Ticagrelor Versus Clopidogrel in Ischemic Stroke

Study Overview
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Brief Summary
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Along with the current clinical trial, the efficacy and safety of 180 mg loading dose of ticagrelor administered within the first 24 hours of first-ever ischemic stroke compared to 300 mg clopidogrel were assessed through NIHSS, mRS, duration of hospital stay, and possible adverse effects.

Detailed Description
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The investigators will conduct an open-label randomized controlled trial between October 2022 and July 2023 after approval of the ethical committee of the faculty of medicine at Kafr el-Sheik University. The investigators got written informed consent from all eligible patients or their first order of kin before randomization. The study will be composed of 2 arms ticagrelor arm, which consisted of 450 patients who received 180 mg loading dose followed by 90 mg b.i.d from the 2nd to the 90th day), and the Clopidogrel arm consisted of 450 patients who received (a 300 mg loading dose during the first 24 hours of stroke onset followed by 75 mg once daily from the 2nd day to the 90th day), All the patients in the two groups received open-label aspirin at a loading dose of 75 to 300 mg, followed by 75 mg daily for 21 days. Study Procedures: Every patient in our study will undergo: clinical workup: History, clinical assessment & NIHSS were recorded on admission, day 7, and the Modified Rankin Scale as a follow-up after one week and 3 months. Detection of Risk Factors & Profiles: Echocardiography& TOE: in indicated patients ECG Monitoring: daily ECG monitoring will be performed in indicated patients. 3- Carotid Duplex: carotid duplex in indicated patients. 4- ESR & Lipid Profile& liver functions: All will be tested routinely for all patients. Imaging Follow UP Non-contrast CT brain on admission Day 2 MRI: after 2 days of admission, all the patients in this study will have a brain MRI (stroke protocol; T1W, T2W, FLAIR, DWI, T2 Echo Gradient, MRA of all intra-cerebral vessels). CT brain: Any patient with unexplained clinical deterioration at any time throughout his/her hospital stay will be urgently imaged by CT. Primary End Point: The primary efficacy outcome was the rate of new ischemic stroke at 90 days, and the primary safety outcome was the rate of drug hemorrhagic complications using the PLATO bleeding definition. • Secondary End Point: the secondary efficacy outcomes were to evaluate the rates of patients who achieved significant reduction in NIHSS (decrease of four points or more) (21) at the seventh day or discharge compared to baseline, the rates of a favorable outcome with (mRS = 0-2) (19,20) after one week and after 90 days in a face-to-face interview in the outpatient clinic, rates of composite of recurrent stroke, myocardial infarction and death due to vascular events after 90 days of follow-up, while the secondary safety outcome was the rate of treatment-related adverse effects assessed by a follow-up questionnaire.

Official Title
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Ticagrelor Versus Clopidogrel in Ischemic Stroke. a Randomized Double-blinded Controlled Trial

