What is the role of clopidogrel in the treatment of acute coronary syndrome (ACS)?

Updated: Sep 30, 2020
  • Author: David L Coven, MD, PhD; Chief Editor: Eric H Yang, MD  more...
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Clopidogrel (thienopyridine) inhibits adenosine 5'-diphosphate (ADP)–dependent activation of the glycoprotein IIb/IIIa complex, a necessary step for platelet aggregation. This process results in intense inhibition of platelet function, particularly in combination with aspirin. In the CURE trial, thienopyridine reduced the rate of myocardial infarction by 20%. [53]

The optimal loading dose for clopidogrel is still being evaluated. Reports show that a loading dose of 600 mg might be more beneficial than 300 mg. Withhold clopidogrel for at least 5 days before elective coronary artery bypass grafting (CABG). Since 12% of patients with non-ST elevation ACS have coronary anatomy that favors CABG, the use of clopidogrel is withheld until coronary angiography at some institutions.

A meta-analysis of 34 studies analyzed the safety of CABG among patients with ACS continuing clopidogrel. The investigators found that although mortality is increased in those receiving clopidogrel, it is influenced by ACS status and case urgency in primarily nonrandomized studies. Among patients with ACS, no differences in mortality or postoperative myocardial infarction or stroke rates were found. This suggests that in patients with ACS who require urgent CABG, proceeding despite the continuation of clopidogrel is likely safe. [63]

Clopidogrel can be considered an alternative to aspirin in patients with aspirin intolerance or who are allergic to aspirin.

Patients with chronic kidney disease who have low platelet response to clopidogrel tend to have worse outcomes after PCI. [64]

Evidence has shown that dexlansoprazole and lansoprazole do not significantly reduce the conversion of clopidogrel to its active metabolite (reduced by 9% and 14%, respectively), and no dose adjustment of clopidogrel is required. [65, 66]

The group’s findings and recommendations are listed below.

  • 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. [67]

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

  • Clopidogrel requires metabolic activation by cytochrome P450 2C19 (CYP2C19). PPIs that inhibit CYP2C19 are commonly coadministered with clopidogrel to reduce the risk of GI bleeding. A study by Simon et al showed that PPI use is not associated with an increased risk of cardiovascular events or mortality in patients who have been treated with clopidogrel for a recent MI, regardless of CYP2C19 genotype. [68]

  • Patients with prior GI bleeding are at highest risk for recurrent bleeding on antiplatelet therapy; other risk factors include advanced age, concurrent use of anticoagulants, steroids, or NSAIDs including aspirin, and Helicobacter pylori infection; risk increases as the number of risk factors increases.

  • Use of PPIs or histamine H2 receptor antagonists (H2RAs) 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.

  • Pharmacokinetic and pharmacodynamic studies, using platelet assays as surrogate endpoints, suggest that concomitant use of clopidogrel and a PPI 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.

  • 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.

  • The role of either pharmacogenomic testing or platelet function testing in managing therapy with thienopyridines and PPIs has not yet been established.

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