NICE опубликовало рекомендации по генетическому тестированию для оптимизации терапии клопидогрелом

After reading this article, you should be able to: - Describe clopidogrel’s mechanism of action, including its prodrug status, CYP2C19‑dependent and irreversible activation pathway, and how genetic variation alters drug metabolism and clinical response; - Assess the safety and effectiveness of clopidogrel, including contraindications, gastrointestinal bleeding risk and drug–drug interactions; - Interpret CYP2C19 diplotype and phenotype results and apply UK‑specific guidance (e.g. National Institute for Health and Care Excellence and Centre for Excellence in Regulatory Science and Innovation in Pharmacogenomics) to recommend appropriate antiplatelet therapy across stroke, coronary and peripheral artery disease; - Provide effective patient counselling on clopidogrel use, promoting adherence and identifying challenges to compliance, as well as management of side‑effects. Introduction Clopidogrel is an antiplatelet (i.e. P2Y12 platelet inhibitor) widely used in the prevention and treatment of atherothrombotic events, with 12 million items dispensed in England between June 2025 and May 20261,2. In 2024, the National Institute for Health and Care Excellence (NICE) published guidance on CYP2C19 genotype testing to guide clopidogrel use after ischaemic stroke or transient ischaemic attack3. In 2025, the Centre of Excellence for Regulatory Science and Innovation in Pharmacogenomics (CERSI-PGx) published their first UK guideline, focusing on pharmacogenomic-informed clopidogrel prescribing4. While these guidelines may seem most relevant to hospital-driven, niche prescribing, the NHS ten-year plan emphasised the importance of genomic medicine and pharmacogenomics in how we prevent disease, as well as diagnose and treat patients5. Therefore, clopidogrel may be the first of many commonly prescribed drugs where pharmacogenomic testing plays a role in the prescribing decision process, creating the opportunity to make prescribing safer and tailored to the individual. Clopidogrel mechanism of action Clopidogrel is a prodrug which requires hepatic biotransformation to form an active metabolite that selectively and irreversibly inhibits platelet aggregation, with only around 15% of clopidogrel being converted to its active form6. Several cytochrome p450 enzymes are involved in this process, but the predominant enzyme is CYP2C19, which is the only one involved in both steps of this oxidative process7,8. Figure 1: Absorption and metabolisation of clopidogrel to form an active metabolite Impact of genetic variation The CYP2C19 gene is highly polymorphic and can lead to a number of phenotypes resulting in decreased or increased enzyme activity where the most common loss-of-function (LOF) variant alleles are CYP2C19*2 and *3 alleles, which result in degraded or non-functional proteins9. CYP2C19 LOF allele carriers have significantly reduced active clopidogrel metabolite levels when compared with wild type individuals10. These individuals will be at an increased risk of recurrent events when compared with non-carriers of LOF alleles while treated with clopidogrel11–17. The frequency of these polymorphisms varies according to ethnicity — for example, 25-30% of white European population are estimated to carry 1 or 2 of these LOF variants18,19, while frequencies are higher than 50% among some Asian ethnicities19. Despite this evidence, the CYP2C19 metaboliser status of most patients prescribed clopidogrel is still often unknown at the point of prescribing. Pharmacogenomic testing in the UK NICE recommends that CYP2C19 pharmacogenomic testing is carried out in patients presenting with acute non-cardioembolic ischaemic stroke. This recommendation is being rolled out at varied speeds across the four nations of the UK as practical challenges are being addressed, with Scotland aiming for nationwide adoption by the end of 202620. The indication for the use of clopidogrel extends beyond stroke prevention with licensed indications for secondary prevention of atherothrombotic events in patients presenting with myocardial infarction and peripheral arterial disease21. This equates to a disparity in current practice when it comes to clopidogrel prescribing and use of pharmacogenomic testing to identify patients at risk of treatment failure. Clopidogrel indications Clopidogrel’s clinical indications encompass prevention and management of cardiovascular and cerebrovascular events, as well as peripheral arterial disease (see Table 1)21–34. Table 1: Currently licensed indications for clopidogrel in adults in the UK Clopidogrel cautions and contraindications The UK summary of product characteristics (SmPC) for clopidogrel lists the following contraindications: