Clinical and cost-effectiveness of clopidogrel resistance genotype testing after ischaemic stroke or transient ischaemic attack: a systematic review and economic model
Authors: Carroll Joe , Lopez Manzano Catalina , Tomlinson Eve , Sadek Ayman , Cooper Chris , Jones Hayley E , Rowsell Lorraine , Knight John , Mumford Andrew , Palmer Rachel , Hollingworth William , Welton Nicky J. , Whiting Penny 
Published: July 2023

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.