Genotype-guided antiplatelet therapy strategy shows benefit after PCI
Click Here to Manage Email Alerts
While not meeting a performance goal, genetic screening of patients with ACS or stable CAD after PCI to guide antiplatelet therapy choice numerically reduced serious adverse CV events, according to the results of the TAILOR PCI trial.
Although the primary analysis of time to first events was not significant, a prespecified sensitivity analysis of cumulative events reflecting ischemic burden favored the genetic-screening group, Naveen L. Pereira, MD, FACC, FAHA, FRCPE, professor of medicine and associate professor of pharmacology at Mayo Clinic, said during a presentation at the virtual American College of Cardiology Scientific Session.
The overall cohort included 5,302 patients (median age, 62 years; 76% men). The primary analysis pertained to 1,849 patients — 903 of whom were assigned genotype-guided therapy and 946 of whom were assigned conventional therapy — who were carriers of loss-of-function alleles of CYP2C19 tthat results in an inability to metabolize clopidogrel to the active prodrug. Carriers of loss-of-function alleles in the genotype-guided group received ticagrelor (Brilinta, AstraZeneca) instead of clopidogrel; all patients in the conventional therapy group received clopidogrel.
“Currently, clopidogrel is the most widely prescribed P2Y12 inhibitor after PCI,” Pereira said during his presentation. “Clopidogrel is a prodrug that is metabolized by CYP2C19 into an active metabolite that is responsible for its antiplatelet effect. Up to 30% of the population have a genotype that results in reduced or loss of enzymatic function, translating to increased ischemic events. Therefore ... there is a black box warning that advises prescribers to identify such patients and prescribe an alternative therapy. The research question TAILOR PCI was designed to answer was, does identifying loss-of-function CYP2C19 patients and altering P2Y12 inhibitor therapy based on the genotype reduce ischemic outcomes in the first 12 months after PCI?”
In the main analysis, the primary endpoint of CV death, MI, stroke, definite or probable stent thrombosis or severe recurrent ischemia at 1 year after index PCI was reduced by 34% in the genetic screening group compared with the conventional therapy group (HR = 0.66; 95% CI, 0.43-1.02; number needed to treat to prevent one event in those with a loss-of-function variant, 55), which fell short of the goal of a 50% reduction, Pereira said.
However, the treatment effect significantly favored the genetic-guided group at 3 months (absolute difference, 2.1%; 95% CI, 1-3.4; HR = 0.21; P = .001), he said.
There was no difference between the groups in TIMI major or minor bleeding, and subgroup analyses did not detect any subgroup differences in treatment effect for the primary endpoint, he said.
However, in a prespecified sensitivity analysis of total events, which included first and subsequent events up to 1 year, the genetic screening group had a significant 40% reduction in cumulative primary outcome events compared with the conventional therapy group (HR = 0.6; 95% CI, 0.41-0.89).
“We found that a genotype-guided antiplatelet strategy compared with conventional clopidogrel treatment in CYP2C19 loss-of-function patients who had acute coronary syndrome or stable coronary artery disease and underwent PCI did not result in a significant difference in reducing ischemic events at 12 months based on the 50% treatment effect that the study was designed to detect. [But] CYP2C19 guidance can significantly reduce multiple ischemic events per patient, and ... we saw the potential benefit of the strategy appears greatest within the 3 months post-PCI.”
During a discussion of the trial, Roxana Mehran, MD, professor of medicine and director of interventional cardiovascular research and clinical trials at the Zena and Michael A. Wiener Cardiovascular Institute at Icahn School of Medicine at Mount Sinai, said “this important study underlines one of the biggest dilemmas clinicians have in treating patients with clopidogrel and knowing that about 35% of these patients will have the carrier gene that would deem them not responsive to clopidogrel.
“This begs the question: Were these patients included in TAILOR PCI (85% with ACS) at the lower risk profile such that clinicians chose clopidogrel instead of more potent agents (prasugrel, ticagrelor), even though the patient presented with an acute coronary syndrome?” Mehran asked. – by Erik Swain
Reference:
Pereira NL, et al. Joint American College of Cardiology and Journal of American College of Cardiology Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 28-30, 2020 (virtual meeting).
Disclosures: Pereira reports no relevant financial disclosures. Mehran reports she has financial ties with multiple pharmaceutical and device companies.
Perspective
Back to Top
B. Hadley Wilson, MD, FACC
The biggest take-home message from TAILOR PCI is that genotyping for patients who are clopidogrel nonresponders failed to meet its primary endpoint at 1 year in this study of more than 5,000 patients. That is further indication that the question of prophylactic genotyping is not settled in this patient population. We can go ahead and treat our patients as we are currently doing around the world with our pick of P2Y12 inhibitor post-stenting in this population and they should do well for the succeeding year after implantation with very low absolute risk and a nonsignificant difference in risk.
In practicality, there was improvement early on, but at 1 year, it leveled out. The potential benefit appeared greatest in the first 3 months but was not borne out over the succeeding year. As a result, most people are not likely to alter their treatment pattern following this trial and further study may be required to alter current guidelines. Any incidence of stent thrombosis is important and serious. To guard against this, ticagrelor is a superior agent to clopidogrel, as has been shown in previous studies.
Click Here to Manage Email Alerts