CYP2C19 genotype testing for clopidogrel: A guideline developed by the UK Centre of Excellence in Regulatory Science and Innovation in Pharmacogenomics (CERSI-PGx)

3.1. Stroke and transient ischaemic attack

A retrospective study of the CHANCE trial population in China showed that the benefit of dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel vs. aspirin monotherapy was absent in intermediate or poor metabolisers with LOF alleles in CYP2C19 (9.4% vs. 10.8%; hazard ratio, HR: 0.93, 95% confidence interval, 95% CI: 0.69–1.26; p = .64). ⁶ CHANCE 2 was a large double‐blind, placebo controlled randomized study also in a Han‐Chinese population with transient ischaemic attack (TIA) or minor stroke, where patients were allocated to ticagrelor or clopidogrel alongside aspirin within 24 h of symptom onset, all of whom had a CYP2C19 LOF allele. The risk of stroke was reduced from 7.6% in patients on clopidogrel to 6% in the ticagrelor group (HR: 0.77; 95% CI: 0.64–0.94; p = .008). ⁷ A subgroup analysis per genotype showed similar efficacy of ticagrelor in both CYP2C19 intermediate and poor metaboliser groups. More bleeding events were observed in the ticagrelor group (5.3% vs. 2.5%, HR: 2.18; 95% CI: 1.66–2.85), although the incidence of severe or moderate bleeding was similar in the two groups (0.3%). ⁷

There have been several recent meta‐analyses summarizing the effects of CYP2C19 LOF alleles on the risk of recurrent vascular events. Pan et al. conducted a meta‐analysis of 15 studies in 4762 stroke or TIA patients from all ethnic groups with LOF alleles (*2, *3 and *8) treated with clopidogrel and found an increased risk of stroke compared to individuals without any LOF alleles (12% vs. 5.8%; risk ratio, RR: 1.92, 95% CI: 1.57–2.35; p < .001). ⁸

Biswas et al. conducted a large meta‐analysis looking at endpoints of recurrent stroke, composite vascular events and bleeding. They included 28 studies (22 observational studies and 6 randomized clinical trials, RCTs) with 9443 stroke or TIA patients. They found that patients taking clopidogrel in the LOF allele group showed an increased risk of recurrent stroke compared with those with no LOF alleles (OR: 2.18, 96% CI: 1.80–2.63; p < .00001). ⁹ Cargnin et al. performed a focused meta‐analysis of stroke and TIA patients of non‐East Asian ethnicity; they included eight studies with 1673 patients. Their analysis found a significant increase in recurrent stroke in the LOF allele groups treated with clopidogrel when compared with subjects who were normal metabolisers (RR: 1.68, 95% CI: 1.04–2.71; p = .03). This was also found in European patients with CYP2C19 LOF alleles (RR: 2.69, 95% CI: 1.11–6.51, p = .03). ¹⁰

Maas et al. performed a large meta‐analysis on clopidogrel and CYP2C19 genotype status in all atherothrombotic events. Their analysis included 29 stroke studies and found that subjects with LOF alleles carried a higher risk of major adverse cardiovascular events (RR: 1.61, 95% CI: 1.25–2.08) and recurrent ischaemic stroke compared with CYP2C19 wild‐type subjects (RR: 1.89, 95% CI: 1.48–2.40). ¹¹

The NICE diagnostic guidance undertook a meta‐analysis of 25 studies that showed that patients with LOF alleles are at increased risk of secondary vascular events (HR: 1.72, 95% CI: 1.43–2.08; 18 studies) and ischaemic stroke (HR: 1.99, 95% CI: 1.49–2.64; 12 studies) when treated with clopidogrel alone or in addition to short‐term aspirin compared with patients without LOF alleles. ¹² Meta‐regression did not show any difference in incidence of vaso‐occlusive end points for these studies for location (China, Europe, Asia non‐China, Turkey and International) or different ethnicities (Asian or mixed to white). The authors did an analysis of seven RCTs comparing alternative antiplatelet therapies in LOF allele populations with stroke/TIA. There is a suggestion from two studies that ticagrelor was associated with a reduced risk of secondary vascular events (summary HR: 0.76, 95% CI: 0.65–0.90), albeit with a slightly increased risk of bleeding. ¹² The NICE diagnostic guidance in 2024 has demonstrated that CYP2C19 testing for new non‐minor ischaemic stroke and TIA was both clinically effective and cost effective. ¹³ The 2023 National Clinical Guideline for stroke for the United Kingdom and Ireland ⁵ recommended testing after recurrent events while taking clopidogrel.

