TAILOR PCI: Genotype-guided antiplatelet strategy just misses significance in reducing ischaemic events
Genotype-guided choice of dual antiplatelet therapy just missed significance in reducing ischaemic events in patients with acute coronary syndrome and stable coronary artery disease who underwent percutaneous coronary intervention (PCI), according to the results of the two-arm, parallel, open-label, international, multicentre, randomized superiority TAILOR PCI trial presented at the American College of Cardiology 2020/World Congress of Cardiology (ACC.20/WCC) virtual meeting.
“The primary composite endpoint [of cardiovascular death, myocardial infarction, stroke, definite or probable stent thrombosis, and severe recurrent ischaemia within 1 year of index PCI] occurred in 4 percent of CYP2C19 loss-of-function [LOF] patients in the genotype-guided therapy group and in 5.9 percent of those in the conventional therapy group at 12 months, resulting in a relative risk reduction of 34 percent. This, however, was statistically not significant [p=0.056],” reported primary author, Professor Naveen Pereira of the Department of Cardiovascular Diseases at Mayo Clinic, Rochester, Minnesota. [Pereira N, et al, ACC.20/WCC, abstract 402-12]
“A post hoc analysis demonstrated a risk reduction of almost 80 percent, which was significant for genotype-guided antiplatelet therapy [hazard ratio (HR), 0.21; p=0.001], in the first 3 months vs other time intervals,” noted Pereira.
“Antiplatelet drug therapy is critical during the first 3 months after PCI,” commented Pereira. “The lion’s share of the benefit of genetically guided therapy may occur during this high-risk period. Because this wasn’t a pre-planned analysis, we can’t draw firm conclusions from it, but it merits further study.” A National Heart, Lung, and Blood Institute-funded extended follow-up is ongoing.
The 2017 US FDA-approved drug label for clopidogrel includes a boxed warning concerning its diminished antiplatelet effect in CYP2C19 poor metabolizers. The warning states that tests are available to identify such patients, and recommends prescribing another platelet P2Y12 inhibitor.
“Prescription data from 120 million individuals … indicate that clopidogrel is the most widely prescribed P2Y12 inhibitor after PCI,” stated Pereira. “Clopidogrel is a prodrug and requires an active CYP2C19 enzyme to convert it to an active metabolite. Up to 30 percent of patients are CYP2C19*2 or CYP2C19*3 allele carriers, which causes loss of enzymatic function, translating into increased ischaemic events.” [Clin Pharmacol Ther 2013;94:317-323]
Almost all (99 percent) patients in the conventional arm identified as CYP2C19*2/*3 carriers at 12 months post PCI were receiving clopidogrel, while 85 percent in the genotype-guided therapy arm were on ticagrelor. Notably, 15 percent of patients in the genotype-guided arm were on clopidogrel despite being identified as poor metabolizers.
Of the 2,641 patients randomized to receive genotype-guided therapy who were eligible for analysis, 903 were carriers of LOF CYP2C19 alleles, and the same was true for 946 of the 2,635 patients in the conventional therapy arm. Interestingly, patients of East Asian ethnicity accounted for 38 percent of carriers, while comprising only 22 percent of the overall study population.
“A prespecified sensitivity analysis, which included multiple events per patient within 12 months, demonstrated a 40 percent reduction [HR, 0.60; 95 percent confidence interval, 0.41 to 0.89; p=0.011] in ischaemic events in favour of the genotype-guided strategy,” reported Pereira. “There was no significant difference in safety, including bleeding, between the two groups, and prespecified analyses did not indicate any significant subgroup interactions.”