Clopidogrel Preventive Effect Based on CYP2C19 Genotype in Ischemic Stroke

A Multicenter Prospective observationaL Study to evAluate the effecT of Clopidogrel on the prEvention of Major vascuLar Events According to the gEnotype of Cytochrome P450 2C19 in Ischemic Stroke paTients; PLATELET Study

The hypothesis of this study is that "the poor metabolizer or intermediate metabolizer of the cytochrome P450 2C19 genotype in patients with acute ischemic stroke is associated with increased risk of composite cardiovascular events (recurrent stroke, myocardial infarction, cardiovascular death) compared to those who of extensive metabolizer of the cytochrome P450 2C19 genotype".

Study Overview

• Status: Completed
• Conditions: Acute Ischemic Stroke
• Intervention / Treatment: Drug: General principles of care and judgement of researcher

Detailed Description

Clopidogrel, one of the antiplatelet agents used for secondary prevention in patients with ischemic stroke and coronary artery disease, has been shown to have a superior antiplatelet effect compared to aspirin, and is therefore being administered to many patients with stroke and coronary artery disease. Clopidogrel inhibits platelet-derived ADP receptor, P2Y12, in the liver to produce an anti-platelet effect. It has been suggested that clopidogrel resistance could be occurred from drug-drug interaction via the same pharmacological metabolic pathway. Previous studies reported that the genotypes of Cytochrome P450 2C19, which is involved in the metabolism of clopidogrel in the liver, lead to differences in drug response and recurrence rates of cardiovascular disease. The risk of recurrence of ischemic stroke was reported to be about 4 times higher in patients with a poor metabolizer or intermediate metabolizer genotype of the Cytochrome P450 2C19 genotype compared to the extensive metabolizer genotype. This genotypes of Cytochrome P450 2C19 were also different according to race.

The researches about cytochrome P450 2C19 genotype and clopidogrel resistance have been conducted mainly in patients with coronary artery disease and are not known in stroke patients. Few studies have examined whether the resistance of clopidogrel according to the genotype of cytochrome P450 2C19 in stroke patients is related to the occurrence and/or recurrence of cardiovascular disease. The hypothesis of this study is that "the poor metabolizer or intermediate metabolizer of the cytochrome P450 2C19 genotype in patients with acute ischemic stroke is associated with increased risk of cardiovascular disease and mortality compared to those who of extensive metabolizer of the cytochrome P450 2C19 genotype".

• Study Type: Observational
• Enrollment (Actual): 2927

Contacts and Locations

Study Locations

• Korea, Republic of
  • Ansan, Korea, Republic of, 15355
    • Department of Neurology Korea University Ansan Hospital
  • Anyang, Korea, Republic of, 14068
    • Department of Neurology Hallym University Sacred Heart Hospital
  • Busan, Korea, Republic of, 47392
    • Department of Neurology Inje University Busan Paik Hospital
  • Busan, Korea, Republic of, 49201
    • Department of Neurology Dong-A University Hospital
  • Busan, Korea, Republic of, 49267
    • Department of Neurology Kosin University Gospel Hospital
  • Changwon, Korea, Republic of, 51394
    • Department of Neurology Changwon Fatima Hospital
  • Chuncheon, Korea, Republic of, 24253
    • Department of Neurology Hallym University Chuncheon Sacred Heart Hospital
  • Chuncheon, Korea, Republic of, 24289
    • Department of Neurology Kangwon National University Hospital
  • Daegu, Korea, Republic of, 41931
    • Department of Neurology Keimyung University Dongsan Hospital
  • Daegu, Korea, Republic of, 41944
    • Department of Neurology Kyungpook National University Hospital
  • Daejeon, Korea, Republic of, 35233
    • Department of Neurology Daejeon Eulji Medical Center Eulji University
  • Gimpo-si, Korea, Republic of, 10099
    • Department of Neurology Gimpo Woori Hospital
  • Goyang, Korea, Republic of, 10444
    • Department of Neurology National Health Insurance Service Ilsan Hospital
  • Goyang, Korea, Republic of, 10475
    • Department of Neurology Myongji Hospital
  • Gwangju, Korea, Republic of, 61453
    • Department of Neurology Chosun University Hospital
  • Gwangju, Korea, Republic of, 61469
    • Department of Neurology Chonnam National University Hospital
  • Hwaseong-si, Korea, Republic of, 18450
    • Department of Neurology Hallym University Dongtan Sacred Heart Hospital
  • Iksan, Korea, Republic of, 54538
    • Department of Neurology Wonkwang University Hospital
  • Incheon, Korea, Republic of, 21565
    • Department of Neurology Gachon University Gil Medical Center
  • Incheon, Korea, Republic of, 22332
    • Department of Neurology Inha University Hospital
  • Incheon, Korea, Republic of, 22711
    • Department of Neurology Catholic Kwandong University International St.Mary's Hospital
  • Seongnam, Korea, Republic of, 13620
    • Department of Neurology Seoul National University Bundang Hospital
  • Seoul, Korea, Republic of, 01757
    • Department of Neurology Inje University Sanggye Paik Hospital
  • Seoul, Korea, Republic of, 02053
    • Department of Neurology Seoul Medical Center
  • Seoul, Korea, Republic of, 02447
    • Department of Neurology KyungHee University Hospital
  • Seoul, Korea, Republic of, 02841
    • Department of Neurology Korea University Anam Hospital
  • Seoul, Korea, Republic of, 03080
    • Department of Neurology Seoul National University Hospital
  • Seoul, Korea, Republic of, 03722
    • Department of Neurology Severance Hospital, Yonsei University College of Medicine
  • Seoul, Korea, Republic of, 04564
    • Department of Neurology National Medical Center
  • Seoul, Korea, Republic of, 04763
    • Department of Neurology Hanyang University Seoul Hospital
  • Seoul, Korea, Republic of, 05278
    • Department of Neurology KyungHee University Hospital at Gangdong
  • Seoul, Korea, Republic of, 05355
    • Department of Neurology Kangdong Sacred Heart Hospital
  • Seoul, Korea, Republic of, 06273
    • Department of Neurology, Gangnam Severance Hospital, Yonsei Univ. College of Medicine
  • Seoul, Korea, Republic of, 06973
    • Department of Neurology Chung-Ang University Hospital
  • Seoul, Korea, Republic of, 07804
    • Department of Neurology Ewha Womans University Seoul Hospital
  • Seoul, Korea, Republic of, 08308
    • Department of Neurology Korea University Guro Hospital
  • Gyeonggi-do
    • Yongin-si, Gyeonggi-do, Korea, Republic of, 16995
      • Yongin Severance Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with acute ischemic stroke who received clopidogrel 75 mg to 300 mg (in the case of loading dose) within 24 hours of symptom onset and who underwent Cytochrome P450 2C19 genotyping test

