RAPID GENE: Validation of Point-of-Care Genetic Testing

SAN FRANCISCO, CALIF.—In the RAPID GENE study, the first ever point-of-care genetic test in clinical medicine demonstrated that rapid genotyping of the CYP2C19 gene can help personalize antiplatelet treatment after PCI and improve rates of on-treatment platelet reactivity.

“Point-of-care genetic testing is clinically feasible and facilitates rapid personalization of antiplatelet therapy,” said Derek So, MD, of the University of Ottawa Heart Institute in Canada, during a presentation of late-breaking clinical trials. “This represents the validation and proof-of-concept of the first point-of-care genetic test in clinical medicine. Results will lead to larger scale studies evaluating the role of pharmacogenomics after PCI.”

The RAPID GENE study enrolled 200 patients undergoing PCI with non-ST-ACS or stable CAD; 102 were randomized to rapid genotyping and 98 to standard therapy. The rapid genotyping was performed with the Spartan RX CYP2C19 device (Spartan Biosciences), which So described as being about the size of a toaster. Nurses needed only a 30-minute instructional course in order to use the device, which employs a one-step insertion from a buccal swab. The test identifies CYP2C19*2 carrier status within 60 minutes; carriers are identified as heterozygous or homozygous. Both groups underwent standard DNA sequencing in order to compare the rapid genotyping results.

In both groups, there were 23 carriers of CYP2C19*2; the rapid genotyping was found to have a sensitivity of 100% and a specificity of 99.4%. None of the subjects in the rapid genotyping group had on-treatment platelet reactivity greater than 234 PRU after 7 days of prasugrel (Effient, Daiichi Sankyo) treatment. In contrast, 30.4% of the 23 CYP2C19*2 carriers who underwent standard clopidogrel therapy (Plavix, Sanofi-Aventis, Bristol-Myers Squibb) without rapid genotyping had high on-treatment platelet reactivity after 7 days (P=.009).

Numerous earlier studies have suggested an association between CYP2C19 loss-of-function alleles and MACE and stent thrombosis, So said. The CYP2C19*2 allele occurs in up to 25% of whites and 40% of Asians.

The study also examined a secondary endpoint where the PRU value cutoff was lowered from 234 to 208. This endpoint also showed significant reductions for the rapid genotyping group: 4.3% of those patients exceeded the lower PRU cutoff, compared with 47.8% of standard therapy patients (P=.002). The baseline PRU for both groups was 198.7; PRU at day 7, percent platelet inhibition at day 7, and change in PRU from baseline to day 7 were all significantly better in the rapid genotyping group (P<.001 for all). No MACE occurred in either group at 7 or 30 days, and TIMI bleeding rates were not significantly different between the two groups.

TRIGGER-PCI

In another study, a similar reduction in high on-treatment platelet reactivity was observed with prasugrel vs. clopidogrel. The TRIGGER-PCI study was stopped early for futility, however, in failing to demonstrate any differences in clinical outcome between the two treatments after elective PCI.

After 90 days of treatment, 5.9% of prasugrel patients and 70.4% of clopidogrel patients had a PRU of >208 (P<.001). After 176 days, 5.8% of 139 prasugrel patients and 70.8% of 144 clopidogrel patients met the cutoff rate for high on-treatment platelet reactivity (P<.001). Only patients who had an initial PRU after one dose of clopidogrel of >208 were included in the study.

The study’s primary endpoint was a composite of cardiovascular death or MI; among the 423 patients randomized there was only one such event — in the clopidogrel group — after a median of 174 days on treatment. Secondary efficacy endpoints included MI, rehospitalization, TVR, definite ST, stroke, CV death and all-cause death  (see Figure).

Dietmar Trenk, PhD, a professor at Herz-Zentrum Bad Krozingen in Germany, who presented the study during the same session, said that previous work—notably the EXCELSIOR trial—indicated strong clinical predictive power of on-treatment platelet reactivity. Trenk said that in the TRIGGER-PCI study, “high on-clopidogrel platelet reactivity was observed less frequently than expected.” This meant that even with 3,525 patients screened for the study only 625 were identified as candidates, of whom 423 agreed to be randomized. All patients received DES, with everolimus-eluting stents (Xience V/Promus, Abbott Vascular) accounting for about 50% of the total, followed by sirolimus- (Cypher, Cordis Corporation) and zotarolimus-eluting stents (Endeavor, Medtronic).

“Given the low event rate in elective PCI patients without periprocedural complications it was not possible to assess the risk-benefit ratio with prasugrel treatment,” Trenk said. “Therefore, the study was terminated prematurely for futility.” It remains to be seen whether the apparent decreases in platelet reactivity rates with prasugrel produce clinical outcome benefits in elective PCI patients receiving DES.