Rapid bedside genetic testing enhances safety, efficacy of antiplatelet therapy
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The landmark TAILOR-PCI trial showed encouraging evidence for genotype-guided antiplatelet therapy.
The 7-year, 5,300-patient trial, results of which were presented at the virtual American College of Cardiology Scientific Session in March, investigated whether a prospective approach using rapid on-site CYP2C19 testing could improve patient outcomes when selecting P2Y12 inhibitor therapy following PCI. The results demonstrated a 34% reduction in adverse events at 1 year and a significant 79% reduction in the first 3 months. The researchers should be commended for executing an insightful study.
Challenges of antiplatelet therapies
In the past decade, antiplatelet therapy has become the routine clinical recommendation after cardiac surgery and insertion of cardiac devices such as stents. This therapy is usually continued for at least 1 year. Clopidogrel was the first — and remains the most commonly prescribed — P2Y12 inhibitor after PCI in many parts of the world.
However, we learned early on that clopidogrel is a prodrug that must be transformed into its active metabolite by hepatic P450 enzymes to exert any antiplatelet activity. Thirty percent to 50% of patients carrying loss-of-function mutations for the CYP2C19 enzyme exhibit decreased metabolism, and therefore a decrease in response to clopidogrel. This contributed to the reasoning for a universal clopidogrel approach to be investigated in the TAILOR-PCI trial.
Some clinicians look to the alternative P2Y12 inhibitors, ticagrelor (Brilinta, AstraZeneca) and prasugrel (Effient, Daiichi Sankyo/Eli Lilly), for which the CYP2C19 genotype has been shown to have little to no effect on their metabolism. However, because these therapies are more potent, they also exhibit increased likelihood for significant bleeding. We are now in a position of trying to balance the extra bleeding with the extra efficacy of preventing thrombosis.
This balance is all the more precarious because most individuals with CAD are aged 70 years or older, which means they are even more vulnerable to cerebral bleeds. A hemorrhagic stroke in this age group is a major concern for dual antiplatelet therapy. In addition, many patients discontinue ticagrelor or prasugrel therapy after only 30 days because of the substantially higher cost (10 to 20 times more than clopidogrel in certain markets); lack of reimbursement; and adverse events, primarily dyspnea. In a study published in January in Coronary Artery Disease, in which researchers analyzed patients with ACS to determine the most common reasons for changes in antiplatelet therapy, the most common reason cited for switching from ticagrelor was dyspnea. Therefore, despite the potential benefits of these more potent P2Y12 inhibitors, clopidogrel remains the most commonly prescribed antiplatelet in many parts of the world because it is well tolerated, efficacious and inexpensive.
Bedside genotyping
It is evident to us clinicians that a universal “one-for-all” approach to prescribing antiplatelet therapy is not feasible. This is why the TAILOR-PCI trial, and many studies before it, investigated the benefit of implementing CYP2C19 genetics to guide this choice. In 2019, the 7-year, 2,500-patient POPular Genetics trial from Europe comparing genotype-guided therapy to a universal ticagrelor or prasugrel approach was published in The New England Journal of Medicine. In that study, researchers concluded that using rapid CYP2C19 testing to identify patients who are normal metabolizers and therefore can be prescribed clopidogrel — approximately 70% of patients — was associated with similar efficacy to that of prescribing all patients ticagrelor or prasugrel, but conferred significantly less bleeding. This trial is to be followed by a cost-effectiveness study to show the economic benefit of using a CYP2C19-guided approach to antiplatelet therapy.
In both the POPular Genetics and TAILOR-PCI trials, researchers used a rapid bedside genotyping platform (Spartan CYP2C19 Test, Spartan Bioscience). The availability of CYP2C19 results within 1 hour to guide prescription decisions at the time of procedure is beneficial for multiple reasons. These were described in a study published in May in JACC: Basic to Translational Science demonstrating the feasibility of using this rapid genotyping platform in real-world clinical practice:
Switching antiplatelet treatment after hospital discharge is of limited practicality, likely increasing the incidence of noncompliance.
Patient adherence is improved when medications are prescribed before hospital discharge.
We know that the early post-PCI period is when the risk for thrombotic complications is highest. This was observed in the TAILOR-PCI trial in which genotype-guided clopidogrel therapy resulted in a 79% reduction in adverse events compared with clopidogrel therapy without genotype guiding in the first 3 months. This emphasizes the importance of making rapid treatment decisions for optimized antiplatelet therapy during this early post-PCI time frame.
Embracing genetic testing
We as physicians must express more concern over the cost of drug therapy and embrace the genetic selection of safer and less costly drugs for the benefit of our patients and the overall health care system.
Our colleagues the oncologists have integrated genetic testing to select the most appropriate therapeutic agent for more than 10 years. We are on the eve of clinical application of polygenic risk scores to direct primary and secondary prevention of CAD, the leading cause of death in the world. It is necessary in the 21st century for cardiologists to embrace the results of genetic testing at the bedside. Perhaps an intense education of these new approaches for selecting therapy will be necessary.
- References:
- Claassens DMF, et al. N Engl J Med. 2019; doi:10.1056/NEJMoa1907096.
- Franchi F, et al. JACC Basic Trans Science. 2020; doi:10.1016/j.jacbts.2020.02.009.
- Gimbel ME, et al. Coron Artery Dis. 2020;doi:10. 1097/MCA.0000000000000787.
- Pereira NL, et al. JAMA. 2020;doi:10.1001/jama. 2020.12443.
- Spartan Bioscience. www.spartanbio.com/products/medical/cyp2c19. Accessed July 30, 2020.
- For more information:
- Robert Roberts, MD, FRSC, FRCPC, MACC, LLD (Hon.), FAHA, is professor of cardiology and chair of the International Society for Cardiovascular Translational Research at the University of Arizona and cardiologist at Dignity Health Medical Group. He is also a member of the Cardiology Today Editorial Board. He can be reached at 500 W. Thomas Road, Phoenix, AZ 85013; email: robert.roberts@dignityhealth.org.
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