Description

Inclusion Criteria:

1. Ischemic stroke confirmed by brain CT or MRI
2. Patient who received clopidogrel within 72 hours after onset of ischemic stroke
3. Adults over 19 years
4. Patients who agreed to participate in this study within 7 days after ischemic stroke
5. Patients who underwent Cytochrome P450 2C19 genotype test.

Exclusion Criteria:

1. Patients who currently take anticoagulation or is expected to take anticoagulation with 6 months from the screening date
2. Patients who need other antiplatelet drugs except aspirin and clopidogrel
3. Patients who were taking clopidogrel prior to ischemic stroke
4. Patients scheduled for coronary artery stenting, coronary artery bypass surgery, carotid endarterectomy, carotid and cerebral artery stenting
5. Patients with severe comorbidities or active cancer with an estimated life expectancy of less than two years
6. Patients who participated in other drug clinical trials within the past 30 days
7. Patients with high risk source of potential cardiac source of embolism in TOAST classification
8. Patients who are expected to unable to participate or continue the study

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
1. Poor and intermediate metabolizer group; Poor and intermediate metabolizer group: acute ischemic stroke patients with poor and intermediate metabolizer genotype of cytochrome P450 2C19 for clopidogrel.	Drug: General principles of care and judgement of researcher; Because our study will be performed by observational design, there will be no intervention for our study. Because it is a registry-based study, overall decision making for medications will be performed according to the general principles of care and judgement of researcher.
2. Extensive metabolizer group; Extensive metabolizer group: acute ischemic stroke patients with Extensive metabolizer genotype of cytochrome P450 2C19 for clopidogrel.	Drug: General principles of care and judgement of researcher; Because our study will be performed by observational design, there will be no intervention for our study. Because it is a registry-based study, overall decision making for medications will be performed according to the general principles of care and judgement of researcher.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
composite cardiovascular events	Occurrence of composite cardiovascular events (recurrent stroke, myocardial infarction, cardiovascular death)	up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
cardiovascular events	Occurrence of ischemic stroke	up to 6 months
cardiovascular events	Occurrence of transient ischemic attack	up to 6 months
cardiovascular events	Revascularization of cerebral, coronary, peripheral artery or aorta	up to 6 months
cardiovascular events	Occurrence of myocardial infarction	up to 6 months
early neurological worsening	increased National Institutes of Health Stroke Scale within 7 day after admission)	up to 7 days
Prognosis	ratio of modified Rankin scale (0 - 2) at 3 months	3 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of major adverse events	Occurrence of major bleeding (fatal bleeding, symptomatic cerebral hemorrhage, ocular hemorrhage, bleeding which needs absolute bed rest or hospitalization or transfusion (more than 2 pack of whole blood or RBC). Occurrence of all-causes mortality	Tile frame: participants will be followed at 0, 1, 3, 6 months

