TAILOR-PCI Proves Genotype-guided Antiplatelet Therapy Reduces MACE
After seven years and 5,300-patients tested, the results of the landmark TAILOR-PCI trial were announced in a virtual ACC session. This trial investigated whether a prospective approach using rapid on-site CYP2C19 testing could improve patient outcomes when selecting P2Y12 inhibitor therapy following PCI procedure. This is based on the well-established evidence that approximately 30-50% of patients carry loss-of-function mutations for the CYP2C19 enzyme responsible for Clopidogrel bioactivation. These patients exhibit decreased metabolism and subsequently, a reduced response to Clopidogrel.
The team at Genomadix had the opportunity to sit down with Dr. Davide Capodanno, M.D., Ph.D., and Associate Professor of Cardiology at the University of Catania to discuss his take on the TAILOR-PCI results. Dr. Capodanno is also an Interventional Cardiologist at the Cardiac-Thoracic-Vascular Department, Azienda Policlinico-Vittorio Emanuele in Catania, Italy.
How do you interpret the TAILOR-PCI results?
This trial is relevant to the field of interventional cardiology and the results suggest encouraging outcomes for genotype-guided therapy leading to escalation from Clopidogrel to Ticagrelor in carriers of CYP2C19 loss-of-function mutations, despite the results falling just short of their ambitious endpoint. Indeed, the trial showed a 34% versus 50% anticipated reduction in adverse events at 1 year, with a p value of 0.056. However, the study also showed a statistically significant 79% reduction in adverse events at the first 3-month timepoint post-PCI (p = 0.001). This emphasizes the known high-risk period shortly following a PCI procedure, during which patients are likely to see the greatest benefit of optimized antiplatelet therapy.
What would you say to clinicians who say the TAILOR-PCI results are not relevant to them because they rarely prescribe clopidogrel to their patients?
Clopidogrel continues to be frequently prescribed in Europe and in many other parts of the world, not only in patients undergoing PCI where it represents the front-line therapy but also for Acute Coronary Syndrome (ACS). This is owing to the list of contraindications for the more potent therapies, patients being de-escalated by need or choice, or reimbursement issues. In the POPular Genetics trial published in the New England Journal of Medicine last year, significantly more bleeding was observed when all patients were prescribed Ticagrelor or Prasugrel as front-line therapy. However, when a rapid bedside CYP2C19-guided approach was implemented to enable de-escalation to clopidogrel in non-carriers of loss-of-function mutations, the bleeding risk was reduced following primary PCI. This provides evidence to support adopting a ‘tailored’ approach to prescribing P2Y12 inhibitors.
What do you recommend for clinicians who consider a de-escalation approach to prescribing P2Y12 inhibitors due to want or need (de-escalating from Ticagrelor/Prasugrel to Clopidogrel)?
Currently, de-escalation of antiplatelet therapy that is not informed by platelet or genetic testing happens in clinical practice, at a rate that is difficult to capture and may be higher than assumed. In an effort to improve personalized medicine in this area, I recently collaborated on the ABCD-GENE Score, a simple tool that can potentially enhance our ability to identify subjects at risk for high platelet reactivity and thrombotic complications while on Clopidogrel. Our goal was that by integrating clinical risk factors known to influence clopidogrel response (age, body mass index, Chronic Kidney Disease, and Diabetes Mellitus) with the CYP2C19 genetic factor into a score, we can improve the precision of guided de-escalation for P2Y12 inhibitor therapy such that this can be safely performed in “real-world” practice. In external validation datasets, the use of the ABCD-GENE Score was independently associated with high platelet reactivity and clinical endpoints such as death and the composite of death, stroke, or MI at one year. It is important to note that all of these clinical and genetic variables can be made available at the time of decision-making with the addition of rapid genotyping assays, as used in TAILOR-PCI and POPular Genetics.
Is there an advantage to incorporating CYP2C19 genotyping into the ABCD-GENE Score over alternative phenotyping-based strategies (i.e. platelet function tests)?
While personalized medicine efforts have initially focused on phenotyping to guide therapy, this often requires extensive use of resources. The addition of rapid, easy-to-use genotyping tests overcomes the previous barriers of genetics (for example, turnaround time, lab prep) and likely provides more compelling information when assessing Clopidogrel resistance through the addition of clinical variables. Pending more validation, using the ABCD-GENE Score with rapid bedside CYP2C19 testing may become a meaningful aid in “real-world” clinical practice to guide safe de-escalation of antiplatelet therapy for any reason and improve patient outcomes.
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