Health Technology Assessment (Sep 2024)
Clinical and cost-effectiveness of clopidogrel resistance genotype testing after ischaemic stroke or transient ischaemic attack: a systematic review and economic model
Abstract
Background Stroke or transient ischaemic attack patients are at increased risk of secondary vascular events. Antiplatelet medications, most commonly clopidogrel, are prescribed to reduce this risk. Factors including CYP2C19 genetic variants can hinder clopidogrel metabolism. Laboratory-based or point-of-care tests can detect these variants, enabling targeted treatment. Objective To assess the effectiveness of genetic testing to identify clopidogrel resistance in people with ischaemic stroke or transient ischaemic attack. Specific objectives: Do people tested for clopidogrel resistance, and treated accordingly, have a reduced risk of secondary vascular events? Do people with loss-of-function alleles associated with clopidogrel resistance have a reduced risk of secondary vascular events if treated with alternative interventions compared to clopidogrel? Do people with loss-of-function alleles associated with clopidogrel resistance have an increased risk of secondary vascular events when treated with clopidogrel? What is the accuracy of point-of-care tests for detecting variants associated with clopidogrel resistance? What is the technical performance and cost of CYP2C19 genetic tests? Is genetic testing for clopidogrel resistance cost-effective compared with no testing? Design Systematic review and economic model. Results Objective 1: Two studies assessed secondary vascular events in patients tested for loss-of-function alleles and treated accordingly. They found a reduced risk, but confidence intervals were wide (hazard ratio 0.50, 95% confidence interval 0.09 to 2.74 and hazard ratio 0.53, 95% confidence interval 0.24 to 1.18). Objective 2: Seven randomised controlled trials compared clopidogrel with alternative treatment in people with genetic variants. Ticagrelor was associated with a lower risk of secondary vascular events than clopidogrel (summary hazard ratio 0.76, 95% confidence interval 0.65 to 0.90; two studies). Objective 3: Twenty-five studies compared outcomes in people with and without genetic variants treated with clopidogrel. People with genetic variants were at an increased risk of secondary vascular events (hazard ratio 1.72, 95% confidence interval 1.43 to 2.08; 18 studies). There was no difference in bleeding risk (hazard ratio 0.98, 95% confidence interval 0.68 to 1.40; five studies). Objective 4: Eleven studies evaluated Genomadix Cube accuracy; no studies evaluated Genedrive. Summary sensitivity and specificity against laboratory reference standards were both 100% (95% confidence interval 94% to 100% and 99% to 100%). Objective 5: Seventeen studies evaluated technical performance of point-of-care tests. Test failure rate ranged from 0.4% to 19% for Genomadix Cube. A survey of 8/10 genomic laboratory hubs revealed variation in preferred technologies for testing, and cost per test ranging from £15 to £250. Most laboratories expected test failure rate to be < 1%. Additional resources could enhance testing capacity and expedite turnaround times. Objective 6: Laboratory and point-of-care CYP2C19 testing strategies were cost-saving and increase quality-adjusted life-years compared with no testing. Both strategies gave similar costs, quality-adjusted life-years and expected net monetary benefit. Conclusions Our results suggest that CYP2C19 testing followed by tailored treatment is likely to be effective and cost-effective in both populations. Future work Accuracy and technical performance of Genedrive. Test failure rate of Genomadix Cube in a National Health Service setting. Value of testing additional loss-of-function alleles. Appropriateness of treatment dichotomy based on loss-of-function alleles. Limitations Lack of data on Genedrive. No randomised ‘test-and-treat’ studies of dipyramidole plus aspirin. Study registration This study is registered as PROSPERO CRD42022357661. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135620) and is published in full in Health Technology Assessment; Vol. 28, No. 57. See the NIHR Funding and Awards website for further award information. Plain language summary What is the problem? The most common type of stroke occurs when the supply of blood to the brain is cut off. Symptoms of stroke happen suddenly and vary depending on which part of the brain is affected. They usually include problems with movement, speech, vision and the face drooping on one side. A ‘transient ischaemic attack’ is a milder related condition. There are around 100,000 strokes and 60,000 transient ischaemic attacks every year in the UK. People who have a stroke or transient ischaemic attack are at greater risk of having another stroke. To reduce the chances of this happening, doctors will often prescribe medication. The most common medication used is called ‘clopidogrel’. However, clopidogrel does not work for everyone. One reason for this is having specific variations of a gene called the CYP2C19 gene. Around one in three people in the UK have this variation. What did we do? We wanted to know whether introducing genetic testing to identify variations in the CYP2C19 gene for people who have had a stroke or transient ischaemic attack can help doctors prescribe a treatment