As has been discussed previously in this column, the Food and Drug Administration label for clopidogrel now carries a black box warning about reduced efficacy in patients with diminished activity of the CYP450 enzyme 2C19.
Clopidogrel is a prodrug that needs to be converted to an active metabolite in order to inhibit platelet function. CYP2C19 is involved in a principal step in that activation process, and poor metabolizers who are treated with standard doses of clopidogrel tend to have increased rates of adverse cardiovascular events, compared with normal metabolizers. The label suggests that alternative treatment strategies for poor metabolizers should be considered, but there is still debate over exactly how to manage such patients. Furthermore, controversy exists regarding both the degree to which 2C19 variants explain the overall variation in clinical response to clopidogrel, and the role of genetic and functional testing in the use of clopidogrel.
By Dr. Howard P. Levy
While we await better scientific data to inform clinical decision making, we must do our best to determine practical applications of pharmacogenetics for our patients today.
The following are a few recent cases from my practice:
• Case 1. A 72-year-old man has vascular dementia resulting from recurrent strokes and small vessel cerebral ischemia. Clopidogrel (75 mg daily) was added to his daily aspirin for stroke prophylaxis 2 years ago. Unfortunately, his dementia progressed and cerebral MRI showed additional infarcts and progression of small vessel ischemic changes. His wife has been assisting with his medications, and he is not believed to be missing any doses. He used to take omeprazole, but that was stopped within a few months after the initiation of clopidogrel, and he is not currently taking any proton pump inhibitors (PPIs). He was started on fluoxetine for severe depression and anxiety about a year prior to starting clopidogrel, and the dose was gradually increased to 40 mg daily over the past few years. His depression is currently under good control.
The clopidogrel label includes a warning that PPIs reduce its pharmacologic activity by inhibiting 2C19 activity. Omeprazole is probably the most significant of the PPIs in this respect, but pantoprazole and lansoprazole have been reported to have some inhibitory effect on 2C19 activity, thus potentially limiting clopidogrel’s activation and efficacy. In addition to the PPIs, there are several other important 2C19 inhibitors, including fluoxetine, fluvoxamine and ketoconazole. A list of other substrates and inhibitors of 2C19 – as well as other CYP450 enzymes – is available.
In this case, two possible explanations for the failure of clopidogrel to prevent further cerebrovascular events are that he has a 2C19 genetic variant causing the poor metabolizer phenotype, and/or fluoxetine is inhibiting 2C19 and mimicking the poor metabolizer phenotype. However, his depression is doing well on fluoxetine, and he’d prefer not to change to a different antidepressant.
We therefore agreed to start by testing for a 2C19 variant.
If he is a poor metabolizer, then he is unlikely to respond to clopidogrel, regardless of the inhibitory effects of fluoxetine. In that scenario, the fluoxetine can be continued and a different drug can be substituted for clopidogrel. On the other hand, if he has normal predicted 2C19 function, then it makes sense to change his antidepressant medication and continue clopidogrel.
• Case 2. A 71-year-old man is in good health, other than having gastroesophageal reflux, for which he takes omeprazole. He developed angina and was found to have single-vessel coronary artery stenosis. He received a drug-eluting stent, was taken off omeprazole, and was started on clopidogrel. The following day, a VerifyNow P2Y12 assay showed that his platelet function was adequately inhibited. CYP2C19 testing was not performed.
The FDA label suggests consideration of testing in association with clopidogrel therapy, but doesn’t make any specific recommendations. In situations in which it is pursued, this case presents an opportunity to examine the differences between a functional test and a DNA test.
Functional tests measure an actual biological end point, such as platelet inhibition. The Accumetrics VerifyNow test is one of several options that have been shown to correlate to some extent with treatment failure and cardiovascular events. They vary in cost, availability, standardization, simplicity, sensitivity, and specificity, and there is not yet agreement on the threshold for a suboptimal response.
Notwithstanding those limitations, their primary benefit is that they may provide a timely answer to the clinically relevant question of whether or not the drug is having the desired effect.
However, functional tests typically don’t identify the cause of the observed effect, which may be important if the desired outcome is not achieved. For clopidogrel failure, this could include 2C19 genetic variation, 2C19 inhibition from a PPI or other drug, missed doses, concurrent illness, or a variety of other genetic and environmental factors affecting absorption, distribution, metabolism, and elimination of the drug. Without this information, it can be difficult to determine how to improve therapy.