You’ve heard a lot lately about so-called “clopidogrel resistance.” That sounds straightforward, but the underlying reason can be complex, possibly related to how the drug is metabolized by subjects with a certain genetic profile. We seek here to provide some perspective about clopidogrel’s metabolic and gene-related complexities. First, some brief background:
Clopidogrel, a thienopyridine, is a “prodrug” that is metabolized to its active form via the cytochrome P450 enzyme system — specifically, enzyme CYP2C19. A patient with certain genetic variants, or polymorphisms, can have diminished CYP2C19 activity (so-called “loss of function” alleles). The most common of these polymorphisms, CYP2C19*2, has been associated (in vitro) with reduced concentrations of active clopidogrel metabolites and with diminished platelet inhibition. About 25% of Caucasians have one copy of this variant, and about 2% have two copies. Higher percentages of black (3%–7%) and Japanese (11%) patients have two copies of CYP2C19*2.
Now let’s address some common questions about clopidogrel and CYP2C19:
1. Are all thienopyridines influenced by CYP2C19? No
Unlike clopidogrel (and ticlopidine), neither of the newer agents — prasugrel or ticagrelor — appears to be influenced by CYPC219 polymorphisms.
2. Is the CYP2C19 issue clinically important? Yes and No
Three studies of patients taking clopidogrel after PCI (TRITON-TIMI 38, PLATO, and a meta-analysis by Mega et al.) documented a 50% to 70% greater relative risk for adverse cardiovascular (CV) events, principally stent thrombosis, among patients with a loss-of-function allele (vs. those without such an allele). Most of the events occurred within one month after PCI.
In contrast, in the ACTIVE-A study of patients with atrial fibrillation and in the CURE trial of “conservatively managed” acute coronary syndrome (ACS) patients (only 15% of whom had PCI), clopidogrel recipients with a loss-of-function allele did not have greater risk for adverse CV events than those without the polymorphism.
3. Why the discrepancy between these two sets of studies? At least 3 possible explanations (if this were easy, we wouldn’t be blogging about it)
First, perhaps the interaction of clopidogrel and genetic polymorphisms that results in diminished CYP2C19 activity is clinically important in patients who are at high risk for a thrombotic event (such as those who receive a drug-eluting stent during PCI) but not in those at lower risk (such as patients with atrial fibrillation or medically treated ACS).
Second, a CYP2C19 genetic variant may put a patient at increased risk for adverse CV events regardless of whether he or she receives clopidogrel. The CHARISMA Genomics Substudy, for example, showed that even placebo recipients with a loss-of-function allele had a higher CV-event rate than those without the polymorphism.
Third, other genetic factors may be involved. Only 12% of the variation in response to clopidogrel is attributable to the CYP2C19*2 loss-of-function allele.
4. Should I routinely order genetic testing for my patients who take clopidogrel? No. It’s not yet ready for prime time.
Not only is genetic testing not routinely available, but when it is available, the results are not readily accessible (there’s no point-of-care testing). That makes the test not useful for patients who undergo nonelective PCI. Furthermore, in ACS patients undergoing PCI, the positive predictive value of the test is low (only 12% to 20%). Furthermore, at least 25 variants of the CYP2C19 gene have been identified, not to mention other genes that affect platelet responsiveness (i.e., CYP3A4 and ABCB1). In short, no single genetic test is a silver bullet.
5. What about the FDA warning? A classic example of pulling the trigger too early
The FDA’s “boxed warning” to use other antiplatelet medications or alternative dosing strategies for clopidogrel in patients with 2 loss-of-function alleles was based on observations from a study, involving 40 healthy subjects, in which poor metabolizers had diminished active metabolite exposure and higher platelet aggregation. The study reported no clinical outcomes. You gotta be kidding, right? We wish we were.
6. Does platelet-reactivity testing have any value? As far as we can tell right now, No.
According to a recently published white paper by the platelet gurus, “the routine use of platelet function measurements in the care of patients with cardiovascular disease cannot be recommended.” They agree that a lack of consensus exists about the optimal method of quantifying platelet reactivity and that we still have no large-scale clinical studies showing that using any of these tests to adjust antiplatelet therapy is clinically beneficial.
7. What can I do as a clinician? There is something.
If you’re caring for a patient with presumed “clopidogrel resistance” (i.e., has had stent thrombosis), testing to identify genetic polymorphisms is reasonable. Alternative treatment strategies (higher clopidogrel dosing regimens or the use of other antiplatelet agents) should be considered in such an individual.
8. What research is in the pipeline? Six studies
Three ongoing investigations (GIANT, GeCCO, and TARGET-PCI) will attempt to find the best genetic-guided strategy for these higher-risk patients. Also, the ongoing GRAVITAS, ARCTIC, and TRIGGER-PCI trials will address whether we should routinely test platelet responsiveness to clopidogrel (rather than performing genetic testing).
Given all this information, what are your instincts as a clinician as you confront the clopidogrel/CYP2C19 issue?