that will work for them, reducing the risk of having another stroke. We also wanted to know if doing this test would be a good use of NHS money. What did we find? Doing a genetic test to identify variations in the CYP2C19 gene, and prescribing an alternative medication for people with these variations, may reduce the chances of having a new stroke. It is likely that a genetic test for variations of the CYP2C19 gene would represent value for money for the NHS. Scientific summary Background Stroke is a neurological condition that can cause lasting brain damage, disability and death. Symptoms of stroke happen suddenly and include problems with movement, speech, vision and the face drooping on one side. A TIA (transient ischaemic attack) is a milder related condition. Each year, there are around 100,000 strokes and 60,000 TIAs in the UK. People who have a stroke or TIA are at increased risk of another vascular occlusive event. To reduce this risk, doctors often prescribe antiplatelet medication, most commonly clopidogrel. Clopidogrel is a prodrug, which means it needs to be metabolised by an enzyme called P450 CYP to achieve its pharmacological effect; a substantial proportion of the population have a reduced ability to perform this conversion. This is known as ‘clopidogrel resistance’ and can be caused by genetic variants, mainly in the CYP2C19 gene, in addition to other clinical factors. Relevant genetic variants can be detected using laboratory-based tests or point-of-care tests (POCTs). Opportune detection of patients with genetic variants associated with ‘clopidogrel resistance’ could help doctors to initiate a more suitable treatment, potentially preventing new occlusive vascular events in this population. Objectives The overall aim was to summarise the clinical and cost-effectiveness of genetic testing to identify clopidogrel resistance in people with non-cardioembolic ischaemic stroke or TIA. Objective 1: Do people who have genetic testing for clopidogrel resistance, and who are treated based on these results, have a reduced risk of secondary vascular occlusive events compared to those who are not tested and are treated with clopidogrel following standard guidelines? Objective 2: Do people who have loss-of-function (LOF) alleles associated with clopidogrel resistance have a reduced risk of secondary vascular occlusive events if treated with alternative interventions compared to treatment with clopidogrel? Objective 3: Do people who have LOF alleles associated with clopidogrel resistance have an increased risk of secondary vascular occlusive events when treated with clopidogrel compared to patients without LOF alleles who are treated with clopidogrel? Objective 4: What is the accuracy of point-of-care genotype tests for detecting variants associated with clopidogrel resistance? Objective 5: What is the technical performance (other than accuracy) and cost of the different CYP2C19 genetic tests? Objective 6: What is the cost-effectiveness of different POCT and laboratory-based genetic tests for clopidogrel resistance compared with not testing for clopidogrel resistance? Methods Clinical effectiveness review A systematic review was conducted. This was supplemented by a survey of genomic laboratory hubs on the technical performance of CYPC19 genetic tests. Eight databases and two trial registries were searched. We screened trial registries, reference lists of reviews and study reports, relevant websites and information submitted by test manufacturers. Title and abstract screening were conducted by two reviewers independently. Inclusion assessment, data extraction and risk-of-bias (RoB) assessment were performed by one reviewer and checked by a second. Risk of bias was assessed using the RoB 2 [randomised controlled trials (RCTs)], ROBINS-E (observational studies) and modified QUADAS-2 (diagnostic accuracy studies) tools. For each objective, we provided a narrative summary of study details, RoB and results. Random and fixed-effects meta-analysis was performed to generate summary effect estimates; heterogeneity was investigated using stratified analyses and metaregression. Forest plots were produced to show individual and summary effect estimates with 95% confidence intervals (CIs). Cost-effectiveness We developed a decision-analytic model to evaluate the cost-effectiveness of POCT and laboratory tests for CYP2C19 LOF alleles, compared with no testing in two populations in England and Wales: (1) TIA/minor ischaemic stroke and (2) non-minor ischaemic stroke; and also present results for a mixed ischaemic stroke and TIA population. We modelled patients moving between five health states: no recurrent stroke, minor stroke, major bleed or intracranial haemorrhage, moderate stroke and severe stroke, with mortality rate depending on health state. A decision tree was used to capture short-term (90 day) outcomes, and a Markov model with 1-year cycles captured longer-term outcomes over a lifetime horizon. Costs and quality-adjusted life-years (QALYs) were estimated using a 3.5% discount rate for both and summarised as expected net monetary benefit at willingness to pay of £20,000 per QALY, where higher expected net benefit is preferred. Model inputs were derived from the clinical effectiveness review, reviews of previous cost-effectiveness models of CYP2C19 testing and cost-effectiveness models of antiplatelets for