Genotype Guided Antiplatelet Therapy In Ischemic Stroke

NCT05763862 | Active Not Recruiting

• 1 other identifier: GGAT Protocol
• Study Type: interventional
• Target: 350
• Locations: 1 country
• Sites: 1

Brief Summary

A fifth of ischemic stroke or transient ischemic attack (TIA) patients will have recurrent events within the first 3 months \[Refs 1-3\] despite aggressive medical therapy with antiplatelets and risk factor control. Clopidogrel is one of the mainstays of antiplatelet secondary prevention therapy in patients with ischemic stroke. CYP2C19 loss of function (LOF) mutations impair the effectiveness of clopidogrel \[Ref 4\]. The prevalence of LOF mutations is approximately 60% in the local population \[Ref 5\], rendering the effectiveness of empiric clopidogrel treatment doubtful. For patients who have LOF mutations, other treatment options for secondary prevention of ischemic stroke need to be tested. This study aims to determine the feasibility and clinical impact of genetic testing guided antiplatelet therapy in ischemic stroke patients on the prevention of major adverse cardiovascular or cerebrovascular events. Clopidogrel naive ischemic stroke or TIA patients aged 21 years and above will be randomised to genetic testing guided antiplatelet therapy or standard medical therapy within 7 days of their index event. Patients allocated to testing group will have blood sample drawn for diagnosis of CYP2C19 LOF mutations. Patients who test positive for an LOF mutation (intermediate and poor metabolisers) will be offered alternative antiplatelet therapy in the form of aspirn (for those who need monotherapy) or aspirin plus ticagrelor or dipyridamole (for those who need dual antiplatelet therapy) to be decided by the managing physician. Patients who test negative for LOF mutation will continue on clopidogrel. Platelet reactivity index (enables the identification of patients with an inadequate response to antiplatelet agents) will be measured at baseline.

Conditions

Ischemic Stroke; Transient Ischemic Attack

Keywords

Genotype Guided Antiplatelet Therapy

Outcome Measures

Primary Outcomes (1)

• Major adverse cardiovascular or cerebrovascular events (MACCE) over 12 months following the index stroke

  MACCE includes either death, myocardial infarction, stent thrombosis, admission for acute coronary syndrome / unstable angina, ischemic cerebrovascular accident or transient ischemic event.

  12 months

Secondary Outcomes (1)

• Clinically significant bleeding

  12 months

Other Outcomes (2)

• Ischemic stroke, myocardial ischemic events, and death from vascular outcomes

  12 months

• Compliance to medications

  3 months and 12 months

Study Arms (2)

Genetic testing

EXPERIMENTAL

Patients randomised to testing will have blood drawn for testing of CYP2C19 LOF mutations. Physicians of patients who test positive for an LOF mutation (intermediate and poor metabolizers) will be notified of the mutation with recommendations of possible alternative antiplatelet regimens suggested. Aspirin will be the recommended monotherapy, and aspirin in combination with ticagrelor or dipyridamole will be the recommended dual antiplatelet regimen. Decision of alternative medications used in patients with LOF mutations will be left to the discretion of the primary physician. Patients in the genotype guided antiplatelet therapy group who do not have LOF mutations will be left to continue the original intended antiplatelet regimen (this may be clopidogrel monotherapy, or in combination with aspirin). No randomisation for patients with known CYP2C19 status prior to recruitment as these patients will be recruited as a comparison arm for outcomes measurements.

Genetic: Genetic testing

Standard medical therapy

NO INTERVENTION

Patients on this arm will be placed on clopidogrel monotherapy, or in combination with aspirin, which is the original intended antiplatelet regimen.

Interventions

Genetic testing GENETIC

Same information as details in the experimental arm.

Also known as: Testing of CYP2C19 LOF mutations

Genetic testing

Eligibility Criteria

• Age: 21 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients diagnosed with acute ischemic stroke or transient ischemic attack.
• Age 21 years to 100 years.
• Can be randomised within 7 days of onset of index event \[Refer to footnote 1\].
• Clopidogrel naive immediately prior to index event \[Refer to footnote 2\].

You may not qualify if:

• Known diagnosis of dementia \[Refer to footnote 3\].
• Known diagnosis of a life limiting illness with life expectancy of less than 1 year.
• Known cardioembolism or prothrombotic state necessitating the use of anticoagulation, or having a contraindication to clopidogrel.
• Footnote 3: "Known diagnosis of dementia" will be defined as clinical diagnosis of dementia prior to the index stroke event as indicated in the patient's medical records.

Sponsors & Collaborators

• National Neuroscience Institute: lead
• Singapore General Hospital: collaborator

Study Sites (1)

Singapore General Hospital

Singapore, Singapore

Location

Related Publications (16)

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  PMID: 10797166 BACKGROUND

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  PMID: 17962602 BACKGROUND

• 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.

  PMID: 8918275 BACKGROUND

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  PMID: 27348249 BACKGROUND

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• Humbert M, Nurden P, Bihour C, Pasquet JM, Winckler J, Heilmann E, Savi P, Herbert JM, Kunicki TJ, Nurden AT. Ultrastructural studies of platelet aggregates from human subjects receiving clopidogrel and from a patient with an inherited defect of an ADP-dependent pathway of platelet activation. Arterioscler Thromb Vasc Biol. 1996 Dec;16(12):1532-43. doi: 10.1161/01.atv.16.12.1532.

  PMID: 8977459 BACKGROUND

• Scott SA, Sangkuhl K, Stein CM, Hulot JS, Mega JL, Roden DM, Klein TE, Sabatine MS, Johnson JA, Shuldiner AR; Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013 Sep;94(3):317-23. doi: 10.1038/clpt.2013.105. Epub 2013 May 22.

  PMID: 23698643 BACKGROUND

• Goh LL, Lim CW, Sim WC, Toh LX, Leong KP. Analysis of Genetic Variation in CYP450 Genes for Clinical Implementation. PLoS One. 2017 Jan 3;12(1):e0169233. doi: 10.1371/journal.pone.0169233. eCollection 2017.

  PMID: 28046094 BACKGROUND

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  PMID: 32568642 BACKGROUND

• Narasimhalu K, Ang YK, Tan DSY, De Silva DA, Tan KB. Cost Effectiveness of Genotype-Guided Antiplatelet Therapy in Asian Ischemic Stroke Patients: Ticagrelor as an Alternative to Clopidogrel in Patients with CYP2C19 Loss of Function Mutations. Clin Drug Investig. 2020 Nov;40(11):1063-1070. doi: 10.1007/s40261-020-00970-y.

  PMID: 32959334 BACKGROUND

• Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011 Jun 14;123(23):2736-47. doi: 10.1161/CIRCULATIONAHA.110.009449. No abstract available.

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MeSH Terms

Conditions

Ischemic Stroke; Ischemic Attack, Transient

Interventions

Genetic Testing

Condition Hierarchy (Ancestors)

Stroke; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Brain Ischemia

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Genetic Techniques; Genetic Services; Health Services; Health Care Facilities Workforce and Services; Diagnostic Services; Preventive Health Services

Study Officials

• Kaavya Narasimhalu

  National Neuroscience Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Patients will be randomised to genetic testing versus standard medical therapy in a 1:1 ratio, via a block randomisation process. The block randomisation sequence will be generated by a web-based randomisation service in blocks of four for each recruitment site. Blinding is not applicable for the treatment assigned.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a multicentre, prospective, randomised, open blinded endpoint trial.

Study Record Dates

• First Submitted: February 28, 2023
• First Posted: March 10, 2023
• Study Start: April 24, 2023
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2026
• Last Updated: April 16, 2026

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

SG (1)