3.2. CAD

Upfront use of pharmacogenetic testing for clopidogrel is not currently routine clinical practice in the United Kingdom for the management of individuals with CAD. ¹⁴ While this could be driven by the use of more potent P2Y12 inhibitors as part of DAPT regimens (such as aspirin + ticagrelor or aspirin + prasugrel), the underutilization may also reflect the high success (and low complication) rates of contemporary percutaneous coronary intervention (PCI), as well as a lack of awareness among physicians as to the role of routine pharmacogenetic testing. Against this backdrop, in 2024, the American Heart Association released a statement supporting clopidogrel pharmacogenetic testing when used for cardiovascular disease. ¹⁵ Their analysis included a summary of meta‐analyses, which all point to subjects with CYP2C19 LOF alleles experiencing more major adverse cardiovascular events (MACE).

Of the clinical trials reviewing outcomes with genotype guided care, the TAILOR‐PCI and POPular Genetics trials had the largest cohorts. In the TAILOR‐PCI trial ¹⁶ the primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis and severe recurrent ischemia at 12 months occurred in 4% of the genotype‐guided group (where patients with the *2 and *3 LOF variants were prescribed ticagrelor instead of clopidogrel) and in 5.9% of the conventional therapy group (HR: 0.66, 95% CI: 0.43–1.02; p = .06). A further analysis of the TAILOR‐PCI trial which captured both the first ischaemic event and subsequent events showed a reduction in the cumulative primary endpoint in the genotype‐guided group vs. the conventional therapy group (HR: 0.61, 95% CI: 0.41–0.89; p = .011). ¹⁷ Importantly, in both the primary and the subsequent analyses, there was no evidence of an increase in minor or major bleeding from genotype guided care. The POPular Genetics trial showed that the genotype‐guided strategy was non‐inferior to standard treatment with ticagrelor or prasugrel, with a reduction in bleeding (HR: 0.78, 95% CI: 0.61–0.98; p = .04) in the genotype‐guided group, reinforcing the safety of genotype guided care. ¹⁸

Following this, a 2022 meta‐analysis that included the results of the TAILOR‐PCI trial and POPular Genetics trial (alongside others) demonstrated a statistically significant reduction in MACE post‐PCI with genotype guided care (RR: 0.60, 95% CI: 0.44–0.82, p = .001, I ² = 67%). ¹⁹

3.3. PAD

Clopidogrel is licensed for PAD in the United Kingdom and remains first line therapy for secondary prevention of PAD, consistent with the guidelines from Vascular Society of Great Britain & Ireland (VSGBI) ²⁰ and NICE. ²¹ It is accepted that the evidence base for the use of clopidogrel in PAD is not as extensive as that for stroke and coronary disease. However, it is also important to note that patients with PAD are likely to have atherosclerotic arterial disease in both the coronary and cerebral circulations, and hence, the use of clopidogrel will protect patients from atherothrombosis in both the peripheral and central arterial circulations.

In a systematic review of patients undergoing CYP2C19 pharmacogenetic testing, 44 studies were included (CAD, Stroke and PAD), with just four relating to PAD. ¹¹ Of these studies, most of the included patients had undergone an intervention. While this review concluded that no meaningful conclusion could be drawn with regard to PAD outcomes, it was noted that patients with LOF alleles who had undergone endovascular therapy had a higher rate of restenosis.