stroke prevention, results from the survey of laboratories, information provided by Genedrive and Genomadix, and additional targeted searches. Uncertainty was explored using probabilistic analysis, and a range of scenario analyses to test robustness of results to model assumptions. Results Objective 1 Two non-randomised studies evaluated the clinical impact of genetic testing plus personalised treatment. Both were at high RoB due to potential confounding. Both studies treated patients in the control group, who were either not tested or were not treated based on their CYP2C19 status, with clopidogrel 75 mg/day. The intervention group were then treated based on the presence of LOF alleles. Both studies treated those with no LOF alleles in the same way as the control group (i.e. clopidogrel 75 mg/day), one study gave high-dose clopidogrel to those with one LOF allele and ticagrelor to those with two LOF alleles. In the other study, those with at least one LOF allele were given aspirin 100 mg/day. There was a suggestion that the risk of secondary vascular events was reduced in patients tested for LOF alleles and treated accordingly, but CIs were wide and overlapped the null [composite outcome of secondary vascular events: hazard ratios (HRs) 0.50, 95% CI 0.09 to 2.74 and HR 0.53, 95% CI 0.24 to 1.18]. Objective 2 Seven RCTs compared treatment with clopidogrel with alternative antiplatelet therapies compared in people with LOF alleles. Four were at low RoB, three had concerns regarding missing data and lack of information on allocation concealment. There was evidence that ticagrelor was associated with a lower risk of secondary vascular events than clopidogrel (summary HR 0.76, 95% CI 0.65 to 0.90; two studies), including ischaemic stroke (HR 0.77, 95% CI 0.65 to 0.93; two studies). One study suggested that ticagrelor was associated with an increased risk of bleeding (HR 2.18, 95% CI 1.66 to 2.86); the other found no difference in the risk of bleeding with ticagrelor compared to clopidogrel (HR 1.01, 95% CI 0.60 to 1.69). There was no statistical evidence for differences between antiplatelet treatment strategies for other comparisons or bleeding outcomes. Objective 3 Twenty-five studies (20 cohort studies and five trials) compared people with and without LOF alleles, all of whom were treated with clopidogrel (alone or combined with aspirin or other antiplatelet drugs) to see whether the risk of secondary vascular occlusive events differed between groups. Six studies were judged at high RoB as we considered that loss to follow-up could potentially be related to incidence of vascular events. There was strong evidence that people with LOF alleles treated with clopidogrel (or clopidogrel plus short-term aspirin) have a greater incidence of secondary vascular events (HR 1.72, 95% CI 1.43 to 2.08; 18 studies), stroke (HR 1.46, 95% CI 1.09 to 1.95; 5 studies) and ischaemic stroke (HR 1.99, 95% CI 1.49 to 2.64; 12 studies) than those without LOF alleles. Metaregression analyses showed statistical evidence of a reduced effect of LOF alleles in patients given a loading dose of clopidogrel relative to those who were not [relative hazard ratio (RHR) 0.64, 95% CI 0.43 to 0.96], and in patients taking clopidogrel plus long-term aspirin relative to those taking only clopidogrel or clopidogrel plus short-term aspirin (RHR 0.47, 95% CI 0.22 to 0.96). Metaregression did not show evidence for a difference in LOF alleles effect on vascular occlusive outcomes across different ethnicities (Asian or mixed relative to white), study location (China, Europe, Asia non-China, Turkey and international) or follow-up time (follow-up of 6 months, 1 year, 1–3 years and 3–5 years relative to up to 3 months). There was no difference in the risk of bleeding between those with and without LOF alleles (HR 0.98, 95% CI 0.68 to 1.40; five studies). Objective 4 Eleven studies reported data on the accuracy of the POCTs in scope. All evaluated Spartan versions of the Genomadix Cube test: Spartan Cube, Spartan RX or Spartan FRX, against a laboratory reference standard – there were no studies on the accuracy of Genedrive. All studies were judged at low RoB. None of the studies were conducted in a stroke population. The Genomadix (Spartan) CYP2C19 tests were found to have very high accuracy for the detection of *2 and/or *3 LOF alleles. Summary sensitivity was 100% (95% CI 94% to 100%) and summary specificity was also 100% (95% CI 99% to 100%). There were very few disagreements between the Genomadix (Spartan) CYP2C19 tests and laboratory-based reference standards – 8 of the 11 studies reported perfect agreement between the tests. There was no suggestion of a difference across the three different versions of the test evaluated. Objective 5 Seventeen studies evaluated the technical performance of the POCTs. One evaluated Genedrive; others evaluated Genomadix (Spartan) CYP2C19 tests. Only one study was conducted in a stroke population. Test failure rate for Genomadix (Spartan) CYP2C19 tests ranged from 0.4% to 19%. Most studies reported that time from buccal swab for to results for Genomadix (Spartan) CYP2C19 tests was around 1 hour, although two studies reported higher estimates of 90 minutes and 90–120 minutes. One study of Genedrive reported that it gives results in around 40 minutes. Studies suggested that Genomadix (Spartan) CYP2C19 tests were