No. (%)i | ||
| Anterior circulation infarction | 910/1317 (69.1) | 870/1190 (73.1) |
| Posterior circulation infarction | 371/1317 (28.2) | 280/1190 (23.5) |
| Anterior and posterior circulation infarction | 36/1317 (2.7) | 40/1190 (3.4) |
| Degree of responsible vessel stenosis, No./total No. (%)i | ||
| Mild (<50%) | 249/410 (60.8) | 268/412 (65.1) |
| Moderate (50%-69%) | 81/410 (19.8) | 53/412 (12.9) |
| Severe (70%-99%) | 54/410 (13.2) | 66/412 (15.0) |
| Occlusion (100%) | 26/410 (6.3) | 55/412 (7.0) |
| Previous antiplatelet therapy, No./total No. (%) | 61/1502 (4.1) | 50/1413 (3.6) |
| Taking aspirin before randomization | 58/1502 (3.9) | 49/1413 (3.5) |
| Taking clopidogrel before randomization | 3/1502 (0.2) | 1/1413 (0.1) |
| Previous lipid-lowering therapy, No./total No. (%) | 12/1502 (0.2) | 16/1413 (1.1) |
| Time to hospital discharge, mean (SD), d | 11.4 (3.5) | 11.3 (3.5) |
Abbreviations: NIHSS, National Institutes of Health Stroke Scale; mRS, modified Rankin Scale.
Calculated as weight in kilograms divided by height in meters squared.
Alcohol use defined as consuming alcohol at least once a week within 1 year prior to the onset of stroke.
Comorbidities are based on family or patient report.
Prior ischemic stroke refers only to patients with a premorbid mRS score ≤1.
Scores on the NIHSS range from 0 to 42, with higher scores indicating more severe neurologic deficit. A median NIHSS of 5 indicates mild to moderate neurologic deficit.
Scores on the modified mRS of functional disability range from 0 (no symptoms) to 6 (death).
The presumed stroke cause was classified according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST)15 using clinical findings, brain imaging, and laboratory tests.
Other causes included nonatherosclerotic vasculopathies, hypercoagulable states, and hematologic disorder.
The location and degree of stenosis was determined by cerebral vessel examination. The diagnosis was based on the clinician’s interpretation of the clinical features and examination results at the time of discharge from the hospital.
Primary Outcome
For the primary outcome, the proportion of patients with early neurologic deterioration at 7 days was 4.8% (72/1502) in the clopidogrel plus aspirin group and 6.7% (95/1413) in the aspirin alone group. In the modified intention-to-treat population, there was a significant difference in risk of early neurologic deterioration between the clopidogrel plus aspirin and aspirin alone groups (unadjusted RD, −1.9%; 95% CI, −3.6 to −0.2; P = .03; RR, 0.71; 95% CI, 0.53 to 0.96; P = .03) (Table 2). Given that there were 85 patients who dropped out, sensitivity analyses were performed and similar RD results were observed (eTable 2 in Supplement 2). The difference in risk of early neurologic deterioration remained significant after adjustment for prespecified prognostic variables (RD, −1.9%; 95% CI, −3.6 to −0.2; P = .03; RR, 0.71; 95% CI, 0.53 to 0.96; P = .03) (Table 2). The per-protocol analysis yielded similar results (unadjusted RD, −1.8%; 95% CI, −3.5 to −0.2; P = .03; RR, 0.69; 95% CI, 0.50 to 0.96; P = .03) (eTable 3 in Supplement 2).
Table 2. Efficacy and Safety Outcomes.