This is complemented by Huang et al. who carried out a systematic review of four observational studies (sample sizes from 50 to 278) which showed that the presence of LOF alleles was associated with reduced clinical effectiveness of clopidogrel. However, they noted that the evidence base was limited and recommended the need for randomized controlled trials in PAD patients. ²²

5.1. Stroke and transient ischaemic attack

5.2. CAD

Pharmacogenetic testing for CYP2C19 variants in people with CAD should take into the account: (a) acuity of clinical presentation, (b) concomitant use of oral anticoagulants (OACs) and (c) risk of bleeding and recurrent CVD events in the individuals treated with clopidogrel. In the context of acute coronary syndromes, clopidogrel pharmacogenetic testing is recommended at the time of hospital admission for those individuals in whom clopidogrel is deemed to be the more suitable alternative to other potent P2Y12 inhibitors (due to high bleeding risk or concomitant use of OACs). In individuals diagnosed with chronic coronary syndromes (CCS, previously known as ‘stable CAD’), clopidogrel pharmacogenetic testing is recommended upon first contact with a specialist centre involved in either outpatient or day‐case management of these individuals (e.g., individuals attending cardiac catheterisation procedures). Regardless of the clinical context, initiation of clopidogrel (if deemed appropriate) should not be delayed following the first contact but must be modified based on the results of the genetic test.

5.3. PAD

PAD technically refers to areas beyond the lower limbs, including carotid and upper limb disease. Disease affecting the lower limbs is now termed lower extremity arterial disease (LEAD).

For lower limb ischaemia, there are three broad clinical scenarios:

1. Symptomatic LEAD (e.g., intermittent claudication).

   Pharmacogenetic testing for CYP2C19 variants in people with LEAD should be undertaken at the time of diagnosis with aspirin being commenced while waiting for the CYP2C19 pharmacogenetic test result. Treatment decisions should then be revised based on genotype results. Dual antiplatelet therapy is not recommended for secondary prevention in symptomatic LEAD. ²³

2. Chronic limb‐threatening ischaemia (CLTI).

   Pharmacogenetic testing for CYP2C19 variants should be undertaken urgently. Most of these patients will already be on an antiplatelet agent at the time of presentation which should be continued, with the antiplatelet choice being amended based on the test result. For any CLTI patient not on an antiplatelet agent at the time of presentation, aspirin should be used until the genotyping result is available.

3. Post‐intervention.

   Intervention for symptomatic PAD and CLTI may be endovascular alone, open surgery alone or combined endovascular and open surgery (hybrid). Pharmacogenetic testing for CYP2C19 variants should be requested in the pre‐operative period to guide post procedural prescription in combination with existing local policies and national guidelines on antiplatelet prescription after intervention.

Ischaemic events may also occur in other arterial circulations (for example, upper limb, renal or mesenteric). CYP2C19 genotyping should be undertaken if clopidogrel is being considered for treatment.

5.4. Communication with primary care

In all the above scenarios, communication with primary care (and other clinical teams) is extremely important. This communication should provide the results of the CYP2C19 pharmacogenetic testing, and whether clopidogrel prescribing needs to be initiated, modified or discontinued, based on the CYP2C19 genetic test result. This decision—as well as recommendations for ongoing anti‐platelet treatment—should be made by the specialist clinical teams who have ordered the pharmacogenetic test for the patient prior to initiation, though sharing this information to support ongoing patient care is important and can be done by enabling the result to be entered in the patient's record (e.g., by highlighting relevant SNOMED CT codes to primary care practitioners, refer to Table 2). Primary care teams may also want to consult the position statement from the Royal College of General Practitioners (RCGP) on prescribing clopidogrel and the implication of genotyping (https://www.rcgp.org.uk/representing-you/policy-areas/genomic-position-statement).

7.1. Acute non‐cardioembolic ischaemic stroke or TIA

Where clopidogrel is considered to be the choice of therapy in patients with acute presentation of non‐cardioembolic stroke or TIA, the prescribing recommendations reported in Table 5 should be considered.