hypersensitivity to the active substance or excipients; severe hepatic impairment; or active pathological bleeding such as peptic ulcer or intracranial haemorrhage21. Additionally, clopidogrel should be prescribed with caution to people at risk of increased bleeding, taking other drugs known to increase bleeding risk, with renal or hepatic impairment or hypersensitivity to thienopyridines — for example, prasugrel — owing to the risk of cross-sensitivity35. Should a proton pump inhibitor be prescribed along with clopidogrel? One common consideration in clinical practice relates to the increased risk of gastrointestinal (GI) bleeding with the initiation of antiplatelet therapy. GI bleeding may occur because of mucosal breaks along the GI tract, which may be exacerbated by antiplatelet therapy36. NICE advises that those at higher risk of GI adverse effects and taking clopidogrel alone, or in combination with low-dose aspirin, be co-prescribed a proton pump inhibitor (PPI)35,37. Higher risk factors for GI adverse effects include: - Patients aged over 75 years; - History of gastroduodenal ulcer; - GI bleeding or gastroduodenal perforation; - Helicobacter pylori infection or concomitant use of medicines that are known to increase the risk of GI bleed (e.g. another antiplatelet, anticoagulants, non-steroidal anti-inflammatory drugs, corticosteroids and selective serotonin reuptake inhibitors)37. Which PPI should be prescribed? PPIs are inhibitors of CYP2C19, meaning that concurrent use can reduce plasma levels of activated clopidogrel. However, varied clinical significance has been observed in observational studies and meta-analysis38,39. Treatment decisions in individual patients must balance the risks of cardiovascular and GI complications, while sometimes the benefits of a PPI may outweigh the risk of reduced clopidogrel efficacy. The Medicines and Healthcare products Regulatory Agency (MHRA) and European Medicines Agency discourage the use of omeprazole and esomeprazole in patients taking clopidogrel. In addition, the European Society of Cardiology advises that lansoprazole, pantoprazole and rabeprazole have intermediate-to-reduced probability of interacting with clopidogrel and should be preferred in detriment of omeprazole or esomeprazole40–42. Elective surgery and dental procedures A single oral dose of 75 mg clopidogrel has a half-life of around 6 hours21. Owing to irreversible binding, platelets exposed to clopidogrel are affected for the remainder of their 7–10-day lifespan43,44. Consequently, owing to bleeding risk, consideration should be given to the risk-benefit of continuing or stopping clopidogrel prior to elective surgery and dental procedures. The SmPC for clopidogrel advises: “If a patient is to undergo elective surgery and antiplatelet effect is temporarily not desirable, clopidogrel should be discontinued 7 days prior to surgery.”21 Prior to dental procedures, individual circumstances will need to be evaluated; however, usually clopidogrel does not need to be stopped45,46. Drug interactions Use of medicines that inhibit CYP2C19 activity may result in reduced drug levels of the active metabolite of clopidogrel21. However, clinical significance of a drug–drug interaction is not determined solely by the existence of a mechanistic interaction — it requires a careful and structured evaluation, which includes pharmacological principles, patient-specific factors and consultation of evidence-based resources47–49. Drugs that may reduce the antiplatelet effect The manufacturer of clopidogrel advises — as a precaution — that concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged21. Examples of such CYP2C19 inhibitors include antifungals (e.g. voriconazole, fluconazole and ketoconazole), carbamazepine, efavirenz, moclobemide and some PPIs (e.g. omeprazole and esomeprazole). Antidepressants, such as fluoxetine and fluvoxamine, may reduce levels of the active metabolite of clopidogrel; however, the clinical significance is unclear, although some studies suggest a small increase in the risk of ischemic events, especially in older adults (i.e. patients aged under 65 years)50. If clopidogrel is prescribed for cardiac indications concomitant use with some antidepressants may carry additional risks. Sertraline is often the first-line choice in these scenarios owing to fewer known cardiac side effects and reduced likelihood of interactions with cardiac medicines51. Close evaluation is needed when balancing the significance and risk of these drug interactions, as well as how to best mitigate them. Consider that switching to an alternative drug may disrupt an established treatment and that switching may carry additional risks — for example, in the management of depression or epilepsy. NICE guidance