Treatment Options for Patients With Poor Clopidogrel Response

A significant percentage of patients demonstrate a poor antiplatelet response to clopidogrel. With the emergence of testing for genetic variations in drug-metabolizing enzyme function and testing for platelet function, it is becoming more common to identify patients as poor responders to clopidogrel. This leaves the clinician in a difficult situation when confronted with a patient deemed to be a poor clopidogrel responder as there is no clear therapeutic strategy for treating these patients. In this situation, a number of alternatives to conventional dosing of clopidogrel have been investigated, including increasing the dosage of clopidogrel, switching from clopidogrel to either prasugrel or ticagrelor, or adding cilostazol to clopidogrel therapy. All of these options have demonstrated pharmacologic benefit in terms of greater antiplatelet effects compared with standard clopidogrel dosing in patients with high on-treatment platelet reactivity or a genetic loss-of-function variant of CYP2C19, the main enzyme responsible for clopidogrel activation. However, the impact of each of these alternative therapies on clinical outcomes is poorly understood. Early studies have not shown a clinical benefit by increasing the clopidogrel dosage or switching to prasugrel although there is still much to be discovered in this area. Of the alternatives to standard dosing of clopidogrel, switching to either prasugrel or ticagrelor has the most potential benefit, but again, there is limited evidence to support this practice in patients who demonstrate high on-treatment platelet reactivity while on clopidogrel although the evidence is somewhat more supportive in patients who have a CYP2C19 loss-of-function variant allele. The evidence for increasing the dosage of clopidogrel or adding cilostazol is the least supportive, making these alternatives difficult to justify. Given the limited evidence to support switching treatments, some providers may simply opt to continue standard dosing of clopidogrel pending the results of ongoing trials. Much research is needed and is currently underway in this area, which will be helpful in establishing future treatment protocols for patients with poor clopidogrel response.