The following points need to be considered when prescribing for patients with acute non‐cardioembolic ischaemic stroke or TIA:

• Clinicians should also consult the relevant clinical guidelines from specialist societies, ⁵ Royal Colleges, or NICE, ¹³ when available as well as relevant local guidelines.
• Aspirin 75 mg once daily plus ticagrelor 90 mg twice daily may be used in the acute phase for up to 30 days. A loading dose of 300 mg once daily of aspirin is only required if >72 hrs since last dose of aspirin or naïve.
• There is limited safety data on the long‐term use of ticagrelor ²⁶ , ²⁷
• The use of prasugrel for stroke is contra‐indicated
• The licences for ticagrelor and clopidogrel include information on contraindications and cautions, and it is important that these are followed. Prescribers should also be aware of drug–drug interactions with ticagrelor and clopidogrel.
• Ticagrelor is recommended as an alternative anti‐platelet agent in the 2023 National Clinical Guideline for Stroke in the United Kingdom and Ireland ⁵ although it is not licensed for use in stroke or TIA, and its use would be off label.
• Please see further discussion on the use of 150 mg once daily of clopidogrel in intermediate metabolisers below.
• In the absence of available relevant pharmacogenetic information or testing the current best practice clinical guidelines should be followed.

7.2. CAD

Where clopidogrel is considered to be the choice of therapy in patients with different clinical presentations of CAD, the prescribing recommendations reported in Table 6 should be considered.

The following points need to be considered when prescribing for patients with different presentations of CAD:

• Clinicians should also consult the relevant clinical guidelines from specialist societies, ²⁸ , ²⁹ , ³⁰ , ³¹ Royal Colleges, or NICE, when available, as well as relevant local guidelines. Guidance should also be followed on the duration of antiplatelet therapy, including both monotherapy and dual therapy.
• Prasugrel has a licensed 5 mg dose for adults <60 kg and adults over 75 years.
• Loading doses of prasugrel (60 mg) or ticagrelor (180 mg) may need to be used in certain instances depending on clinical need. Local guidance should be followed for that.
• The licences for prasugrel, ticagrelor and clopidogrel include information on contraindications and cautions, and it is important that these are followed. Prescribers should also be aware of drug–drug interactions with ticagrelor, prasugrel and clopidogrel.
• If a patient is an intermediate or poor metaboliser, loading doses of clopidogrel should be avoided.
• Licensed doses of antiplatelet agents, or those recommended in clinical guidelines, and the recommended duration of therapy should be used whenever possible.
• In the absence of available relevant pharmacogenetic information or testing, the current best practice clinical guidelines should be followed.

7.3. PAD

For lower extremity arterial disease (LEAD), clopidogrel is considered to be the standard of care, but its use should be modified according to CYP2C19 genotype as outlined in the Table 7.

The following points need to be considered when prescribing for patients with different presentations of PAD:

• The European Society for Vascular Surgery does not recommend dual antiplatelet therapy for secondary prevention in symptomatic LEAD. ²³
• Dual antiplatelet therapy may be needed after revascularisation procedures for a period of 1–6 months. This may be clopidogrel and aspirin (in ultra‐rapid and normal metabolisers). However, in intermediate and poor metabolisers, alternative regimens should be considered such as aspirin alone, or in those patients at high risk of ischaemic events but with low bleeding risk, the use of aspirin combined with low‐dose rivaroxaban, 2.5 mg twice daily. Please consult the relevant specialist guidelines. ²⁰ , ²¹ , ²³ , ³²
• For CLTI, the time‐to‐treatment guidelines in the United Kingdom recommend revascularization within 5 days for hospitalized patients and 14 days for outpatients with CLTI. These timeframes are based on the UK's Vascular Society's Peripheral Arterial Disease Quality Improvement Framework (PAD‐QIF), ²⁰ emphasizing the urgency of treatment to prevent major amputation and mortality.
• Ticagrelor is not used in vascular surgery patients. It was found to be non‐superior to clopidogrel in the EUCLID ³³ study in preventing MACE events in patients with symptomatic PAD. Its use is not advocated in any of the above‐mentioned guidelines. Among the key exclusion criteria of this trial, there was the poor clopidogrel metaboliser status for the CYP2C19 allele, defined as a genotype with two LOF alleles.
• For the treatment and prevention of atherothrombotic events in other arterial circulatory systems (upper limb, renal or mesenteric), if clopidogrel is used, please used the guidance in the table above. Please note that the evidence base on choice of antiplatelet agent(s) and duration of therapy is poor in these patients, and specialist guidelines should be consulted. ²⁰ , ²¹ , ²³ , ³²
• The licences for clopidogrel and rivaroxaban include information on contraindications and cautions, and it is important that these are followed. Prescribers should also be aware of drug–drug interactions with ticagrelor and clopidogrel.
• In the absence of available relevant pharmacogenetic information or testing, the current best practice clinical guidelines should be followed

