November 10, 2011

November 9, 2011 (San Francisco, California) — A genotyping assay device billed as "the first point-of-care genetic test in medicine," which produces a result within 60 minutes, seems to accurately identify patients who carry a gene variant that signals reduced responsiveness to clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis).

Dr Derek So

The CYP2C19*2 allele is found in up to 25% of whites and 40% of African Americans, and its presence triples the risk of in-stent thrombosis in patients supposedly protected by dual agent antiplatelet therapy, usually including clopidogrel, pointed out Dr Derek So (University of Ottawa Heart Institute, ON).

But in the Reassessment of Antiplatelet Therapy Using an Individualized Strategy Based on Genetic Evaluation (RAPID GENE) study, patients undergoing PCI who were positive for the allele according to the bedside test and who therefore received prasugrel (Effient, Lilly/Daiichi) instead of clopidogrel had a significantly decreased likelihood of high platelet reactivity (greater platelet-associated risk) by platelet-function testing compared with standard management with clopidogrel.

So presented the study here at TCT 2011. "RAPID GENE is essentially proof of concept that rapid genetic testing and tailored therapy is now feasible," he said during his presentation, "and facilitates rapid personalization of antiplatelet therapy."

Questions have been raised, however, about the clinical usefulness of the test, at least on its own, in using CYP2C19*2 status to guide antiplatelet therapy--in particular, to choose perhaps a more expensive antiplatelet agent instead of tried-and-true clopidogrel.

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Dr Paul Gurbel

At a media briefing on RAPID GENE, Dr Paul Gurbel (Sinai Hospital of Baltimore, MD), who wasn't involved in the study, commented that "there are many patients on clopidogrel who are CYP2C19*2 carriers but who respond very nicely to the drug. This [tailoring strategy] would entail a major decision based on CYP2C19*2, where a lot of patients who would have responded to clopidogrel are given another agent."

Responding to Gurbel's concerns, So told heartwire that should the strategy become standard practice, more than just genetic information would likely be needed for such a management decision. "It's not going to be genetics alone, it's not going to be platelet function alone, it's not going to be clinical factors alone; it's going to be the combination of all those."

In RAPID GENE, 200 patients undergoing PCI for ACS or stable angina were randomized to prasugrel 10 mg/day for CYP2C19*2 carriers, clopidogrel 75 mg/day for those negative for the allele at point-of-care genotyping, or standard antiplatelet therapy with clopidogrel 75 mg/day without prospective genotyping.

The assay device, operated by nursing staff after a 30-minute training session, is "about the size of a toaster," according to So.

Results of Point-of-Care Genotyping

CYP219*2 status Rapid genotyping, n=91 (%) Standard care, n=96 (%)
CYP219*2 carrier 25.3 24.0
1 copy 20.9 20.8
2 copies 4.4 3.1

Platelet-function testing was performed one week later, and those randomized to standard care were retrospectively genotyped. Sensitivity of the genotyping assay for the allele, compared with gold-standard DNA sequencing, was 100%, with a specificity of 99.4%, So reported.

Of the 187 patients who completed follow-up, none of those in the prospectively genotyped group met the primary end point--the presence of CYP219*2 and "high" on-treatment platelet reactivity (>234 platelet reactivity units [PRU]), which was significantly different from the 30.4% of patients with that degree of platelet activity in the standard-care group (p=0.0009).

Secondary End Points, PRU Changes, and Bleeding

End points Rapid genotyping, n=91 (%) Standard care, n=96 (%) p
Platelet-function measures in CYP219*2 carriers n=23 n=23  
Baseline PRU 198.7 198.7 --
PRU day 7 75.6 207.3 <0.001
Platelet inhibition day 7, % 73.3 27.0 <0.001
Change in PRU, day 0–7 123.09 –8.48 <0.001
Bleeding outcomes n=91 (%) n=96 (%)  
TIMI major/minor bleed 5.5 2.1 0.27
TIMI major bleed 2.2 1.0 0.61

PRU=platelet reactivity units

"One criticism of genetic testing in this area is that there's never been the ability to do it rapidly, [allowing] a decision quickly enough in PCI or acute coronary syndrome," according to So. "Now we've proven clinically, at least from a feasibility point of view, that we can do it quickly and accurately." He said the one hour it currently takes the device to produce a genotype result "we think will be down to half an hour within a year."

The RAPID GENE trial was sponsored by Spartan Bioscience. So discloses grant support from Spartan Bioscience, Abbott Vascular Canada, and Sanofi-Aventis Canada and consulting fees/honoraria from Lilly Canada and Medtronic Canada within the past 12 months. Gurbel discloses receiving consulting fees or honoraria or serving on a speaker's bureau for Boston Scientific, Cordis, Abbott Vascular, Direct Flow Medical, Mitralign, Claret, Biosensors, and Medtronic.