Conditions
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Ischemic Stroke

Intervention / Treatment
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* Drug: Ticagrelor 90 MG Oral Tablet
* Drug: Clopidogrel tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: the investigators included both genders with eligible ages ranging between 18-75 years, with the first-ever presentation with acute ischemic stroke who received antiplatelet treatment within the first 24 hours of the onset of ischemic stroke. Patients with previous transient ischemic attacks (TIA) were not excluded from the study. Patients are not eligible for rt-PA treatment Exclusion Criteria: The investigators excluded patients who had not been followed up on for 90 days after enrollment, those with NIHSS < 4 or ≥ 25 or who had rapidly resolving symptoms before imaging results, and patients with a known history of persistent or recurrent CNS pathology (e.g., epilepsy, meningioma, multiple sclerosis, history of head trauma with a residual neurological deficit). We excluded patients who had clinical seizures at the onset of their stroke, as well as those who had symptoms of any major organ failure, active malignancies, or an acute myocardial infarction within the previous six weeks, and those who were on warfarin, regular ticagrelor during the week before admission, or chemotherapy within the previous year. For safety measures and to avoid associated confounders, we excluded patients with active peptic ulcers, GIT surgery, bleeding history within the last year, and those with a history of major surgery within the last three months. We ruled out of our trial patients who had a known allergy to the study drugs and those with INR > 1.4 or P.T. >18 or blood glucose level < 50 or > 400 mg/DL or blood pressure < 90/60 or > 185/110 mmHg on admission or Platelets < 100,000. The investigators considered pregnant and lactating patients or those with stroke due to venous thrombosis, those with wake-up stroke and stroke following cardiac arrest or profuse hypotension ineligible for our trial. The investigators excluded patients who were regular users of drugs that affect clopidogrel metabolism, such as proton pump inhibitors, statins, ketoconazole, dihydropyridine calcium channel blockers, and rifampin. -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: We will conduct our randomized controlled trial, which will contain 2 arms; the ticagrelor arm (group A) will receive (a 180 mg loading dose during the first 24 hours of stroke onset, followed by 90 mg b.i.d from the 2nd to the 90th day), and the Clopidogrel arm will receive (300 mg loading dose during the first 24 hours of stroke onset followed by 75 mg once daily from the 2nd day to the 90th day). All the patients in the two groups will receive aspirin at a loading dose of 75 to 300 mg, followed by 75 mg daily for 21 days.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ticagrelor arm<br>the ticagrelor arm will receive (180 mg loading dose during the first 12 hours of stroke onset followed by 90 mg b.i.d from the 2nd to the 90th day) and aspirin at a loading dose of 75 to 300 mg, followed by 75 mg daily for 21 days. | Drug: Ticagrelor 90 MG Oral Tablet<br>* Efficacy and safety of 180 mg loading dose of ticagrelor administered within 24 hours of first-ever ischemic stroke followed by 90 mg bid for 3 months will be assessed through NIHSS, mRS, duration of hospital stay, new ischemic stroke, and possible adverse effects.<br>* Other names: group A;|
| Active Comparator: clopidogrel arm<br>the clopidogrel arm will receive (300 mg loading dose during the first 12 hours of stroke onset followed by 75 mg once daily from the 2nd day to the 90th day) and aspirin at a loading dose of 75 to 300 mg, followed by 75 mg daily for 21 days. | Drug: Clopidogrel tablet<br>* efficacy and safety of 300 mg clopidogrel followed by 75 mg once daily for 3 months will be assessed through NIHSS, mRS, duration of hospital stay, new ischemic stroke and possible adverse effects.<br>* Other names: group B;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| -the rate of new ischemic in each group | Assessed during the follow-up period through telephone calls twice per week, a face-to-face interview, and suitable brain imaging in the outpatient clinic once per month and continued for three months | 90 days | 
| Rate of drug-related hemorrhagic complications | the rate of drug hemorrhagic complications which was evaluated using the PLATO bleeding definition which classified hemorrhagic complications into three types as follows: Major bleeding which had one or more of the following criteria: fatal bleeding, intracranial, intrapericardial, bleeding associated with reduction of hemoglobin > 3-5 g/dl, bleeding required transfusion of two to four units whole blood or PRBCs, bleeding produced hypovolemic shock or severe hypotension that required pressor or surgery; Minor bleeding that required medical intervention to stop or treat bleeding: Minimal bleeding: any bleeding that did not require intervention or treatment such as bruising, bleeding gums, oozing from injection sites. | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Value of National Institute of Health Stroke Scale (NIHSS) after one week | NIHSS is a tool used by healthcare providers to objectively quantify the impairment caused by a stroke and aid in planning post-acute care disposition. It ranges from 0 to 42; the lower the score, the better the stroke condition. The improvement will be counted only if there is a decrease in NIHSS score by four points or more within one week of stroke onset. | 7 days | 
| value of Modified Rankin Scale (mRS) at one week | mRS Measures the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability its value ranges from 0 to 6; the lower the score, the better the stroke outcome favorable stroke outcome is considered with mRS value equals two or less. | 90 days | 
| value of Modified Rankin Scale(mRS) at three months | mRS Measures the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability its value ranges from 0 to 6; the lower the score, the better the stroke outcome favorable stroke outcome is considered with mRS value equals two or less. | 90 days | 
| rate of composite recurrent stroke, myocardial infarction, and death due to vascular events | rates of new ischemic stroke, TIA, myocardial infarction, or death from vascular events within three months of treatment the investigators will perform follow-ups of the patient during visits to the outpatient clinic and perform needed investigations such as brain imaging, Electrocardiography, arterial and venous duplex ultrasound imaging . | 90 days | 
| rate of drug adverse effects | Drug adverse effects: all side effects related to the drugs of our study will be reported | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ticagrelor, clopidogrel, ischemic stroke, egypt, kafr el-sheikh faculty of medicine