7.4. Use of alternatively dosed clopidogrel in CYP2C19 intermediate metabolisers

The use of alternatively dosed clopidogrel (150 mg once daily, 600 mg loading dose), which would be off label, has been suggested based on the patient's bleeding risk and drug efficacy considerations. The Dutch Pharmacogenetics Working Group (DPWG) guideline on clopidogrel, available through the ClinPGx database, ³⁴ recommends the use of 150 mg once daily of clopidogrel in CYP2C19 intermediate metabolisers, for those patients who have undergone percutaneous coronary intervention for whom the bleeding risk with prasugrel or ticagrelor is considered too high or for stroke/TIA patients who do not tolerate the combination of aspirin and dipyridamole. However, there is lack of consensus on its use since the CPIC ³⁵ and French National Network of Pharmacogenetics (RNPGx) guidelines ³⁴ do not recommend the use of 150 mg once daily of clopidogrel.

We have assessed the pharmacokinetic and clinical literature in this area and note that (a) the 150 mg dose of clopidogrel does lead to higher exposure to the active metabolite of clopidogrel than 75 mg; (b) the risk of bleeding is increased with 150 mg clopidogrel compared to 75 mg; and (c) the clinical benefit appears greater with ticagrelor than with 150 mg clopidogrel.

Therefore, we recommend the use of ticagrelor (when appropriate), or other non‐CYP2C19 metabolized antiplatelets if licensed, rather than 150 mg clopidogrel in intermediate metabolisers. We acknowledge, in certain patient populations, such as frail patients with multiple comorbidities, the bleeding risk associated with ticagrelor, or other antiplatelet agents may be considered too high. In such cases, clinical discretion is advised. If use of 150 mg once daily of clopidogrel is considered, the extent to which this reduces bleeding risk relative to alternatives remains uncertain, and careful clinical monitoring for bleeding is crucial.

8.1. The clinical pharmacogenetics implementation consortium guideline

CPIC published the first guideline on the use of CYP2C19 genotyping to improve the prescription of clopidogrel in 2011, ³⁶ followed by two updates in 2013 ³⁷ and 2022. ³⁵ The latest guideline ³⁵ recommends avoiding clopidogrel in CYP2C19 intermediate metabolisers (or likely intermediate metabolisers) and poor metabolisers (or likely poor metabolisers) and using an alternative antiplatelet agent, such as prasugrel or ticagrelor, if not contraindicated, in patients with acute coronary syndrome and/or undergoing PCI. The recommendations remain unchanged from previous guidelines. The strength of recommendations is ‘strong’ for both phenotypes, with a shift in the strength of recommendations from ‘moderate’ to ‘strong’ for CYP2C19 intermediate metabolisers. A standard dose of clopidogrel is recommended for CYP2C19 normal, rapid and ultrarapid metabolisers. These recommendations also apply to patients undergoing elective PCI. In contrast, there is a ‘moderate’ recommendation to avoid clopidogrel in CYP2C19 poor metabolisers (or likely poor metabolisers) in the other non‐ACS, non‐PCI cardiovascular indications. These include PAD and stable CAD following a recent myocardial infarction outside the PCI setting.

