Ticagrelor Versus Clopidogrel in Ischemic Stroke

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

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.

Study Overview

• Status: Completed
• Conditions: Ischemic Stroke
• Intervention / Treatment: Drug: Clopidogrel tablet; Drug: Ticagrelor 90 MG Oral Tablet

Detailed Description

The investigators will conduct a single-blinded randomized controlled trial between October 2022 and December 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 a 180 mg loading dose followed by 90 mg b.i.d from the 2nd to the 90th day), and the Clopidogrel arm consisting 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)

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:

  1. Echocardiography& TOE: in indicated patients
  2. 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

  1. Non-contrast CT brain on admission
  2. 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).
  3. 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 a significant reduction in NIHSS (decrease of four points or more) (21) at the seventh day or discharge compared to baseline, the rates of a favourable 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.

• Study Type: Interventional
• Enrollment (Actual): 900
• Phase: Phase 3

Contacts and Locations

Study Locations

• Egypt
  • Kafr Ash Shaykh, Egypt, 6850001
    • Kafr Elsheikh University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

-

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: ticagrelor arm; 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)	Drug: Ticagrelor 90 MG Oral Tablet; 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.; Other Names: group A
Active Comparator: clopidogrel arm; The clopidogrel arm will receive (a 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).	Drug: Clopidogrel tablet; 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.; Other Names: group B

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
-the rate of new stroke 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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
rate of drug adverse effects	Drug adverse effects: all side effects related to the drugs of our study will be reported	90 days
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 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

Collaborators and Investigators

• Sponsor: Kafrelsheikh University
• Investigators: Principal Investigator: mohamed G. Zeinhom, PHD, neurology department kafr el-sheikh university

Publications and helpful links

General Publications

• Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet. 2006 May 27;367(9524):1747-57. doi: 10.1016/S0140-6736(06)68770-9.
• Paciaroni M, Ince B, Hu B, Jeng JS, Kutluk K, Liu L, Lou M, Parfenov V, Wong KSL, Zamani B, Paek D, Min Han J, Del Aguila M, Girotra S. Benefits and Risks of Clopidogrel vs. Aspirin Monotherapy after Recent Ischemic Stroke: A Systematic Review and Meta-Analysis. Cardiovasc Ther. 2019 Dec 1;2019:1607181. doi: 10.1155/2019/1607181. eCollection 2019.
• Meyer DM, Albright KC, Allison TA, Grotta JC. LOAD: a pilot study of the safety of loading of aspirin and clopidogrel in acute ischemic stroke and transient ischemic attack. J Stroke Cerebrovasc Dis. 2008 Jan-Feb;17(1):26-9. doi: 10.1016/j.jstrokecerebrovasdis.2007.09.006.
• Gachet C, Stierle A, Cazenave JP, Ohlmann P, Lanza F, Bouloux C, Maffrand JP. The thienopyridine PCR 4099 selectively inhibits ADP-induced platelet aggregation and fibrinogen binding without modifying the membrane glycoprotein IIb-IIIa complex in rat and in man. Biochem Pharmacol. 1990 Jul 15;40(2):229-38. doi: 10.1016/0006-2952(90)90683-c.
• Jacobson KA, Boeynaems JM. P2Y nucleotide receptors: promise of therapeutic applications. Drug Discov Today. 2010 Jul;15(13-14):570-8. doi: 10.1016/j.drudis.2010.05.011. Epub 2010 Jun 2.
• Johnston SC, Amarenco P, Albers GW, Denison H, Easton JD, Held P, Jonasson J, Minematsu K, Molina CA, Wong LK. Acute Stroke or Transient Ischemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial: rationale and design. Int J Stroke. 2015 Dec;10(8):1304-8. doi: 10.1111/ijs.12610. Epub 2015 Aug 26.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2022
• Primary Completion (Actual): October 1, 2023
• Study Completion (Actual): January 1, 2024

Study Registration Dates

• First Submitted: September 19, 2022
• First Submitted That Met QC Criteria: September 21, 2022
• First Posted (Actual): September 23, 2022

Study Record Updates

• Last Update Posted (Actual): May 14, 2024
• Last Update Submitted That Met QC Criteria: May 11, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: ticagrelor; ischemic stroke; clopidogrel; egypt; kafr el-sheikh faculty of medicine
• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Infarction; Brain Infarction; Stroke; Ischemic Stroke; Ischemia; Cerebral Infarction; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Ticagrelor; Clopidogrel
• Other Study ID Numbers: 23988

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: All the data that support the findings of this research will be available from the corresponding author M. Zeinhom upon reasonable request.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes