Clopidogrel and CYP2C19

Updated: Mar 24, 2020
  • Author: Kyong Chong, MD, PharmD; Chief Editor: Karl S Roth, MD  more...
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Practice Essentials

Clopidogrel (Plavix), a second-generation thienopyridine that inhibits platelet aggregation, is a mainstay, along with aspirin, in the management of patients with coronary artery disease, with acute coronary syndromes (ACS), and/or after percutaneous coronary interventions (PCI). [1, 2] Yet, a significant proportion of patients remain at risk for subsequent death, myocardial infarction (MI), stent thrombosis, and stroke because of insufficient clopidogrel-induced platelet inhibition. Approximately 30% of the US population carries a CYP2C19 loss-of-function (LOF) allele, which puts these individuals at increased risk for major adverse cardiovascular events (MACE) if treated with clopidogrel after undergoing percutaneous coronary intervention. [3, 4, 5, 6]

Clopidogrel is an inactive prodrug that requires hepatic bioactivation via several cytochrome P450 enzymes, including CYP2C19. The active metabolite irreversibly inhibits the platelet ADP receptor, P2Y12. A number of different alleles of CYP2C19 have been identified; depending on the allele present, laboratory demonstrations of the enzymatic activity of CYP2C19 can be normal, reduced, or increased. [7, 8, 9, 10]

The *1 ("star 1") allele is the normal copy that has full enzymatic activity. The *2 ("star 2") and *3 ("star 3") alleles are the most common variants and result in complete loss of enzymatic activity. [7] Consequently, carriers of the *2 and *3 alleles have reduced formation of clopidogrel's active metabolite and demonstrate reduced clopidogrel-induced platelet inhibition. [8, 11]

The prevalence of the *2 and *3 alleles vary by ethnicity. In Caucasians, Blacks, and Asians, the proportion of patients who carry at least one copy of *2 is 25%, 30%, and 40-50% respectively, while the proportion for *3 is less than 1%, less than 1%, and 7%, respectively. Additional variants, *4 and *5, also result in no enzymatic activity, but these variants are rare in all ethnicities (< 1%) and their effect on laboratory outcomes has not been fully documented. Finally, the variant *17 is present in nearly 40% of Caucasians, Blacks, and Asians, and results in increased CYP2C19 activity, higher production of active metabolite, and improved clopidogrel-induced platelet inhibition. [9, 10]

Approximately 2% of Caucasians, 4% of African Americans, and 14% of Chinese are CYP2C19 poor metabolizers, and up to 45% of patients are CYP2C19 intermediate metabolizers. Individuals who carry 1 or 2 nonfunctional copies of the CYP2C19 gene are classified as intermediate metabolizers and poor metabolizers, respectively. Patients with 2 normal copies of the CYP2C19 gene are normal metabolizers. [9, 12, 13, 14, 15, 16, 17, 18, 19]

A growing body of evidence suggests that CYP2C19 genotype-guided antiplatelet therapy improves patient outcomes following PCI. Studies demonstrate that a genotype-guided approach reduces risk of MACE in CYP2C19 intermediate and poor metabolizers without increasing bleeding risk. [3, 4, 20, 21, 22, 23]

In a study by Rodriguez-Gonzalez et al of 368 patients receiving combined antiaggregation therapy with aspirin and clopidogrel who were followed for 1 year, the strongest independent predictors of disease relapse were, in order, type 2 diabetes mellitus requiring insulin, having several vessels affected, and concurrent medication with calcium channel blockers, regardless of CYP3A5 genotype or drug class. [24]

Table 1. Prevalence of Genetic Variants, Their Enzymatic Activity, and Platelet Aggregation (Open Table in a new window)

Genetic Variant


CYP2C19 Enzymatic Activity

Degree of Platelet Aggregation With Clopidogrel






25% Caucasian

30% Black

40% to 50% Asian




< 1% Caucasian

< 1% Black

7% Asian



*4 and *5

< 1% of Caucasians, Blacks, and Asians




Nearly 40% of Caucasians, Blacks, and Asians




To see more information about platelet inhibition for Acute Coronary Syndrome, please go to the main article. To see more information about platelet inhibition for Percutaneous Transluminal Angioplasty Balloons, please go to the main article.


Clinical Implications of the Genetic Mutation

Because of the profound influences of genetic variation in CYP2C19 activity on clopidogrel-induced inhibition of platelet aggregation, there has been considerable investigation in extending these observations to clinical outcomes. [25, 26]

In patients who received PCI after ACS (71% non-ST segment elevation ACS, 29% ST segment elevation MI) and were treated with clopidogrel, carriers of at least one *2 allele experienced a 1.5-fold increase in the risk of cardiovascular death, MI, and stroke in the subsequent year of follow up compared with noncarriers. [9] In patients treated for ST-segment elevation MI (69% with primary PCI), carriers of any two alleles (*2, *3, *4, or *5) who were treated with clopidogrel had a 2-fold increase in the risk of the same composite outcome during follow up. [12] The highest risk appears to be in younger (age < 45 yr) patients with ST-segment elevation MI, who demonstrated a 3-fold increased risk with at least one *2 allele.

In addition to an increased risk of this composite endpoint, these and additional studies demonstrated that, in patients treated with PCI, the incidence of stent thrombosis is increased 3- to 6-fold in carriers of at least one *2 allele. [9, 27, 28, 29] A meta-analysis of 8000 patients with coronary artery disease undergoing clopidogrel treatment found that the CYP2C19*2 polymorphism was associated with a heightened risk of a cardiovascular event and stent thrombosis. [30, 31] These risks appear to be consistent across indications for PCI (elective vs ACS) and stent type (bare metal vs drug-eluting).

Finally, evidence demonstrates a graded, increased risk with the number of CYP2C9*2 alleles. Individuals with 2 copies are at higher risk than are those with one copy, who are, in turn, at higher risk than those with no copies. [13]

A variety of genotyping platforms are available to test for CYP2C19 variants. [32]  Although all vendors report CYP2C19*2 status, to what extent less common variants (eg, *3, *4, *5) are reported is variable.

Dosing Recommendations

Due to the totality of evidence supporting the influence of genetic variation in CYP2C19 activity on clopidogrel's pharmacokinetics, degree of platelet inhibition, and protection from subsequent cardiovascular events, the Food and Drug Administration updated clopidogrel's package insert to reflect these genetic associations. The FDA has stated that poor metabolizers taking higher doses of clopidogrel (ie, 600 mg loading dose followed by 150 mg once daily) show an increased antiplatelet response and that alternative treatment strategies can be considered in these patients. However, it also states that an appropriate dose regimen for this patient population has not been established in clinical outcome trials.

Because carriers of *2 alleles demonstrate no CYP2C19 enzymatic activity with normal dosing of clopidogrel, 2 potential alternative treatment strategies for carriers of *2 are to use higher doses of clopidogrel or to use alternativee P2Y12 inhibitors. Higher loading and maintenance doses (eg, 1200 mg loading and 150 mg maintenance) appear, in part, to overcome the genetic deficiency of the *2 allele, although maintenance doses of up to 300 mg/day might be required to achieve adequate platelet inhibition. [33, 34, 35]

Ticlopidine (Ticlid), a first-generation thienopyridine, is also a prodrug, but it is unclear to what extent CYP2C19 enzymatic activity is required for its bioactivation. Prasugrel (Effient), a third-generation thienopyridine, is also a prodrug, but it is unique in that its bioactivation appears to be less dependent on CYP2C19 activity. In fact, carriers of the *2 allele produce equivalent concentrations of active metabolite and achieve similar degrees of platelet inhibition compared with noncarriers. [36, 37, 38] Accordingly, when carriers of the *2 allele are treated with prasugrel after PCI for ACS, there appears to be no increased risk of cardiovascular death, MI, stroke, or stent thrombosis. [36, 39] Ticagrelor (Brilinta) is a nonprodrug P2Y12 inhibitor that is not sensitive to the effects of the CYP2C9*2 allele. [40, 41, 42, 43]

According to Klein et al, sufficient evidence supports the use of genetic testing by physicians to provide additional information regarding the risks and benefits of clopidogrel. Evidence from prospective studies demonstrates that a genotype-guided strategy for antiplatelet therapy reduces the risk of major adverse cardiovascular events without increasing the risk of major bleeding. [44, 4]

A meta‐analysis of randomized clinical trials reported there is no reduction in major adverse cardiovascular events (MACE) in patients who receive genotype‐guided antiplatelet therapy, but there is a significant reduction in MACE when including only patients who present with acute coronary syndromes and a significant reduction in myocardial infarction. [45]

The Veterans Health Administration (VHA) guidelines on pharmacogenetic testing do not routinely recommendCYP2C19 genotyping for the initiation of clopidogrel. However, the guidelines do allow CYP2C19 genotyping in specific patients, such as patients who have had a cardiovascular event while on clopidogrel or patients who are at high risk for poor outcomes. [46]

Antiplatelet therapy with thienopyridines increases the risk of gastrointestinal (GI) bleeding, likely by promoting bleeding at the site of preexisting ulcerous lesions. This effect might be particularly pronounced in poor metabolizers of clopidogrel who require higher doses of clopidogrel to achieve adequate platelet inhibition. Histamine H2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) suppress gastric acid secretion, which allows for ulcer healing and thrombus stabilization, thereby reducing the risk of GI bleeding.

A consensus statement issued by the American College of Cardiology, the American College of Gastroenterology, and the American Heart Association recommended the use of PPIs in patients on antiplatelet therapy at risk of GI bleeding. [47, 48, 49, 3]

The consensus group findings and recommendations are as follows [47, 48, 49] :

  • Clopidogrel reduces major CV events compared with placebo or aspirin.

  • Dual antiplatelet therapy with clopidogrel and aspirin, compared with aspirin alone, reduces major CV events in patients with established ischemic heart disease, and it reduces coronary stent thrombosis but is not routinely recommended for patients with prior ischemic stroke because of the risk of bleeding.

  • Clopidogrel alone, aspirin alone, and their combination are all associated with increased risk of GI bleeding.

  • Patients with prior GI bleeding are at highest risk for recurrent bleeding on antiplatelet therapy. Other clinical characteristics that increase the risk of GI bleeding include advanced age; concurrent use of anticoagulants, steroids, or nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin; and Helicobacter pylori infection. The risk of GI bleeding increases as the number of risk factors increases.

  • Use of a PPI or H2RA reduces the risk of upper GI bleeding compared with no therapy. PPIs reduce upper GI bleeding to a greater degree than do H2RAs.

  • PPIs are recommended to reduce GI bleeding among patients with a history of upper GI bleeding. PPIs are appropriate in patients with multiple risk factors for GI bleeding who require antiplatelet therapy.

  • Routine use of either a PPI or an H2RA is not recommended for patients at lower risk of upper GI bleeding, who have much less potential to benefit from prophylactic therapy.

  • Clinical decisions regarding concomitant use of PPIs and thienopyridines must balance overall risks and benefits, considering both CV and GI complications.

  • Genetic testing might be considered to identify whether a patient at high risk for poor clinical outcomes is predisposed to inadequate platelet inhibition with clopidogrel.

  • When a patient predisposed to inadequate platelet inhibition with clopidogrel is identified by genetic testing, treatment with an alternative P2Y12 inhibitor (eg, prasugrel or ticagrelor) might be considered.

The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) recommend an alternative drug to clopidogrel in poor metabolizers, and for intermediate metabolizers, they recommend choosing an alternative drug or doubling the dose of clopidogrel to 150 mg daily dose, 600 mg loading dose. [24, 50, 5]

PPIs are metabolized by CYP2C19, and pharmacokinetic and pharmacodynamic studies, using platelet assays as surrogate endpoints, suggest that concomitant use of clopidogrel and a PPI inhibits activation of CYP2C19 by clopidogrel and reduces the antiplatelet effects of clopidogrel. The strongest evidence for an interaction is between omeprazole and clopidogrel. It is not established that changes in these surrogate endpoints translate into clinically meaningful differences. Evidence has shown that the PPIs dexlansoprazole and lansoprazole do not significantly reduce the conversion of clopidogrel to its active metabolite, and no dose adjustment of clopidogrel with these agents is required. [51, 52]

Observational studies and a single randomized clinical trial have shown inconsistent effects on CV outcomes of concomitant use of thienopyridines and PPIs. A clinically important interaction cannot be excluded, particularly in certain subgroups, such as poor metabolizers of clopidogrel.