ARCTIC-GENE Throws Cold Water on Genotype-Guided Antiplatelet Therapy at PCI

September 04, 2013

AMSTERDAM — One-fourth to a third of patients getting PCI show a poor platelet response to clopidogrel, which with aspirin has long been a mainstay antiplatelet adjuvant to PCI, especially with drug-eluting stents. Efforts to identify likely poor responders so they can get intensified or alternative treatment have had mixed results.

In the 2440-patient randomized ARCTIC trial, antiplatelet therapy guided by platelet-function monitoring failed to make a significant difference to ischemic outcomes after PCI; its investigators concluded against the strategy's routine use in coronary stenting, as previously covered by heartwire .

The trial didn't end there. Hopes were that its genetic substudy, ARCTIC-GENE [1], would show that poor clopidogrel responsiveness would concentrate in PCI candidates carrying clopidogrel-metabolization loss-of-function gene variants and that treatment adjustments based on their genotype would improve ischemic outcomes--in particular, the trial's primary end point of death, MI, stroke, stent thrombosis, or urgent revascularization at one year.

But that just didn't happen, according to ARCTIC co–principal investigator Dr Jean-Philippe Collet (Groupe Hospitalier Pitié-Salpêtrière, Paris, France), who presented the substudy's results here at the European Society of Cardiology (ESC) 2013 Congress.

Based on the study, he said, "We can say that determination of the metabolizer profile according to genotyping in these kinds of patients undergoing angioplasty is a good marker of treatment response." That observation was expected, he said. Unexpected was the "very low concordance" between genotyping and either pharmacodynamic response to clopidogrel or associated clinical outcomes.

"I think that these findings support the recent guidelines that were released on stable CAD stating that we should not in routine practice use that kind of [platelet-function or genotype-guided] approach to refine treatment with the goal of improving clinical outcomes."

The discussant for Collet's presentation, Dr Jurriën M ten Berg (St Antonius Hospital, Nieuwegein, the Netherlands), said ARCTIC-GENE's results aren't "the end of personalized medicine," but "we may conclude from [it and ARCTIC] that [neither] platelet-function testing nor genotyping alone is enough to risk-stratify our PCI patients." Researchers should look for better risk markers for guiding antiplatelet therapy, and they'll probably "be based on a combination of clinical factors such as ACS and diabetes."

ARCTIC-GENE included 1390 patients from the parent trial who were genotyped and consented to participation; of those, 935 were genotyped as rapid metabolizers of clopidogrel (456 had been in the parent trial's standard-therapy and 479 in its monitoring arms) and 459 as slow metabolizers of the drug (238 and 221, respectively) based on their distribution of several variants of CYP2C19.

As it turned out, according to Collet, "there was a high proportion of poor responders [to clopidogrel based on platelet-function testing] among the slow metabolizers [determined by genotype]," both periprocedurally and 14 to 30 days later (by which time antiplatelet therapy in poor responders had been adjusted). "The decline in [prevalence of] poor responders was much more pronounced in the rapid metabolizers vs slow metabolizers, and this was expected, because it's more difficult to override poor response in slow metabolizers vs rapid metabolizers."

Prevalence (%) of High On-Treatment Reactivity (Poor Clopidogrel Response) at PCI and at Day 14–30 in Rapid and Slow Metabolizer Groups

Time frame Rapid metabolizers, n=935 (%) Slow metabolizers, n=459 (%) p
At PCI 30.9 40.3 0.015
Day 14–30 9.7 22.7 <0.0001

There was poor concordance between patients' pharmacodynamic profiles (based on platelet function) and metabolizer profiles (based on genotype). "We were puzzled by this. You can see that among the slow metabolizers, there was still a very high proportion of good responders. [Among] rapid-metabolizer patients, there was still a high proportion of poor responders."

Good or Poor Concordance Between Genetic Metabolizer Profile and Pharmacodynamic Profile by Metabolizer Group

Concordance Rapid metabolizers, n=935 (%) Slow metabolizers, n=459 (%)
Good 69.1 40.3
Poor 30.9 59.7

Slow metabolizers also were more likely to have their clopidogrel dosage increased on day 14 to 30. "And at the last follow-up visit, these patients were more likely to be treated with prasugrel [Effient, Lilly/Daiichi-Sanyo]. This was expected, but as you can see, the difference is not so much."

Treatment Adjustments According to Predicted Metabolizer Phenotype

Treatment adjustment Rapid metabolizers, n=935 (%) Slow metabolizers, n=459 (%) p
Clopidogrel at day 14–30 39.1 50 0.013
Prasugrel at last visit 8.1 11.5 0.038

Among patients assigned to the monitoring group who were found to be clopidogrel nonresponders, 81.8% of the rapid metabolizers "had on-table clopidogrel reloading before stenting," Collet said. Also, 77.7% received glycoprotein IIb/IIIa inhibitors "to prevent pre-PCI MI," and 23.6% were receiving prasugrel at their last follow-up visit. These adjustments, he said, were just as prevalent among rapid and slow metabolizers who had been identified as poor clopidogrel responders.

Rapid and slow metabolizers didn't differ significantly with respect to ischemic end points, including the primary end point and all of its components, nor were there differences in the key safety end points of major, minor, and major or minor bleeding.

The addition of genotyping to pharmacodynamics data obtained from the platelet-function tests, according to Collet, did not significantly improve their already-poor accuracy in predicting ischemic outcomes, "showing clearly that these tools are not very accurate in the setting of PCI in clopidogrel-treated patients."

According to ten Berg, ARCTIC-GENE underscores that many factors influence platelet reactivity; presumably controlling one or a few is unlikely to make a comprehensive difference to thrombotic risk. Still, he took exception to the ARCTIC-GENE investigators' conclusion that platelet monitoring and related genotyping won't improve outcomes. "We have to remember that this was not an interventional study. It was only an observational study. We would like to see a larger study in patients with slow metabolizers randomized to intensified antiplatelet therapy vs routine antiplatelet therapy," namely, clopidogrel.

Collet discloses receiving research grants to his center or fees for consulting or lectures from Abbott Vascular, AstraZeneca, Bayer, Boston Scientific, Cordis, Daiichi-Sankyo, Duke Cardiovascular Research Institute, Eli Lilly, Europa, GlaxoSmithKline, ICM, INSERM, Medtronic, Nanospheres, Sanofi, the Medicines Company, and the TIMI Group.

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