suggests that grapefruit juice should be avoided owing to reduced inhibition of platelet aggregation. It is also noted that opioids have the potential to delay gastric emptying, which may reduce the rate of absorption of clopidogrel35, although the clinical significance is limited and unlikely to be a factor in drug choice52. Drugs that may be affected by clopidogrel Drugs such as montelukast, pioglitazone and repaglinide may have their levels increased owing to inhibition of the CYP2C8 isoenzyme by metabolites of clopidogrel30,53. Clopidogrel may increase exposure to rosuvastatin; however, the SmPC for rosuvastatin54 indicates this interaction not to be clinically relevant at standard treatment doses. In the case of rifampicin, the manufacturer discourages concurrent use with clopidogrel because of an increased bleeding risk owing to induction of CYP2C1920. Pharmacy teams should be mindful of these interactions — particularly following initiation of treatment or dose modification — and should monitor for adverse effects and drug efficacy. This is not an exhaustive description of all drug interactions with clopidogrel. The British National Formulary, SmPCs and Stockley’s Drug Interactions46 should be used to inform clinical decisions. Patient counselling Patient’s adherence and concordance with any treatment modification is correlated with positive patient outcomes55,56. At every interaction with a patient taking clopidogrel, pharmacists should address education and counselling. They should engage in active listening to identify any challenges the patient may experience that could contribute to intentional or unintentional non-adherence to treatment. Reasons for behaviours that drive low rates of medication adherence are often complex and multifaceted47,48. Patients need to be informed, motivated and supported to take their medicines optimally, the following points can help facilitate this: - Explain why clopidogrel has been prescribed and more importantly what is the benefit to the patient; - Emphasise that therapy should not be stopped abruptly without consulting a healthcare professional owing to the risk of thrombotic events; - Explain dose and duration of treatment, detailing if treatment is lifelong or should stop on a particular date — for example, following cardiac events clopidogrel duration may be limited in time when prescribed as part of a dual antiplatelet regimens and dependant on risk and indication/procedure; - If a dose is missed and still within 12 hours from the regular scheduled time, patients should be advised to take the dose immediately and then at the next regular time. If more than 12 hours have passed, then take the next dose at the regular time and do not double the dose20; - Discuss, in a reassuring way, common side-effects such as diarrhoea, indigestion and stomach pain20,49. Be specific about the potential side effects but also be realistic about the likelihood of them occurring. Table 249,57–59 suggests some tips to cope with these side effects. For additional information on communicating with patients, see ‘Communication techniques for prescribing’; - Make patients aware that bruising and bleeding may occur more easily and that typical cuts may take longer to stop bleeding. However, patients should be advised to report to their doctor, any unusual or prolonged bleeding such as blood in urine or stools or vomiting blood; - Instruct patients to inform healthcare professionals, including dentists, about clopidogrel use before any surgical or invasive procedure; - Advise patients to avoid over-the-counter (OTC), non-steroidal anti-inflammatory drugs owing to increased GI bleeding risk and to discuss OTC purchases with a pharmacist who can advise on specific drug interactions; - If already taking clopidogrel enquire, in a non-judgemental way, about any challenges to compliance50. Be clear from the start that this is a collaborative process to identify difficulties they may be experiencing taking their medication and finding ways to support them, and there is no intention of assigning blame for missed doses or inappropriate use. This is particularly important after stroke, as it is not uncommon for new dexterity, cognition, visual or swallowing deficits to exist. Explore patient and illness related challenges51 and support these where possible52. The specialist pharmacist service offers advice on how to support specific adherence challenges. Table 2: Common side effects of clopidogrel and management Pharmacogenomic testing Testing is recommended by NICE3, following non-cardioembolic ischaemic stroke and CERSI-PGx4 for any patient who is about to be prescribed clopidogrel, regardless of underlying condition to identify clinically relevant CYP2C19 variants; however, the reality is that