| Outcome | Group, No. (%) | Unadjusted | Adjusteda | |||||
|---|---|---|---|---|---|---|---|---|
| Clopidogrel + aspirin group (n = 1502) | Aspirin alone group (n = 1413) | Treatment effect metric | Treatment difference (95% CI) | P value | Treatment effect metric | Treatment difference (95% CI) | P value | |
| Primary outcome | ||||||||
| Early neurologic deterioration within 7 db,c | 72 /1502(4.8) | 95/1413 (6.7) | Risk difference | −1.9 (−3.6 to −0.2) | .03 | Risk difference | −1.9 (−3.6 to −0.2) | .03 |
| Risk ratio | 0.71 (0.53 to 0.96) | .03 | Risk ratio | 0.71 (0.53 to 0.96) | .03 | |||
| Secondary outcomes | ||||||||
| mRS score of 0 to 1 within 90 dc,d | 1130/1470 (76.9) | 1015/1361 (74.6) | Risk difference | 2.4 (−0.8 to 5.6) | .14 | Risk difference | 2.4 (−0.8 to 5.5) | .14 |
| Risk ratio | 1.10 (0.97 to 1.26) | .16 | Risk ratio | 1.10 (0.97 to 1.26) | .16 | |||
| mRS score distribution at 90 dd,e | Odds ratio | 1.10 (0.96 to 1.25) | .19 | Odds ratio | 1.10 (0.96 to 1.26) | .18 | ||
| Change in NIHSS score at 14 d from baseline, median (IQR)f | −0.56 (−0.99 to −0.22) | −0.51 (−1.10 to −0.22) | Geometric mean ratio | 0.00 (−0.05 to 0.04) | .87 | Geometric mean ratio | 0.00 (−0.05 to 0.04) | .89 |
| New stroke within 90 dg | 12/1470 (0.8) | 13/1361 (1.0) | Hazard ratio | 0.86 (0.39 to 1.87) | .70 | Hazard ratio | 0.84 (0.39 to 1.85) | .67 |
| Ischemic stroke | 11/1470 (0.7) | 11/1361 (0.8) | Hazard ratio | 0.93 (0.40 to 2.14) | .86 | Hazard ratio | 0.99 (0.42 to 2.31) | .98 |
| Hemorrhage stroke | 1/1470 (0.1) | 2/1361 (0.1) | Hazard ratio | 0.46 (0.04 to 5.11) | .53 | Hazard ratio | 0.45 (0.04 to 5.05) | .52 |
| Other vascular events or death within 90 dg | 16/1470 (1.1) | 12/1361 (0.9) | Hazard ratio | 1.24 (0.59 to 2.61) | .58 | Hazard ratio | 1.24 (0.59 to 2.63) | .57 |
| All-cause death | 16/1471 (1.1) | 12/1361 (0.9) | Hazard ratio | 1.24 (0.59 to 2.61) | .58 | Hazard ratio | 1.23 (0.58 to 2.63) | .59 |
| Other vascular events | 0/1471 (0.0) | 3/1361 (0.2) | Hazard ratio | 0.01 (0.00 to 154.19) | .37 | Hazard ratio | 0.00 (0.00 to ∞) | .96 |
| Safety outcomesc | ||||||||
| Mucocutaneous hemorrhage | 3/1521 (0.2) | 1/1442 (0.1) | Risk difference | 0.1 (−0.1 to 0.4) | .37 | Risk difference | 0.1 (−0.3 to 0.5) | .38 |
| Risk ratio | 2.84 (0.30 to 27.31) | .37 | Risk ratio | 2.78 (0.29 to 26.73) | .38 | |||
| Organ hemorrhage | 4/1521 (0.3) | 4/1442 (0.3) | Risk difference | 0.0 (−0.4 to 0.4) | .94 | Risk difference | 0.0 (−0.4 to 0.4) | .92 |
| Risk ratio | 0.95 (0.24 to 3.78) | .94 | Risk ratio | 0.93 (0.23 to 3.71) | .92 | |||
| Intracranial hemorrhageh | 1/1521 (0.1) | 2/1442 (0.1) | Risk difference | −0.1 (−0.3 to 0.2) | .54 | Risk difference | −0.1 (−0.3 to 0.2) | .55 |
| Risk ratio | 0.47 (0.04 to 5.22) | .54 | Risk ratio | 0.48 (0.04 to 5.31) | .55 | |||
| Symptomatic intracranial hemorrhage | 1/1521 (0.1) | 1/1442 (0.1) | Risk difference | 0.00 (−0.00 to 0.00) | .97 | Risk difference | 0.00 (−0.00 to 0.00) | .96 |
| Asymptomatic intracranial hemorrhage | 0 | 1/1442 (0.1) | Risk ratio | NA | NA | NA | NA | NA |
| Any bleeding events | 10/1521 (0.7) | 14/1442 (1.0) | Risk difference | −0.3 (−1.0 to 0.3) | .35 | Risk difference | −0.3 (−1.0 to 0.3) | .34 |
| Risk ratio | 0.68 (0.30 to 1.52) | .35 | Risk ratio | 0.67 (0.30 to 1.51) | .34 | |||
| Adverse events | 132/1521 (8.7) | 138/1442 (9.6) | Risk difference | −0.9 (−3.0 to 1.2) | .40 | Risk difference | −0.9 (−3.0 to 1.2) | .40 |
| Risk ratio | 0.91 (0.72 to 1.14) | .40 | Risk ratio | 0.91 (0.72 to 1.14) | .40 | |||
| Serious adverse events | 8/1521 (0.5) | 5/1442 (0.3) | Risk difference | 0.2 (−0.3 to 0.7) | .47 | Risk difference | 0.2 (−0.3 to 0.7) | .47 |
| Risk ratio | 1.52 (0.50 to 4.63) | .46 | Risk ratio | 1.50 (0.49 to 4.59) | .47 | |||
Abbreviations: mRS, modified Rankin Scale; NA, not applicable; NIHSS, National Institutes of Health Stroke Scale.
Adjusted for prespecified prognostic variables (age, sex, NIHSS score at randomization, time from the onset of symptoms to antiplatelet therapy, stroke etiology, history of diabetes, and history of hypertension).
Early neurologic deterioration was defined as an increase between baseline and 7 days of ≥2 on the NIHSS score, but not as a result of cerebral hemorrhage.
Calculated using a generalized linear model.
mRS scores range from 0 to 6, where 0 = no symptoms, 1 = symptoms without clinically significant disability, 2 = slight disability, 3 = moderate disability, 4 = moderately severe disability, 5 = severe disability, and 6 = death.
A shift in measures of function according to the full range of scores on the mRS at 90 days was analyzed by ordinal logistic regression, and the χ2 for the likelihood ratio test were 7.34 (P = .20) in the unadjusted analysis and 12.20 (P = .27) in the adjusted analysis.
NIHSS scores range from 0 to 42, with higher scores indicating greater stroke severity. The log (NIHSS+1) was analyzed using a generalized linear model.
Calculated using the Cox regression model.
Intracranial hemorrhage was diagnosed and classified according to the Heidelberg Bleeding Classification system. Symptomatic intracranial hemorrhage was defined as new intracranial hemorrhage detected by brain imaging associated with any of (1) ≥4 points total NIHSS score at the time of diagnosis compared to immediately before worsening (note that a 4-point change is not compared with the baseline admission NIHSS score but instead to the immediate predeterioration neurologic status); (2) ≥2 point change in 1 NIHSS category; (3) leading to intubation, hemicraniectomy, external ventricular drain placement, or other major medical or surgical intervention; and (4) absence of alternative explanation for deterioration. A total of 3 patients were diagnosed with intracranial hemorrhage. One had asymptomatic intracranial hemorrhage with no NIHSS score change. In the other 2, symptomatic intracranial hemorrhages occurred at day 11 and day 87, respectively.
Secondary Outcomes
For the secondary outcomes, no differences were observed in either unadjusted or adjusted analyses, including the risk of new ischemic or hemorrhagic stroke within 90 days, change in NIHSS score compared with randomization at 14 days, mRS improvement at 90 days (Figure 2), and other vascular or death events within 90 days (Table 2). In the per-protocol analysis, similar results were obtained in both unadjusted and adjusted per-protocol analyses (eFigure 2 and eTable 3 in Supplement 2).
Figure 2. Distribution of Modified Rankin Scale Scores at 90 Days by Assigned Treatment.
The raw distribution of scores is shown. Scores ranged from 0 to 6, where 0 = no symptoms, 1 = symptoms without clinically significant disability, 2 = slight disability, 3 = moderate disability, 4 = moderately severe disability, 5 = severe disability, and 6 = death. The odds ratio was 1.10 (95% CI, 0.96-1.25; P = .19); the adjusted odds ratio was 1.10 (95% CI, 0.96-1.26; P = .18).
Prespecified subgroup analysis showed no evidence of effect modification in the risk of early neurologic deterioration between the clopidogrel plus aspirin and aspirin alone groups by age, sex, history of diabetes, history of hypertension, NIHSS score at randomization, stroke etiology, degree of responsible vessel stenosis, and location of responsible vessel, with the exception of time from the onset of symptoms to antiplatelet treatment (<24 hours vs ≥24 hours) (Figure 3). The results of the per-protocol analysis were similar to those of the modified intention-to-treat population for the primary outcome (eFigure 3 in Supplement 2).
Figure 3. Risk Difference for the Primary Outcome According to Prespecified Subgroups.
The primary outcome was early neurological deterioration at 7 days. For subcategories, squares represent point estimates (with the area of the square proportional to the number of events), and horizontal lines represent 95% CIs. National Institutes of Health Stroke Scale (NIHSS) scores range from 0 to 42, with higher scores indicating more severe neurological deficits. For the NIHSS score, subgroups were dichotomized according to the median value.