In the setting of neurovascular disease, the CPIC guideline recommends clopidogrel at standard doses in CYP2C19 normal metabolisers, with a ‘moderate’ recommendation to avoid clopidogrel in CYP2C19 poor metabolisers and in both intermediate and poor metabolisers to consider an alternative P2Y12 inhibitor at standard doses, in absence of contraindications. The guideline also highlights the haematological toxicity of ticlopidine (not licensed in the United Kingdom) and the contraindication of prasugrel in patients with a history of stroke and TIA.

The 2022 CPIC guideline does not support the use of 150 mg daily dose of clopidogrel in CYP2C19 intermediate metabolisers. ³⁵

8.2. The Dutch pharmacogenetics working group guideline

The DPWG has published therapeutic dose recommendations for clopidogrel based on CYP2C19 genotype in 2011. ³⁸ The latest update on this gene‐drug pair was issued in 2018 and is available through the ClinPGx website. ³⁴ Currently, the DPWG recommends avoiding clopidogrel in CYP2C19 poor metabolisers undergoing percutaneous coronary intervention, or in those who have a stroke or TIA. The guideline recommends choosing an alternative drug, that is, ticagrelor or prasugrel after PCI, dipyridamole together with aspirin in stroke or TIA, or double the dose of clopidogrel to 150 mg once daily (with 600 mg loading dose) in CYP2C19 intermediate metabolisers. No action is required for CYP2C19 ultrarapid metabolisers. The DPWG underlines that ticagrelor and prasugrel are not metabolized by CYP2C19 or to a lesser extent than clopidogrel, respectively and are associated with an increased bleeding risk compared to clopidogrel. The DPWG has assigned a Clinical Implication Score of 8+ to CYP2C19 pharmacogenetic testing in PCI and stroke/TIA patients prior to clopidogrel meaning that the test is ‘essential’ before starting therapy or shortly after initiation.

8.3. The French National Network of pharmacogenetics guideline

The RNPGx guideline for CYP2C19 and clopidogrel is available via the ClinPGx database. ³⁴ The guideline recommends pharmacogenetic testing for the main CYP2C19 deficiency alleles before clopidogrel administration. The pharmacogenetic test is considered essential for coronary angioplasty with stenting and potentially useful in other indications. The RNPGx recommends using an alternative treatment that is not a substrate of CYP2C19 (prasugrel, ticagrelor, acetylsalicylic acid), in subjects with at least one LOF allele. Based on the available evidence, the RNPGx does not recommend increasing the clopidogrel dose in subjects with one LOF allele. It also underlines that the CYP2C19*17 variant has been associated with increased risk of bleeding but also increased efficacy. There is not sufficient data to modify therapy in this subgroup of patients.

The ClinPGx database provides updated CYP2C19 gene‐specific information tables, including new allelic variants, their function and frequency. ² In addition, the PGx Working Group of the Association for Molecular Pathology Clinical Practice Committee issues periodical recommendation on the CYP2C19 variants that need to be tested as mentioned above. ²⁴

Table 8 provides a summary of current PGx guidelines.

9.1. Stroke and transient ischaemic attack

NICE assessed two point‐of‐care genotype tests (Genedrive CYP2C19 ID Kit and Genomadix Cube CYP2C19 system) and laboratory testing to guide clopidogrel use after ischaemic stroke or transient ischaemic attack. ¹³ The cost per test was calculated as £104 for Genedrive, £197 for Genomadix Cube and and £139 for laboratory testing (reducing to £44 with testing in batches of 55). The economic model informing the assessment was based on a decision tree used to capture short‐term (90 day) outcomes, and a Markov model with a 1‐year cycle to capture outcomes over a patient's life‐time. ¹² Testing done for people with non‐minor stroke resulted in positive incremental net monetary benefit (INMB) irrespective of the method used. While still positive, the INMB was lower for those with minor stroke or transient ischaemic attack, with values ranging from £753 to £1131. Tests remained cost effective when the choice of antiplatelet and timing of treatment were varied. Compared with no testing, the cost of each test would have to be much higher (around £1900 higher for Genedrive, £1800 higher for the Genomadix Cube and £1920 for laboratory‐based testing) for testing not to be cost effective.

The main limitation of the analysis was the absence of studies to provide direct evidence on the efficacy of genotype testing. As a result, the economic model relied on indirect evidence to estimate the effects of alternative antiplatelet therapies depending on LOF status. ³⁹

Although there was little difference in the QALYs generated by the different methods of testing, NICE stated a preference for laboratory‐based tests over point‐of‐care tests because of the greater flexibility available in relation to testing for new variants, the likelihood of introducing greater health inequalities with point‐of‐care tests left to local decision makers, the difficulty in ensuring standardization in quality assurance, and the likely future shift from reactive to pre‐emptive genotyping. ¹³ However, the committee did note that the estimated cost per test for Genedrive is less than for Genomadix Cube and concluded that Genedrive was its preferred point‐of‐care test. This was also based on other advantages of the Genedrive platform including the fact that reagents do not need to be stored in a freezer and the flexibility to detect additional alleles including those that occur at a greater frequency in some ethnic groups.

9.2. CAD

The economic evidence for single gene (CYP2C19) pharmacogenetic testing relates to patients with acute coronary syndrome. ⁴⁰ , ⁴¹ , ⁴² , ⁴³ Of 24 published analyses, 19 examined the effect of escalating antiplatelet treatment from clopidogrel to ticagrelor or prasugrel in patients found to have a loss‐of‐function allele. The majority of cost utility analyses (14/21) considered costs from the perspective of payers in the USA, with the remaining coming from a wide variety of jurisdictions among European, Middle eastern and Asian countries including Hong Kong, Singapore and China. There were no UK economic evaluations. In nine analyses, a genotype guided strategy was found to dominate all other options; among the remaining economic analyses, universal ticagrelor was found to be most cost effective in 3, a genotype approach most cost effective in 8 and a non‐guided de‐escalation approach in 1. While the economic evidence lends support to CYP2C19 pharmacogenetic testing in patients with acute coronary syndrome, cost‐effective analyses that are relevant to the NHS in the United Kingdom are required.

9.3. PAD

No economic evaluations were identified for CYP2C19 pharmacogenetic testing in relation to the use of clopidogrel in PAD.

10.1. Summary of product characteristic (SmPC) 4

The UK SmPC highlights the role of CYP2C19 genetic polymorphisms in clopidogrel metabolism and platelet function in Section 4.4 of the document. It also describes some of the evidence of this genetic polymorphism on clinical outcomes (in Section 5.2 of the SmPC), but states that ‘The influence of CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel has not been evaluated in prospective, randomised, controlled trials’, indicating that it has not been updated with the latest evidence. The SmPC does not recommend pharmacogenetic testing for CYP2C19 prior to clopidogrel therapy, but states that tests are available. The SmPC however does recommend the avoidance of concomitantly administered drugs that are known to be strong or moderate CYP2C19 inhibitors, since they can reduce the formation of the active metabolite of clopidogrel. Clinical actions based on genotype recommended by this guideline are not included in Section 4.2 of the SmPC of clopidogrel containing medicinal products.