Collaborators and Investigators

• Sponsor: Gangnam Severance Hospital
• Collaborators: SAMJIN PHARM
• Investigators: Principal Investigator: KyungYul Lee, Gangnam Severance Hospital

Publications and helpful links

General Publications

• Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: a review of the evidence. J Am Coll Cardiol. 2005 Apr 19;45(8):1157-64. doi: 10.1016/j.jacc.2005.01.034.
• Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009 Jan 22;360(4):354-62. doi: 10.1056/NEJMoa0809171. Epub 2008 Dec 22.
• Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Meneveau N, Steg PG, Ferrieres J, Danchin N, Becquemont L; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009 Jan 22;360(4):363-75. doi: 10.1056/NEJMoa0808227. Epub 2008 Dec 22.
• Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009 Aug 26;302(8):849-57. doi: 10.1001/jama.2009.1232.
• Mitsios JV, Papathanasiou AI, Rodis FI, Elisaf M, Goudevenos JA, Tselepis AD. Atorvastatin does not affect the antiplatelet potency of clopidogrel when it is administered concomitantly for 5 weeks in patients with acute coronary syndromes. Circulation. 2004 Mar 23;109(11):1335-8. doi: 10.1161/01.CIR.0000124581.18191.15. Epub 2004 Mar 15.
• Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS, Tait AR, Carville DG, Guyer KE, Bates ER. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation. 2003 Jan 7;107(1):32-7. doi: 10.1161/01.cir.0000047060.60595.cc.
• Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet. 2009 Jan 24;373(9660):309-17. doi: 10.1016/S0140-6736(08)61845-0. Epub 2008 Dec 26.
• Pan Y, Chen W, Xu Y, Yi X, Han Y, Yang Q, Li X, Huang L, Johnston SC, Zhao X, Liu L, Zhang Q, Wang G, Wang Y, Wang Y. Genetic Polymorphisms and Clopidogrel Efficacy for Acute Ischemic Stroke or Transient Ischemic Attack: A Systematic Review and Meta-Analysis. Circulation. 2017 Jan 3;135(1):21-33. doi: 10.1161/CIRCULATIONAHA.116.024913. Epub 2016 Nov 2.
• Han SW, Kim YJ, Ahn SH, Seo WK, Yu S, Oh SH, Nam HS, Choi HY, Yoon SS, Kim SH, Lee JY, Lee JH, Hwang YH, Lee KO, Jung YH, Lee J, Sohn SI, Kim YN, Lee KA, Bushnell CD, Lee KY. Effects of Triflusal and Clopidogrel on the Secondary Prevention of Stroke Based on Cytochrome P450 2C19 Genotyping. J Stroke. 2017 Sep;19(3):356-364. doi: 10.5853/jos.2017.01249. Epub 2017 Sep 29.
• Lee SS, Lee SJ, Gwak J, Jung HJ, Thi-Le H, Song IS, Kim EY, Shin JG. Comparisons of CYP2C19 genetic polymorphisms between Korean and Vietnamese populations. Ther Drug Monit. 2007 Aug;29(4):455-9. doi: 10.1097/FTD.0b013e31811f383c.
• Wang Y, Zhao X, Lin J, Li H, Johnston SC, Lin Y, Pan Y, Liu L, Wang D, Wang C, Meng X, Xu J, Wang Y; CHANCE investigators. Association Between CYP2C19 Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction Among Patients With Minor Stroke or Transient Ischemic Attack. JAMA. 2016 Jul 5;316(1):70-8. doi: 10.1001/jama.2016.8662.
• CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996 Nov 16;348(9038):1329-39. doi: 10.1016/s0140-6736(96)09457-3.
• Song TJ, Kim J, Han SW, Kim YD, Lee JY, Ahn SH, Lee HS, Jung YH, Lee KY. Clopidogrel preventive effect based on cytochrome P450 2C19 genotype in ischaemic stroke: protocol for multicentre observational study. BMJ Open. 2020 Aug 5;10(8):e038031. doi: 10.1136/bmjopen-2020-038031.

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2019
• Primary Completion (Actual): January 11, 2023
• Study Completion (Actual): July 7, 2023

Study Registration Dates

• First Submitted: August 25, 2019
• First Submitted That Met QC Criteria: August 27, 2019
• First Posted (Actual): August 28, 2019

Study Record Updates

• Last Update Posted (Actual): September 25, 2023
• Last Update Submitted That Met QC Criteria: September 22, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Stroke; Pharmacogenetics; Clopidogrel; Cytochrome P450 2C19
• 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
• Other Study ID Numbers: 3-2019-0195

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No