Adverse Events
Analyses of adverse events were based on the safety population, which consisted of all randomized patients who received at least 1 dose of the study drug. There were no differences in adverse events, including mucocutaneous hemorrhage, organ hemorrhage, intracranial hemorrhage, adverse events, and severe adverse events between the 2 groups (Table 2).
Discussion
To our knowledge, this is the first large-scale, multicenter, randomized clinical trial to investigate the effect of dual antiplatelet treatment in patients with mild to moderate ischemic stroke who are not eligible for intravenous thrombolysis or endovascular therapy presenting within 48 hours of symptom onset. We found that dual antiplatelet therapy with clopidogrel and aspirin reduced the likelihood of early neurologic deterioration at 7 days by 1.9% compared with aspirin alone. Dual antiplatelet therapy with clopidogrel and aspirin, compared with aspirin alone, was not associated with an increased incidence of bleeding events.
Previous studies focused on the role of clopidogrel plus aspirin in the secondary prevention of acute ischemic stroke or high-risk transient ischemic attack.6,7,16,17 Both the CHANCE6 and POINT7 trials evaluated the role of dual antiplatelet in patients with minor stroke or transient ischemic attack as characterized by an NIHSS score of 3 or higher. The Antiplatelet vs R-tPA for Acute Mild Ischemic Stroke (ARAMIS) trial18 evaluated the role of dual antiplatelet therapy compared to intravenous thrombolysis in patients with nondisabling stroke. However there was a lack of evidence for its use in patients with mild to moderate stroke (patients presenting with NIHSS score 4-10), as well as lack of data on its effect on early neurologic function. In the ATAMIS trial, dual antiplatelet with clopidogrel plus aspirin was identified with sufficient power to significantly reduce the incidence of early neurologic deterioration in patients with mild to moderate ischemic stroke. Different from previous trials,6,7,18 the target population in ATAMIS was patients with mild to moderate neurologic deficit (NIHSS score 4 to 10). Additionally, the primary end point in ATAMIS was early neurologic deterioration at 7 days, which was different from the occurrence of stroke or ischemic vascular events within 90 days in the CHANCE6 and POINT7 trials. Given the association of neurologic deterioration after mild to moderate ischemic stroke with poor outcome,19,20 early neurologic deterioration was selected as the primary end point in this trial as a deterioration in 2 points or greater, which can be a clinically meaningful event to the patient. As there were logistical challenges to consistently capture the initial primary end point at 48 hours from randomization, this was changed to the 7-day interval from randomization to optimize completeness in reporting of the primary end point (Supplement 1). The trial was also unique with regard to the short duration of dual antiplatelet treatment (10-14 days). Although a longer duration of dual antiplatelet therapy has been shown to be protective from subsequent ischemic stroke, the higher risk of major hemorrhage over time cannot be ignored.7 As subgroup analysis21 of the CHANCE trial found that the optimal duration of dual antiplatelet therapy may be 14 days, this shorter duration of dual antiplatelet therapy was used in ATAMIS in contrast to the CHANCE6 and POINT7 trials (14 days vs 21 days and 90 days, respectively). In addition, a significant interaction for time of onset (<24 hours vs ≥24 hours) with obvious reduction of early neurologic deterioration was identified for dual antiplatelet therapy in the early-onset group, which suggests that earlier intensive antiplatelet treatment may have a greater effect in reducing the occurrence of early neurologic deterioration. Collectively, the dual antiplatelet therapy of clopidogrel and aspirin with 14 days was proven to improve early neurologic function in mild to moderate ischemic stroke in this trial.
With respect to 90-day functional outcome, we did not find that dual antiplatelet therapy improved functional outcome compared with aspirin alone, although a high probability of excellent functional outcome was found in the clopidogrel plus aspirin group. Given the signal of benefit from antiplatelet therapy in the Efficacy and Safety of Tirofiban Compared with Aspirin in the Treatment of Acute Ischemic Stroke (RESCUE BT2) trial22 in patients with large artery atherosclerosis, we inferred the lack of improved functional outcome with dual antiplatelet therapy in ATAMIS may be attributed to the relatively mild neurological deficits in the enrolled patients (median NIHSS score of 5 in ATAMIS vs 9 in RESCUE-BT2). This proposal was supported by the CHANCE6 and POINT7 trials wherein dual antiplatelet therapy had no effect on 90-day functional outcome. For other secondary end points, there was no difference in change in NIHSS score at 14 days, incidence of new stroke and other vascular events, or all-cause death within 90 days between the 2 groups, which was different from the CHANCE6 and POINT7 trials. This inconsistency may be due to lack of statistical power in the secondary end points and the shorter duration of dual antiplatelet treatment in ATAMIS.