Ticagrelor is not licensed for the treatment of stroke/TIA in the United Kingdom or EU. In 2021, the licence holder withdrew its application to the European Medicines Agency (EMA) for use in stroke/TIA. At the time of withdrawal, the EMA was of the opinion that the benefits did not outweigh the risks. However, ticagrelor is authorized by the FDA ‘to reduce the risk of stroke in patients with acute ischemic stroke (NIH Stroke Scale score ≤5) or high‐risk transient ischemic attack (TIA)’. As mentioned previously, ticagrelor is recommended as an alternative anti‐platelet agent in the 2023 National Clinical Guideline for Stroke in the United Kingdom and Ireland. ⁵

10.2. NICE diagnostics guidance (DG59 – published 31 July 2024) 13

NICE has recommended the use of CYP2C19 pharmacogenetic testing to determine if clopidogrel is a suitable antiplatelet agent for people who have just had an ischaemic stroke or a transient ischaemic attack. NICE recommends the use of lab‐based testing, or point‐of‐care testing when lab‐based testing is not available. Retrospective pharmacogenetic testing of people already on clopidogrel was considered to be outside the scope of assessment and the guidance noted that the risk of recurrent stroke or TIA is highest in the first 90 days after stroke or TIA and then decreases. Pharmacogenetic testing of people with CAD and other indications for the use of clopidogrel was also outside the scope of assessment.

12.1. Variation in CYP2C19 activity

• There are many CYP2C219 allelic variants where the functional effects are unclear. Thus, further work to assess their functional effects would help in improving the phenotype–genotype relationship of CYP2C19.
• CYP2C19*17 is associated with increased activity of the CYP2C19 enzyme. Theoretically, this could increase the risk of bleeding associated with clopidogrel. However, the evidence for this is contradictory, and further work is needed to determine whether having the CYP2C19*17 allele increases the risk of bleeding overall, and in particular, in certain patient sub‐groups, such as the elderly.
• Further work is needed to better understand the utility of 150 mg of clopidogrel in CYP2C19 intermediate metabolisers in terms of clopidogrel pharmacokinetics and clinical efficacy and safety.
• The issue of phenoconversion with concomitant drugs has been mentioned in this guideline. However, there is also evidence that severe forms of non‐alcoholic steatohepatitis reduce the expression of CYP2C19 at the mRNA level, and potentially activity. Further work is required to determine (a) whether clopidogrel use provides inadequate protection in these patients (irrespective of genotype), and (b) whether the same effect is also seen in other forms of severe liver disease where inflammation is prominent.
• There is a need for further research on the utility of CYP2C19 genotyping in PAD ⁴⁵ (lower limb, upper limb, renal, etc.), including health economic evaluation.
• Health economic analysis of CYP2C19 genotyping in CAD in the UK setting is needed.

12.2. Efficacy and safety of antiplatelet agents

• There are limited safety data on the long‐term use of ticagrelor in stroke, CAD and PAD. This is an area that deserves further investigation. Considering the likely wide implementation of CYP2C19 pharmacogenetic testing in this therapeutic area, follow up of patients prescribed ticagrelor according to this guideline may fill in the gap.
• Ticagrelor is not currently recommended for major stroke, and the need for a randomized controlled trial assessing the efficacy and safety needs to be considered.
• The clinical effectiveness of genotyping and antiplatelet switching in prevalent clopidogrel users (i.e., use greater than 6 months since the acute indication) in the three main clinical areas needs to be undertaken, together with an omnibus analysis.

12.3. Platelet function tests (PFTs)

The role of platelet function testing in assessing the response to clopidogrel has not been fully validated. The 2024 update of the International Consensus Statement on Platelet Function and Genetic Testing in Percutaneous Coronary Intervention ⁴⁶ provides different cut‐off points for different PFTs to define the high and low platelet reactivity. The Consensus Statement also highlights the limitations of platelet function assays, including the uncertainty on the optimal timing of testing with relation to the PCI, inter‐assay and intra‐patient variability of readouts, difficulties in using these tests in the context of ACS and during de‐escalation from prasugrel/ticagrelor to clopidogrel. Therefore, there is a need for further research on the role PFTs can play in determining the optimal use of clopidogrel and other antiplatelet agents, whether they should be used instead of pharmacogenetic testing or in conjunction with pharmacogenetic testing, especially in intermediate metabolisers.

Supplementary Materials

Data Availability Statement

The data that support the findings of this guideline are publicly available, as referenced.