Clopidogrel genotype testing after ischaemic stroke or transient ischaemic attack

Clopidogrel and secondary prevention

2.1 People who have had a stroke are at increased risk of further occlusive vascular events, such as recurrent stroke or myocardial infarction. For those with non-cardioembolic ischaemic stroke or transient ischaemic attack (TIA), the antiplatelet drug clopidogrel can be used to reduce this risk.

2.2 People with non-minor ischaemic stroke are normally offered clopidogrel after taking aspirin for 2 weeks. People with TIA or minor stroke may start clopidogrel immediately. Detailed guidance on current practice can be found in NICE's guidance on stroke and transient ischaemic attack in over 16s, NICE's guidance on clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events, and the Royal College of Physicians national clinical guideline for stroke.

Clopidogrel resistance

2.3 Clopidogrel is a prodrug. The CYP2C19 gene encodes the CYP2C19 enzyme that is needed to metabolise clopidogrel to its active form.

2.4 The CYP2C19 gene has many alternative versions or variant forms (alleles) that produce CYP2C19 enzymes with different levels of activity. Each allele is given a star (*) number for identification. The function of each allele can be described as 'normal', 'completely absent', 'decreased' or 'increased', or the function may be uncertain.

2.5 Clopidogrel is less effective in people with alleles that produce CYP2C19 enzymes with completely absent or decreased function.

2.6 People with 2 loss-of-function alleles have no CYP2C19 enzyme activity, cannot activate clopidogrel to its active form and are classed as 'poor metabolisers'. People with only 1 loss-of-function allele are classed as 'intermediate metabolisers' with significantly reduced enzyme activity.

2.7 Loss-of-function alleles are more common in certain ethnic populations, such as people with an Asian family background. The Clinical Pharmacogenetics Implementation Consortium's guideline for clopidogrel and CYP2C19 contains further information about the distribution of loss-of-function alleles by ethnic group.

CYP2C19 genotyping

2.8 CYP2C19 genotype testing can identify variants in the CYP2C19 gene. This provides information on how well a person can metabolise clopidogrel and so can be used to guide antiplatelet treatment.

Genomadix Cube CYP2C19 system

2.10 The Genomadix Cube CYP2C19 system (Genomadix) is a point-of-care DNA test used to detect the *2, *3 and *17 variants of the CYP2C19 gene. The technology consists of:

2.11 Samples are run on the Genomadix Cube system, which combines and automates DNA extraction, PCR amplification, and fluorescence-based detection of CYP2C19 alleles. The test uses 3 cheek swab samples, which are inserted into the reagent cartridge in the Cube. The company states that the test takes 1 hour to run for each cartridge.

2.12 The test report will either display the detected diplotype or an inconclusive result. When the test result is inconclusive, the company state that the test should be repeated with new swabs and a new cartridge. Results are stored locally on a laptop connected to the device and can be exported as a PDF. Optional external controls are available to check proper performance of the platform as per local requirements for accreditation.

Genedrive CYP2C19 ID Kit

2.13 The Genedrive System is a point-of-care gene amplification device used for qualitative in vitro molecular diagnostic tests. At the time of issuing this draft guidance, the technology does not have regulatory approval for use in the UK. The company state that the test will be able to detect the *2, *3, *4, *8, *17 and *35 alleles. The test will consist of:

2.14 The test will use a single cheek swab to collect the sample. The company states that each cartridge will run in less than 1 hour. The result of the test will be automated. The diplotype and metaboliser status will be displayed on the device. The company states that results will be able to be transferred electronically to patient records by internet or through third-party middleware, or printed with an optional label printer. External controls for all targeted alleles will be available in a separate kit to check proper performance of the platform.

Laboratory-based CYP2C19 genotype testing

2.15 Clinical experts indicated that there are several methods that diagnostic genetic laboratories could use to implement CYP2C19 testing. These include: