A comparison of safety and efficacy between long-term DAPT and intensive statins combined with short-term DAPT for acute ischemic stroke

Patients

Patients with mild to moderate AIS admitted to the Emergency Department between January 2017 and December 2019 were recruited. The study was reviewed and approved by the Medical Ethics Committee of our hospital (approval number 2016-065-1). The patients and their legal proxies were informed of the study and signed a consent form.

The inclusion criteria were (1) age ≥ 18 years; (2) onset to medication time (OMT) ≤ 72 h; (3) National Institutes of Health Stroke Scale (NIHSS) scores at registration ≤ 7 points; and (4) head computed tomography (CT) at registration excluding intracranial hemorrhage, and brain magnetic resonance imaging (MRI) showing new infarction lesions within 3 days after registration. The exclusion criteria were (1) intravenous thrombolysis/arterial thrombectomy; (2) taking anticoagulants; (3) other brain diseases such as intracranial tumors, vascular malformations, abscesses, encephalitis, and TIA; (4) severe function disorders of the heart, liver, kidney, lung, immune system, or coagulation, or malignant tumors; and (5) pregnancy or women preparing for pregnancy within 3 months.

In total, 220 patients with focal nerve defect symptoms (excluding simple dizziness/vertigo, ataxia, and sensory or visual impairment) were confirmed via brain MRI, including 102 in the control group and 118 in the study group. There were no withdrawals or unrelated deaths except for 1 patient who died of massive gastrointestinal bleeding in the control group. She was an 84-year-old woman with a known atrial fibrillation and enrolled 70 h after the onset of AIS. During the treatment her existing nerve defect symptoms worsened, she suffered gastrointestinal bleeding on the 12th day, and she died of massive gastrointestinal bleeding on the 15th day of DAPT [17]. Because this patient did not affect efficacy evaluations at 21 days or 90 days, she was not excluded from the statistical analysis (Fig. 1).

Fig. 1figure 1

Enrollment and outcomes (intention-to-treat analysis).

NIHSS is the most commonly used scale for assessing stroke severity, and scores range from 0 to 43. The higher the score the greater the defect, and 0–4 is considered mild, 5–15 is considered moderate, and > 15 is considered severe [18]. Because most severe AIS patients require intravascular treatment (thrombolysis/thrombectomy), only patients with the baseline score of NIHSS (bNIHSS)≤ 7 points were included in the study. bNIHSS ≤ 4 points and bNIHSS > 4 points (5–7 points) were used as the basis for stratification.

Therapy regimen

Due to polymorphism of the liver cytochrome P-450 isoenzyme (clopidogrel-activating enzyme) gene in Asian populations, the clinical efficacy of clopidogrel remains uncertain [19]. Therefore, the DAPT regimen in the current study included aspirin as the main body and clopidogrel as the synergy. The control group received aspirin 100 mg/day (Bayer, 100 mg per tablet, initial dose 300 mg) for 90 days, clopidogrel 75 mg/day (Sanofi, 75 mg per tablet, initial dose 75–300 mg based on clinical symptoms) for 21 days, and rosuvastatin 10 mg/day (Nanjing Chia Tai-Tianqing Pharmaceutical Co., Ltd., 10 mg per tablet) for 90 days.

The study group received aspirin 100 mg/day (100 mg per tablet, initial dose 300 mg) for 90 days, clopidogrel 75 mg/day (75 mg per tablet, initial dose 75–300 mg based on clinical symptoms) for 7 days, and rosuvastatin 20 mg/day (10 mg per tablet) for 21 days, then 10 mg/day for 69 days. The basic treatments were the same and the follow-up time was 90 days in both groups.

Measurement of biomarkers

Venous blood was collected from all patients at registration (before treatment) and after 2 weeks of treatment (14 ± 3 days), and the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatine kinase (CK) were measured using an automatic BS-800M biochemical analyzer (Mindray, China).

Criteria used to evaluate clinical efficacyClinical efficacy over a 21-day period

Yoo et al. [20] reported that a change of  ≥ 2 NIHSS points indicates that a patient’s nerve defect symptoms have changed significantly (improvement or deterioration), and this threshold was used as the basis for judging therapeutic efficacy in the present study. NIHSS scores were determined at eight different time points; before therapy (bNIHSS), 2, 12, 24, and 48 h after therapy, and 1, 2, and 3 weeks after therapy. When the score decreased by ≥ 2 points, one therapeutic effectiveness event and the time of the effectiveness event were recorded (each case was only recorded once). Patients with bNIHSS = 1 and those with an increase in NIHSS score within a 21-day period were treated as deletion events. All patients’ NIHSS scores were jointly assessed by two emergency physicians who had received formal training.

Recurrent ischemic stroke events within 90 days

These events were defined as the appearance of a new focal nerve defect symptom within the 90-day follow-up period, or the rapid worsening of existing focal nerve defect symptoms with a duration of  ≥  24 h, as determined by brain MRI. Non-ischemic factors were excluded (i.e., intracranial infection, trauma, tumor, epilepsy, serious metabolic diseases, and degenerative neurological diseases). When a recurrent ischemic event occurred, one failure event (recurrent ischemic stroke) and the failure time were recorded.

Bleeding events within 90 days

All bleeding events in both groups were recorded over a 90-day period after initial medication. There were several bleeding sites, including intracranial, gastrointestinal, the skin, and the mucosa. All patients with bleeding, including intracranial hemorrhage confirmed by cranial CT, along with gastrointestinal bleeding with occult blood positive for vomit and stools, were recorded as one failure (bleeding) event along with the failure time. In accordance with the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria, bleeding was classified as mild, moderate, or severe, where severe bleeding referred to hemorrhage resulting in hemodynamic compromise requiring vasoactive drug support, fluid or blood replacement, or surgical intervention [17].

Statistical analysis

The study used an incomplete randomized controlled trial design, with type I error α = 0.05 and a test power of (1 − β) = 0.95. G*Power software (Dusseldorf University, Germany) was used to estimate the required sample size. The moderate intensity effect size recommended by the software was 0.3, and the total sample size indicated was 220, with a control group to study group ratio of approximately 1:1. A total of 220 patients were recruited, including 102 in the control group and 118 in the study group.

SPSS 25.0 software (IBM Corporation, Armonk, NY, USA) was used for data analysis. Because baseline characteristics data in the two groups did not conform to a normal distribution, measurement data are expressed as median and interquartile range and were analyzed via the Mann–Whitney U test, and frequency data are expressed as percentages and were analyzed via the chi square test. The log-rank survival function model was used to compare clinical efficacy in the two groups within a 21-day period. A Cox proportional hazards model was used to evaluate recurrent ischemic stroke and hemorrhage within 90 days in the two groups. Age, gender, OMT, systolic blood pressure at registration, bNIHSS, and other factors were stratified to analyze associations with recurrent ischemic stroke in the two groups. P < 0.05 was considered statistically significant.

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