While clopidogrel is a successful antiplatelet drug for PCI patients, its ineffectiveness in certain patient subsets has recently been documented, spurring an FDA boxed warning. Testing patients’ platelet responsiveness or their genotype has shown success, but which tests are most effective and efficacious? Further compounding these cath lab choices, newer antiplatelet agents loom as potential game changers.
Why personalize treatment?
About 30 percent of PCI patients don’t respond to standard clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) loading and maintenance doses. Research also suggests that at least 20 to 30 percent of PCI patients have high platelet reactivity, cites Paul Gurbel, MD, director of cardiovascular research at the Sinai Center for Thrombosis Research in Baltimore (J Am Coll Cardiol 2010;56:919-933). Laurent Bonello, MD, from the cardiology department at Hôpital Universitaire Nord in Marseille, France, postulates that even more than one-third of PCI patients have a CYP2C19*2 loss-of-function allele, based on platelet reactivity testing. “This is not an insignificant number of patients,” Bonello says.
Due to the lack of consensus and guideline-recommended therapy, researchers are scrambling to better understand and treat this vulnerable patient subset. These patients may require a personalized approach. “Rather than change therapy for the entire population and increase the risk of bleeding, we can select the particular patient subset at greatest ischemic risk for high-dose therapy or stronger P2Y12 inhibitions to provide the greatest net clinical benefit,” says GRAVITAS Principal Investigator Matthew J. Price, MD, director of the cardiac cath lab at Scripps Clinic in San Diego.
While GRAVITAS is testing the efficacy of a standardized increase in clopidogrel maintenance dose in patients with high platelet reactivity, others advocate dose titration. “The data suggest that the ‘one-size-fits-all’ approach to administering clopidogrel is not appropriate. Therefore, tailored therapy is necessary to avoid thrombotic or bleeding events,” says Bonello.
Meanwhile, some discrepancy exists about whether the FDA boxed warning was premature or perpetuated confusion about testing. For clopidogrel to be effective, enzymes in the liver (particularly CYP2C19) must metabolize the drug to its active form. Patients who are poor clopidogrel metabolizers do not effectively convert Plavix to its active form, the FDA writes. In these patients, clopidogrel has less effect on platelets and, therefore, less ability to prevent heart attack, stroke and cardiovascular death.
“The FDA’s position is reasonable in that clopidogrel’s effect is mediated by an active metabolite, and poor metabolizers have significantly less active metabolite generation than extensive metabolizers, resulting in the inability of the drug to achieve its intended effect,” Price says. He adds that the FDA warning is “merely informational” and does not mandate genotyping, and did not even mention phenotyping, or platelet testing.
Yet, questions remain about whether this warning has affected real-life clinical practice. “Clinicians haven’t responded to the boxed warning because they do not routinely genotype PCI patients,” Gurbel says. “Also, the FDA dropped the ball by not mentioning platelet function testing. Numerous studies demonstrate the importance of measuring platelet reactivity to gauge post-PCI risk.”
The warning also has been criticized for addressing only patients with two loss-of-function alleles, and providing no information for heterozygotes.
Price suggests that while the boxed warning “may not have changed many people’s practices, it has increased awareness of the variability of platelet responsiveness to clopidogrel.”
Phenotyping vs. genotyping
To inform this burgeoning field, more data are needed to better determine the benefits of testing patients’ responsiveness to clopidogrel either through genetic testing or platelet reactivity testing. Price notes that there is “general confusion” about the two types of tests, and they are “not interchangeable.”
However, there may be a “complementary role for genotyping and phenotyping,” Gurbel says, “but without concrete data, cath lab decisions can’t be based only on supposition. Hopefully, forthcoming trials will answer some of these questions.”
TARGET-PCI, an ongoing, prospective study led by Gurbel, will use the VerifyNow P2Y12 platelet test (Accumetrics), but the researchers