simple, user-friendly and can require minimal training. Limitations included storage conditions (analytes need to be frozen); only one sample can be genotyped at a time, and it only tests for *2, *3 and *17 alleles. The study that evaluated Genedrive noted the test is simple, portable, rapid, does not require analytes to be frozen and tests for *2, *3, *4, *8 and *17 alleles. Genedrive and Genomadix provided information on the platform cost, assay cost and cost of external control kits, which were used in our economic model. Eight of the 10 genomic laboratory hubs completed the survey. All but one had sequencing technologies, and all had targeted CYP2C19 gene variant detection (e.g. TaqMan). Preferred technologies for performing CYP2C19 testing included: next-generation sequencing (NGS) (two labs), MassARRAY (three labs), loop-mediated isothermal amplification (LAMP) (three labs), polymerase chain reaction (PCR)-based single-nucleotide polymorphisms (SNP) genotyping assays (e.g. TaqMan) (one lab). Resource requirements varied. Costs per test ranged from around £15 (MassARRAY, although another lab estimated this as £100) to £250 for next-generation gene sequencing. Most labs reported that tests could be performed by existing staff members with standard training or that the test was fully automated, although one lab stated that their preferred test would be new to their lab and would require training. Most labs expected test failure rate to be < 1%. Testing capacity ranged from 0 to 200 tests per week, and turnaround time (TAT) from 24–72 hours to 1–2 weeks. Most labs reported that additional testing capacity and faster TAT would be possible with additional resources (staff, lab space, automation and equipment). Major barriers to implementing testing were the scale of activity and current capacity (four labs); one highlighted that they do not currently perform any tests of this scale in the NHS. Objective 6 In our base case for all populations, we found that CYP2C19 testing was cost-effective, with both laboratory and point-of-care CYP2C19 testing strategies generating more QALYs and lower costs compared with no testing. In the non-minor ischaemic stroke population, the expected net benefits were £6230, £6214 and £6138 for Genedrive, the laboratory test and the Genomadix Cube CYP2C19 test, respectively. In the TIA/minor stroke population, the expected net benefits were £2932, £2802 and £2829 for Genedrive, the laboratory test and the Genomadix Cube CYP2C19 test, respectively. In both populations, net monetary benefit is similar, suggesting little difference between the tests. Only cost data were available for Genedrive, and so results for this test are illustrative only until more data on test performance data are available. Omitting Genedrive, the highest expected net benefit is for the laboratory test in the non-minor ischaemic stroke population, and the Genomadix Cube CYP2C19 test in the TIA/minor stroke population. The model inputs that have the biggest impact on the cost-effectiveness results were the costs of the different stroke states, and the treatment effects for stroke in patients with CYP2C19 LOF, and the HR for major bleed/intracerebral haemorrhage (ICH) on aspirin relative to clopidogrel. However, varying these parameters did not change the overall finding that CYP2C19 testing is cost saving and generates more QALYs compared with no testing. Cost-effectiveness acceptability curves show that there is a high probability that one of the testing strategies is the most cost-effective. The overall finding that CYP2C19 testing is cost-saving and generates more QALYs compared with no testing was robust in all the scenarios that we explored. The scenarios where CYP2C19 testing was most cost-effective were when prevalence of CYP2C19 LOF was high and for younger cohorts of patients. The scenarios where CYP2C19 testing was least cost-effective were when we assumed that only 69.9% of LOF patients actually receive alternative treatment, and when the alternative treatment was ticagrelor. In these scenarios, CYP2C19 testing was still cost saving but with a smaller increase in QALYs. Conclusions Our results suggest that CYP2C19 testing followed by tailored treatment is likely to be effective and cost-effective in both populations modelled (non-minor ischaemic stroke and TIA/minor ischaemic stroke). Lab tests and POCTs generate similar cost savings and QALY benefits. Implementation of CYP2C19 testing would require sufficient capacity for lab tests and freezers/storage for POCTs, and training and processes in place to encourage uptake of alternative treatment for patients with LOF variants. There are four areas where further research is required: accuracy and technical performance (e.g. test failure rate, cost, time to perform the test) of Genedrive test failure rate of Genomadix Cube in an NHS setting value of testing additional LOF alleles beyond *2 and *3 appropriateness of treatment dichotomy based on LOF alleles used in our appraisal compared to a more complex approach to tailored treatment. Study registration This study is registered as PROSPERO CRD42022357661. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135620) and is published in full in Health Technology Assessment; Vol. 28, No. 57. See the NIHR Funding and Awards website for further award information.
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