Review of clopidogrel dose escalation in the current era of potent P2Y12 inhibitors

Abstract

Dual anti-platelet therapy with aspirin and a P2Y12 inhibitor is the standard of care for patients with acute coronary syndromes (ACS) and for patients undergoing percutaneous coronary intervention (PCI). Clopidogrel is associated with increased risk of high on-treatment platelet reactivity (HTPR) compared to ticagrelor and prasugrel. Investigators have therefore sought to “escalate” clopidogrel dosing to overcome HTPR to reduce ischemic/thrombotic events. In this review, we will summarize the evidence for dose escalation in the context of genetic determinants of resistance and platelet function data. We will review contemporary clinical trials that have sought to improve delivery of dual antiplatelet therapy to patients with coronary artery disease and discuss the potential of clopidogrel dose escalation in specific populations.

Keywords:

• clopidogrel
• genetic testing
• individualized therapy
• pharmacogenomics
• platelet function testing

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• Clopidogrel resistance, or HTPR, is common after loading with 600 mg clopidogrel, and escalating doses have been found to be effective in reducing this risk.

• The P2Y12 inhibitors prasugrel and ticagrelor are associated with a significant reduction in high on-treatment platelet reactivity (HTPR) and improved outcomes compared to standard dose clopidogrel.

• Drug interactions are likely to alter clopidogrel metabolism and response; however there are no data to suggest that clopidogrel dose escalation is useful to overcome the potential pharmacodynamic impact of any known medication class.

• Among patients with CYP2C19*2 alleles, clopidogrel dose escalation with loading doses up to 2400 mg, and maintenance doses up to 300 mg, appear feasible and represent target doses for future studies.

• Despite a large volume of evidence that clopidogrel dose escalation is safe and effective, randomized clinical trials have not demonstrated that dose-escalation strategies utilizing a 150 mg maintenance dose improve outcomes. These trials have significant limitations.

• Platelet function measurement and CYP2C19 genotyping are useful to establish compliance, to provide risk stratification and to evaluate the effect of dose escalation in clinical practice. However, at the present time, HTPR is most effectively treated by using a more potent P2Y12 inhibitor.

• Future studies should address clopidogrel maintenance doses >150 mg in combination with clinical predictors, genetic testing and platelet function testing in order to identify populations most likely to benefit from these alternative strategies.

Notes