Researchers have clinically applied the first point-of-care genetic test in medicine. Results from the study confirm that the test successfully identifies the CYP2C19*2 allele, a common gene mutation linked to higher rates of major side effects in patients receiving clopidogrel following percutaneous coronary intervention (PCI), thus preventing complications in those patients. The study, which has been conducted by Dr Derek Y F So at the University of Ottawa Heart Institute in Ottawa, Canada, and his team is published Online First in The Lancet.
Following PCI, the standard care for patients commonly consists of aspirin and clopidogrel to reduce the risk of blood clot formation, however, this dual antiplatelet therapy results in many patients becoming vulnerable to major adverse cardiovascular events.
This persistent vulnerability is linked to elevated on-treatment platelet reactivity, which can lead to a sudden blockage in the stents that can cause heart attacks or death. The characteristics of elevated on-treatment platelet reactivity are inadequate inhibition of the platelet PsY12 receptor following clopidogrel treatment.
According to scientists, numerous clinical variables have been implicated, however, the strongest predictor is the loss-of-function CYP2C19*2 allele (rs4244285), which is a common genetic variant that occurs in almost 30% of western Europeans and in about 50% of Asians.
Two unique P2Y12 inhibitors are prasugrel and ticagrelor, which compared with clopidogrel provide a more potent platelet inhibition. Although both drugs reduce major adverse cardiovascular events following acute coronary syndrome, they are also linked to higher complications in terms of bleeding. The researchers point out that retrospective genetic studies demonstrated that both, prasugrel and ticagrelor remained unaffected by the CYP2C19*2 allele. According to the authors, personalization of dual antiplatelet therapy after PCI could successfully minimize major adverse cardiovascular and adverse bleeding events if CYP2C19*2 carrier status could be identified in the future.
Spartan Biosciences in Ottawa, ON, Canada, has developed Spartan RX CYP2C19 as a point-of-care genetic test for the CYP2C19*2 allele that is performed with a buccal swab, which enables health-care personnel with no previous training in genetic laboratory techniques to undertake genotyping at the patient’s bedside.
The researchers decided to evaluate the clinical feasibility and pharmacodynamic efficacy of personalized dual antiplatelet therapy in patients who receive PCI treatment for acute coronary syndrome and stable coronary artery disease.
The standard care for these patients is a medical regimen of aspirin and clopidogrel, however, the new genetic test means that physicians can personalize the patient’s therapy and select whether they should opt to administer a more potent anti-platelet drug like prasugrel to those patients who have a high risk of failing treatment with clopidogrel.
The researchers recruited 200 patients in a prospective, randomized, proof-of-concept study, randomly assigning patients who underwent PCI for acute coronary syndrome or stable angina to either rapid point-of-care genotyping or standard treatment. Participants in the rapid genotyping group were screened for the CYP2C19*2 allele, with those who carried the allele being administered with 10 mg prasugrel daily, whilst non-carriers and patients in the standard treatment group received 75 mg clopidogrel daily.
The primary endpoint was determined as the proportion of CYP2C19*2 carriers with elevated on-treatment platelet reactivity, i.e. P2Y12 reactivity unit [PRU] value of more than 234 after 1 week of dual antiplatelet therapy, which is a marker that is linked to higher adverse cardiovascular events.
Of all patients, 187 completed follow-up, i.e. 91 participants in the rapid genotyping group and 96 in the standard therapy group. In each group 23 participants carried at least one CYP2C19*2 allele and the researchers observed that none of the 23 carriers in the rapid genotyping group had a PRU value of over 234 at day 7 in comparison to seven or 30% of the participants in the standard treatment group. The researchers note that the genetic point-of-care test had a sensitivity of 100% and a specificity of 99%.
In a concluding statement the researchers declare:
“As far as we are aware, our study is the first to validate and to show clinical use of point-of-care genetic testing. It is the first randomized investigation of selective use of prasugrel in CYP2C19*2 carriers after PCI. Our findings suggest that personalization of antiplatelet therapy might reduce adverse ischemic outcomes; use of prasugrel only in high-risk individuals might also minimize adverse bleeding events.
The development of practical point-of-care genetic testing in our study will help to integrate genetics into the clinical setting and will allow large-scale investigations to definitively assess the value of pharmacogenetic strategies.”
Dr. So adds:
“For the first time in clinical medicine, we have proven that a simple bedside test can enable rapid genetic testing and subsequent personalized therapy. This is an important step towards integrating pharmacogenomic strategies into clinical care.”
Dr Amber L Beitelshees of the Department of Medicine at the University of Maryland School of Medicine in Baltimore, MD, USA, writes in an associated comment:
“The RAPID GENE study provides much-needed impetus by showing that genotyping can be done in a timely manner and incorporated into the clinical workflow as we wait for the results of large outcome-driven randomized trials.”
Written by Petra Rattue