Skip the Clopidogrel Gene Test, Just Assay the Platelets, New Data Suggest

Shelley Wood

 

May 28, 2010 (Paris, France) — Worried about clopidogrel nonresponse? Skip the gene test and just check for platelet reactivity--that's the advice of Dr Laurent Bonello (Hôpital Université Nord, Marseilles, France), who presented new data to support this strategy here during a EuroPCR 2010 hotline session. In his study, one out of five patients who carried the now-infamous "poor-metabolizer" gene variant actually responded appropriately to an initial clopidogrel loading dose, while one out of two who were not carriers did not.

Dr Laurent Bonello

Bonello told heartwire that his study was in part a response to a recent FDA warning advising physicians that clopidogrel may have reduced benefits in people who are "poor metabolizers" and suggested that genetic testing could help identify patients who ineffectively convert clopidogrel to its active form. Studies show that people who carry loss-of-function variants of the liver enzyme CYP2C19 are at higher risk of stent thrombosis, MI, and death when receiving dual antiplatelet therapy with aspirin and clopidogrel. The FDA warning suggested that people identified as carriers of the 2C19* variants could be given other antiplatelet medications or alternative dosing strategies.
Bonello's study tested this second strategy. "We say, it's okay, you can still use clopidogrel, but you have to test," he explained to heartwire . "And it's not gene testing that you should be doing, it's platelet-reactivity testing."
Testing and Dosing
Bonello and colleagues performed gene and platelet-reactivity tests in a consecutive series of 411 non-ST-elevation acute coronary syndrome (NSTE-ACS) patients after they'd received a 600-mg loading dose of clopidogrel. A cutoff of 50% by vasodilator-stimulated phosphoprotein (VASP) index was used to define high (ie, >50%) on-treatment platelet reactivity. Patients who were found to have high on-treatment platelet reactivity and to be carriers of a mutant allele were given additional 600-mg doses of clopidogrel every 24 hours until a VASP <50% was achieved.
Gene tests showed 277 patients had no genetic variant of CYP2C19, while 134 (35.3%) carried at least one-loss-of-function CYP2C19 allele (11 homozygotes and 123 heterozygotes). After the initial loading dose, platelet reactivity was significantly higher among mutant carriers than among carriers of the wild-type gene (61.7 vs 49.2, p<0.001). After a second 600-mg loading dose, however, platelet reactivity was significantly reduced in carriers of the loss-of-function allele, dropping from a mean VASP index of 69.7% to 50.6% (p<0.0001).
Among the 123 heterozygotes, 88 had high on-treatment platelet reactivity, but after a second, third, or fourth loading dose, only 11 patients had a VASP index >50%. Among the homozygotes, just five out of 11 had high on-treatment platelet reactivity, which was normalized in all but one patient after a second, third, or fourth loading dose. For all 2C192* carriers, dose adjustment with up to three additional loading doses was effective in 88% of the carriers with high platelet reactivity after their initial clopidogrel dose. Importantly, no major TIMI bleeds were seen, and all four minor TIMI bleeds occurred in the wild-type carriers. The only other adverse event was a stent thrombosis, which occurred in a heterozygote who had failed successive dose adjustments.
"Increased and tailored loading dose of clopidogrel can overcome high on-treatment platelet reactivity in carriers of the loss-of-function 2C192* polymorphism," Bonello concluded. "Since studies have demonstrated the clinical benefit of dose adjustment in patients with high on-treatment platelet reactivity undergoing PCI, this therapeutic strategy may improve the prognosis of carriers of this loss-of-function polymorphism."
He also emphasized the shortcomings of gene testing alone. In his series, 20% of patients who were carriers of the polymorphism actually had a good response to the first loading dose of clopidogrel. And on the flip side, a full 50% of patients who were not carriers of the mutant genotype still had a platelet reactivity >50% after the initial loading dose.
"There are some determinants of platelet reactivity that are not genetic, so if you take only the genetic part, you will miss a lot of patients who have a high on-treatment platelet reactivity," he told heartwire .
Uncertainties Remain
Dr Laura Mauri (Brigham and Women's Hospital, Boston, MA), one of the session moderators, hinted that the FDA's warning has left operators uncertain as to just what it is they should be doing with their patients. "It's very difficult. The FDA has issued a statement about testing for genetics, and they've suggested that you may want to increase the long-term follow-up dose or change medications based on genetic testing. What is your recommendation?" she asked Bonello.
He responded saying he does not do any genetic testing in his practice. "I feel that platelet reactivity is more important than the genotype, because it includes more factors that are associated with low response to the drug. This is what we focus on, and we measure platelet reactivity routinely in all patients."

Dr Stephan Windecker

Mauri's comoderator, Dr Stephan Windecker (University Hospital, Bern, Switzerland), spoke with heartwire after the presentation, calling Bonello's study "very important, not only from the regulatory perspective, but from a practical perspective: whether you perform genetic testing vs just testing for platelet reactivity."
These findings "obviously would need to be tested in larger studies and with other measure of platelet reactivity," Windecker observed, noting that the VASP test is not the most widely used assay, although it is "certainly an established assay." It will also be very important to look at clinical outcomes after dose adjustment, he added.
"This is really a good hint that you don't need to perform genetic tests; you might be just as successful by just issuing repeated boluses. Yet I think the question remains--is this clinically relevant? Right now you have this effect on platelet reactivity, but does that translate clearly into a clinical effect? We don't know."
Bonello disclosed receiving grant support from Daiichi Sankyo-Eli Lilly.