Clopidogrel genotype testing after ischaemic stroke or transient ischaemic attack

Clinical benefit of CYP2C19 genotype testing

3.6 The committee said there was strong evidence that people with loss-of-function CYP2C19 alleles had worse outcomes when taking clopidogrel than people without loss-of-function variants. But the evidence was less clear on the benefits of treatment with alternative antiplatelets. The committee recalled that clinical experts had said during scoping that dipyridamole with aspirin was the most likely alternative antiplatelet that would be used in the NHS. But no data was found on the impact on people with loss-of-function alleles if treated with clopidogrel compared with dipyridamole plus aspirin.

3.7 A clinical expert noted that the latest National Clinical Guideline for Stroke recommends ticagrelor as an alternative antiplatelet for people with TIA or minor stroke, but not major stroke. Ticagrelor does not have a marketing authorisation for TIA or stroke in the UK. The committee recalled that the external assessment group (EAG) reported evidence that ticagrelor significantly decreased the risk of secondary vascular events in people with loss-of-function CYP2C19 alleles compared with clopidogrel.

Less common loss-of-function alleles

3.8 The committee considered that tests that only detect the most common loss-of-function alleles are likely to introduce inequalities. This is because less common loss-of-function alleles are more prevalent in certain ethnic groups (see section 2.7). The EAG estimated that the combined prevalence of the *4, *8 and *35 alleles in the UK stroke population would be around 0.6%. However, it noted that the *35 allele has a prevalence of up to 3% in people with sub-Saharan African family background, and that the *4 allele is more common in the Ashkenazi Jewish population. So, tests that detect a smaller range of alleles would likely disproportionately affect certain ethnic groups. Some clinical experts suggested that commissioners could consider the demographics in their local area when deciding how to do CYP2C19 genotype testing. Other committee members felt that a wide range of alleles should be tested for to minimise potential inequalities. The committee noted that the significance of some CYP2C19 alleles, particularly if they are very rare, may be uncertain. Experts highlighted that there is information that could be used to guide decisions on the alleles tested for, such as the Association of Molecular Pathology Pharmacogenetics Working Group's recommendations on minimum and optional sets of alleles, or the Clinical Pharmacogenetics Implementation Consortium's guideline for clopidogrel and CYP2C19. A clinical expert commented that laboratory-based testing is adaptable and can change which alleles are tested for over time, whereas point-of-care tests can only detect certain alleles. Laboratory-based tests are also likely to test for a broader range of loss-of-function alleles than point-of-care tests, although this depends on the specific technologies used (see sections 2.11 to 2.15).

Children and young people with stroke

3.9 The committee agreed that CYP2C19 genotype testing would be appropriate for children and young people after an ischaemic stroke if treatment with clopidogrel was being considered. Clinical experts noted that stroke in children and young people is very rare and normally has a different aetiology to stroke in adults. They also acknowledged that clopidogrel is not indicated for use in children. Clopidogrel is not normally prescribed except where there are other risk factors for cerebrovascular disease, such as cardiovascular conditions. The EAG did not identify any evidence for children or young people in their review of clinical effectiveness. However, clinical experts said that there is no biological reason why the interaction between drug and genotype would be different in children and young people compared with adults. The Clinical Pharmacogenetics Implementation Consortium states that it is reasonable to extrapolate its recommendations to paediatric patients if needed (the guidance was also based on data from studies in adults). Experts also said that the benefits from successfully preventing further clotting events by prescribing appropriate antiplatelet therapy would likely be larger for children and young people because of the longer expected remaining lifetime.

Cost of testing

3.10 Clinical experts felt that the true cost of laboratory-based testing was likely lower than the cost used in the EAG's model (£139 per test). An expert commented that laboratory-based CYP2C19 testing in their region was about £20 to £40 per test (when detecting 3 alleles). The EAG explained that the responses to its survey of genomic laboratory hubs did not express a clear preference for the method of CYP2C19 testing, and there was a lack of agreement on the staff time required. Therefore, the true cost of laboratory-based testing is uncertain. The cost used for laboratory-based testing in the model was for the Agena Bioscience MassARRAY with an assumed 1-year lifespan. The EAG's estimated cost per laboratory test included the cost of the iPlex testing platform, which experts indicated would also be used for tests other than CYP2C19. Some committee members said that the cost of laboratory testing could reduce over time because of economies of scale or new technologies.

3.11 A clinical expert suggested that the costs used for the point-of-care tests may have been underestimated. This is because it is likely that multiple machines would be needed in each centre to handle the volume of testing or as backup in case of failure. The EAG clarified that its cost estimates were based on an average cost per test, which could account for multiple devices. A committee member highlighted that introducing point-of-care tests to stroke services would add new processes such as taking cheek swabs and running the tests, which are not currently part of practice. Cost per laboratory test could therefore be less than cost per point-of-care test (the test costs were very similar in the EAG's base case model).

Differences between point-of-care tests

3.12 The committee agreed that the 2 point-of-care tests considered in the assessment are different and that it was not appropriate to use data for the Genomadix Cube to model performance of the Genedrive CYP2C19 ID Kit. It recalled that several studies were identified for the Genomadix Cube test, but no data on accuracy or failure rate was available for the Genedrive test. More data would be needed for the Genedrive test on these outcomes (see section 4) for the committee to consider recommending its use. The committee also noted that several features of the Genedrive test could offer advantages over the Genomadix Cube, such as reagent storage (Genedrive reagents do not require storage in a freezer), the range of alleles tested for (the Genedrive test detects several additional alleles) and interaction with patient records (see sections 2.11 to 2.14). However, the committee recalled that the Genedrive CYP2C19 ID Kit does not have regulatory approval for use in the UK. A company representative stated that this was being sought.

Laboratory testing versus point-of-care testing

3.13 The committee stated a preference for laboratory testing over the available point-of-care test (the Genomadix Cube). It noted that there was very little difference in the quality-adjusted life years (QALYs) generated by the different methods of testing in the EAG's model. The committee had previously concluded that tests that detected fewer loss-of-function alleles would likely disproportionately affect certain ethnic groups (see section 3.8). The cost per test in the EAG's base case model was lower for laboratory-based testing (£139) than for the Genomadix Cube (£197). The committee had also concluded that the true cost of laboratory testing would be lower than this (see section 3.10), and the true cost of point-of-care tests could be higher. Some committee members stated that existing infrastructure should be preferentially used over investing in new single purpose technologies.

CYP2C19 genotype testing is likely to be cost effective

3.14 The committee agreed that CYP2C19 genotype testing was likely to be cost effective. It recalled that in the EAG's base case analysis and in all sensitivity and scenario analyses, genotype testing dominated no testing (it cost less and produced more QALYs). This was true for all alternative antiplatelet agents modelled (dipyridamole with aspirin, ticagrelor with aspirin or aspirin alone), based on potential variation in UK practice.

3.15 The committee also considered that CYP2C19 testing was likely to be cost effective for children or young people. The committee recognised that there was no data for children or young people, and that clopidogrel is rarely used in this population. However, clinical experts advised that, if clopidogrel was being considered, information on CYP2C19 genotype would still be useful (see section 3.9). The committee noted that CYP2C19 genotype testing was more cost effective in the EAG's scenario analysis, which used a younger cohort of adults (average age 40) than in the base case (average age 71). Clinical experts suggested that this would be more pronounced in children and young people because of their longer expected remaining lifetime.