By Rachel Sass, PharmD

Should providers increase the clopidogrel dose in patients with decreased functioning CYP2C19 enzymes?

Clopidogrel (Plavix) is one of the most well studied medications in pharmacogenetics.  Clopidogrel is a prodrug, meaning that it needs to be converted to an active metabolite in the body to have an effect.

This metabolizing process occurs in part via the polymorphic enzyme CYP2C19. Researchers have found that individuals with decreased CYP2C19 activity have increased major adverse cardiovascular outcomes (e.g., cardiovascular death, heart attack, stroke, and stent thrombosis) compared to those with normal functioning CYP2C19 enzymes.

So what to do? Most prescribers already know the clopidogrel product insert contains a black box warning (effective March 2010) that confirms the increased cardiovascular events rates in patients who are CYP2C19 poor metabolizers who have had acute coronary syndrome or percutaneous coronary intervention (PCI). The warning also recommends considering “alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.” We can certainly identify what alternative treatment means (e.g., alternatives drugs such as prasugrel (Effient) or ticagrelor (Brilinta), but what does “alternative treatment strategy” mean?

Many studies have investigated whether increasing the dose of clopidogrel could decrease platelet reactivity, and some studies have investigated if dose increases could overcome genetic resistance (that is, patients who are CYP2C19 intermediate or poor metabolizers). Most of the studies use pharmacodynamic measures, such as platelet aggregation tests, to determine an adequate antiplatelet response.

In CYP2C19 intermediate metabolizer patients, doubling the standard maintenance dose of 75 mg daily to 150 mg daily seemed to be only of limited benefit. Tripling the clopidogrel maintenance dose (225 mg daily) did seem to improve platelet response in CYP2C19 intermediate metabolizers, however CYP2C19 poor metabolizers did not seem to benefit even with doses up to 300 mg daily. See the review article that details these studies here.

In a recent small trial, Hornstein et al. examined 18 patients who were CYP2C19 normal metabolizers, intermediate metabolizers, and poor metabolizers and dosed them at 75 mg, 150 mg, 225 mg, and 300 mg daily for eight days each. The study evaluated the four-hour post-dose maximal platelet aggregation on day eight for each treatment period for each genotype group.

The study authors found that poor metabolizers required 300 mg daily, four times the daily standard dose, to achieve the same platelet aggregation of normal metabolizers taking the standard dose of 75 mg daily. The researchers also found that intermediate metabolizers required 150 mg daily to get the same effects of normal metabolizer on 75 mg daily.

These results differed from the previous studies discussed above in two main ways. The previous studies found that even higher doses (225 mg) were required in intermediate metabolizers and that doses up to 300 mg daily in poor metabolizers did not achieve equal platelet aggregation response to normal metabolizers taking 75 mg daily. This re-emphasizes the fact that we have not yet found the most appropriate clopidogrel dose in patients with decreased functioning CYP2C19 enzymes.

But there is one common theme missing in all these studies. No study has demonstrated an improvement in clinical outcomes (such as a reduction in major adverse cardiovascular events) when looking at increased doses of clopidogrel in patients with decreased functioning CYP2C19 enzymes.

Basically, we know that increased doses have been shown to decrease platelet aggregation, but does this truly help keep our patients from having future adverse cardiovascular events? We might never know for sure until this type of study is conducted.

Additionally, safety of these increased doses will need to be established prior to routinely recommending such doses. Lastly, a standard platelet aggregation test and standard cut-off for adequate response to antiplatelet agents using the standard platelet aggregation test needs to be established, as studies often use different cut-offs and different aggregation tests to determine response to treatment.

There are viable alternatives to clopidogrel available, such as prasugrel and ticagrelor, which the provider can use if the patient has a decreased functioning CYP2C19 enzyme. While the clinical outcomes of switching from clopidogrel to an alternative has not been directly studied in patients with CYP2C19 loss of function alleles, a cohort analysis from the TRITON-TIMI 38 trial demonstrated that cardiovascular outcomes were not different in patients taking prasugrel with or without a CYP2C19 loss of function allele.

This result is in contrast to an increase in ischemic events seen with clopidogrel in patients that had a reduced functioning CYP2C19 enzyme. Additionally, in a subanalysis of the PLATO trial, efficacy of ticagrelor was preserved in patients with decreased functioning CYP2C19 enzymes.

The Clinical Pharmacogenetic Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group both recommend an alternative treatment (both recommend prasugrel, and CPIC recommends ticagrelor as well) in patients with ACS undergoing PCI as long as no contraindications are present. Genelex also makes these recommendations in all CYP2C19 intermediate and poor metabolizers.

Prasugrel and ticagrelor may not be appropriate alternatives for everyone, however, as both have contraindications and warnings in specific patient populations. Knowing that these alternative strategies may not be appropriate in patients who have decreased functioning CYP2C19 enzymes and have specific contraindications to ticagrelor or prasugrel reinforces the need to establish a specific clopidogrel dose that is safe and effective in patients with CYP2C19 variants.

Rachel Sass, PharmD, is a board-certified pharmacotherapy specialist who has worked at a Genelex as a personalized prescribing clinical pharmacist for one year.