availability of pharmacogenomic testing will vary greatly depending on geography and indication3,4. Ordering a pharmacogenomic test Current NICE and CERSI-PGx guidance recommend reactive pharmacogenomic testing, triggered by a thrombo-occlusive event. However, if CYP2C19 results already exist in the patient’s record these should be used to inform prescribing4. Therefore, when reviewing patients who are prescribed clopidogrel, pharmacists with clinical access to this information should consider if there are pre-existing CYP2C19 results in the patient’s medical records, as it may have been performed owing to a previous event. However, caution should be exercised with pharmacogenetic test results from commercial, direct-to-consumer providers from non-accredited laboratories, which are becoming increasingly advertised and available to patients60. If a CYP2C19 PGx result does not yet exist on the patient’s records, consider if testing would be appropriate, indicated and available to request. Accounting for: - What the indication is — as a local pharmacogenomic testing pathway may be implemented for patients following stroke in accordance to NICE recommendation3 but not yet implemented for cardiology related events; - If it is an acutely initiated or long-standing prescription, currently NICE and CERSI-PGx recommend PGx testing for acute initiation of clopidogrel; - How it is commissioned — commissioning of pharmacogenomic testing will differ between regions and nations. Pharmacists will order the pharmacogenomic test or discuss the recommendation to test with the clinician responsible for the care of the patient in accordance with the locally agreed protocol for testing. Interpreting a pharmacogenomic test When a CYP2C19 PGx result is available, pharmacists should review how it is presented. Results are often presented as phenotype or diplotype. See Table 361 for a summary of the correlation between the two. Table 3: CYP2C19 phenotype based on the most common CYP2C19 allelic variants Actions following a pharmacogenomic test While some reports may include a recommended clinical action specific to the clopidogrel indication others may report the diplotype/phenotype identified. The interpretation will be made by the clinician with resort to established pharmacogenomic prescribing guidelines; however, local practice may differ. CERSI-PGx, following evaluation of existing evidence and UK expert consensus, has published prescribing suggestions for clopidogrel based on pharmacogenomic test results, which are detailed in Table 44,22. Recommendations from this UK guideline shows overall concordance with recommendations from other established international pharmacogenomic guidelines such as those produced by the Clinical Pharmacogenomics Implementation Consortium (CPIC)62 and the Dutch Pharmacogenomic Working Group (DPWG)63. Table 4: Recommended clinical actions based on the pharmacogenetic test results adapted from CERSI-PGx guidelines for clopidogrel Other drugs metabolised by CYP2C19 In addition to reviewing the suitability of clopidogrel following a CYP2C19 PGx test, consider that other co-prescribed drugs may be metabolised by the same enzyme. Consider the pharmacokinetics of these drugs and its relevance to drug–gene or drug–drug-gene interactions, as well as understand the existing legal framework to support a PGx-informed prescribing decision for a specific medicine: - Consult the SmPC and BNF — an increasing number of drug labels describe the impact of pharmacogenomic variability has on drug metabolism. For example, citalopram64 has specific dose adjustment recommendation for those found to be CYP2C19 poor metabolisers, while drugs such as lansoprazole describe pharmacokinetic variation linked to phenotype but without specific recommendation for dose modification65. In either case, it is important to holistically assess the patient, consider all characteristics that may contribute to increased or decreased drug exposure and clinically assess the risks involved in the decision to modify or continue treatment (e.g. treatment failure from reduced drug exposure and QT prolongation risk from increased exposure). - Consult local, national or international guidelines— Both CPIC and DPWG have published international pharmacogenomic guidelines for drugs metabolised by CYP2C19, such as selective serotonin reuptake inhibitors66,67 and tricyclic antidepressants68,69 and PPIs70 among others, these can be accessed here. In the UK, CERSI-PGx published their first CYP2C19 pharmacogenomic guideline focused on clopidogrel4, but further CYP2C19 guidelines are expected later in 2026. Mavacamten is approved by the MHRA71 with a specific dose algorithm dependent on CYP2C19 phenotype. 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