For adverse events, similar rates of symptomatic intracranial hemorrhage were observed between the clopidogrel plus aspirin group and the aspirin alone group, which was consistent with a prior study.7 In this trial, the rate of bleeding events was 0.7%, which was comparable to the 1.6% bleeding rate in the ARAMIS trial.18 However, the 0.7% bleeding rate in ATAMIS was lower than the 2.3% bleeding event rate in the CHANCE trial, despite patients in ATAMIS presenting with a higher severity of disease compared to CHANCE.6 This lower bleeding rate may be due to the shorter duration of dual antiplatelet therapy in the present study, which was comparable to a recent study23 involving patients with mild to moderate ischemic stroke. Collectively, the current results suggest the safety and feasibility of dual antiplatelet therapy in this population.
Limitations
This study has limitations. First, the imbalance in sample size (1541 vs 1459) between groups occurred due to the use of a simple randomization method, which may have reduced the statistical power of the study. Second, due to the open-label design, the present study did not conceal the assigned treatment from participants and physicians. However, the blinded end point assessments were used to reduce measurement bias and ensure that the primary end point was measured objectively. Third, more patients with mild neurologic deficit (67.4%, with NIHSS score 4 to 5) were enrolled in this trial, which may have weakened the statistical power in the analysis of patients with moderate stroke. Fourth, patients receiving thrombolysis and endovascular treatment were excluded, which would limit the generalization of this finding. Fifth, the duration of dual antiplatelet therapy treatment was 14 days, and we do not know the ideal duration of treatment. Moreover, considering that approximately 30% of this patient population had a history of a prior stroke, the use of prior antiplatelet therapy was low in our study, with approximately 4% reporting prior use. This discrepancy may be related to patient compliance with antiplatelet therapy or differences in long-term secondary stroke prevention strategies in this patient population. Sixth, a NIHSS change of 2 points at 7 days may not have been an optimal definition of early neurologic deterioration in this trial, which may have been affected by neurological fluctuation. Seventh, further confirmation of these findings in a non-Chinese population would be of interest, given potential differences in body mass index, comorbidities, secondary stroke prevention strategies, and etiology of patients with acute ischemic stroke across different ethnic populations.
Conclusions
In this study of patients with acute mild to moderate ischemic stroke who are not eligible for intravenous thrombolysis or endovascular therapy, treatment with clopidogrel plus aspirin was superior to aspirin alone with regard to reducing early neurologic deterioration at 7 days with comparable safety profile. Given a lack of improvement of 90-day clinical outcome and the benefit of earlier dual antiplatelet treatment observed in this study, future clinical trials focusing on patients with mild to moderate stroke presenting within 24 hours of symptom onset are needed.
Trial protocol
eAppendix. List of Administrative Staff
eMethods
eResults
eFigure 1. Trial Profile
eFigure 2. Distribution of Modified Rankin Scale Scores at 90 Days in the Per-Protocol Analysis
eFigure 3. Primary Outcome by Prespecified Subgroups in the Per-Protocol Analysis
eTable 1. Baseline Characteristics of Population in the Per-Protocol Analysis
eTable 2. Sensitive Analysis for Dropout Subjects in the Modified Intention-to-treat Analysis
eTable 3. Trial Outcomes in the Per-Protocol Analysis
eTable 4. Causes of Early Neurological Deterioration by Groups
eTable 5. Baseline Characteristics in Dropouts Patients from the Modified Intention-to-treat Population
eReferences
ATAMIS investigators
Data sharing statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial protocol
eAppendix. List of Administrative Staff
eMethods
eResults
eFigure 1. Trial Profile
eFigure 2. Distribution of Modified Rankin Scale Scores at 90 Days in the Per-Protocol Analysis
eFigure 3. Primary Outcome by Prespecified Subgroups in the Per-Protocol Analysis
eTable 1. Baseline Characteristics of Population in the Per-Protocol Analysis
eTable 2. Sensitive Analysis for Dropout Subjects in the Modified Intention-to-treat Analysis
eTable 3. Trial Outcomes in the Per-Protocol Analysis
eTable 4. Causes of Early Neurological Deterioration by Groups
eTable 5. Baseline Characteristics in Dropouts Patients from the Modified Intention-to-treat Population
eReferences
ATAMIS investigators
Data sharing statement