Personalized antiplatelet therapy after PCI based on genotyping barely misses primary endpoint
Genotyping-guided antiplatelet therapy following percutaneous coronary intervention (PCI) did not meet the stringent goal of halving the incidence of serious adverse cardiovascular events in the year following the procedure. However, the TAILOR-PCI trial did demonstrate a 34% reduction in such events at 1 year, in addition to a significant reduction in the number of events per patient, said Naveen L. Pereira, MD, from Mayo Clinic, Rochester, Minn.
TAILOR-PCI was designed to determine whether identifying carriers of the loss-of-function CYP2C19 allele and altering P2Y12 inhibitor therapy based on CYP2C19 genotype reduces the rate of ischemic outcomes.
In the United States, 30% to 35% of people carry the genetic variant that makes them less capable of metabolizing and, hence, activating the antiplatelet drug clopidogrel. This proportion increases to 50% among people of Asian heritage.
TAILOR-PCI was a two-arm, parallel, open-label, international multicenter randomized clinical trial designed to show superiority of genotyping-guided antiplatelet therapy. Eligible patients were 18 or older who underwent PCI for acute coronary syndrome or stable coronary artery disease and required 12 months of dual antiplatelet therapy.
The study had 2 arms. A conventional therapy arm was prescribed clopidogrel after PCI, and at the end of 12 months, underwent genotyping that enabled identification of those who carried the loss of function CYPC19*2/*3 variants, and those who were noncarriers. “The reason that genotyping was performed at the end of 12 months was that if patients were identified to be poor metabolizers prior to the 12-month mark as per therapeutic guidelines, we would have to prescribe alternative antiplatelet drug therapy, therefore not allowing a comparison,” said Dr. Pereira.
In the other arm, point-of-care genotyping that provided results within 60 minutes was performed and enabled identification of those patients who had loss of function variants for whom ticagrelor was prescribed and those who were noncarriers for whom clopidogrel was prescribed.
To permit uniform comparison, both arms underwent genotyping by TaqMan assay at 12 months. No difference in ischemic outcomes was expected between conventional therapy and genotyping-guided therapy in patients who were noncarriers of the loss of function allele. The primary analysis, therefore, was undertaken only in those patients who had loss of function variants in the conventional arm who received clopidogrel and patients who had loss of function variants in the genotyping-guided arm who received ticagrelor.
Some 5,302 patients were randomized; 2,641 patients in the genotype-guided therapy arm (of whom 903 had loss of function variants) and 2,635 in the conventional therapy arm (of whom 946 had loss of function variants). Therefore, a total of 1,849 CYP2C19*2/*3 carriers were included in the primary analysis.
The primary end point was the composite of cardiovascular death, myocardial infarction, stroke, definite or probable stent thrombosis, and severe recurrent ischemia with 1 year after index PCI.
The average time to randomization after PCI was less than 5 hours in the CYP2C19*2/*3 carriers. Among loss-of-function carriers, 99% in the conventional therapy arm received clopidogrel and 85% in the genotype-guided therapy arm received ticagrelor and 15% received clopidogrel.
Event rates of 6% in the conventional therapy and 3% in the genotype-guided arm were assumed with a minimum detectable hazard ratio of 0.50 with 85% power.
The primary composite end point occurred in 4% of loss of function carriers in the genotyping-guided therapy group and 5.9% in the conventional therapy group, resulting in an adjusted hazard ratio of 0.66, which narrowly missed statistical significance (P = 0.056).
A post hoc analysis demonstrated a risk reduction of 79% in the first 3 months compared with later time intervals, favoring genotyping-guided antiplatelet therapy (P = 0.001). “We now know from clinical practice and other studies that antiplatelet drug therapy is critical during the first 3 months after PCI,” said Dr. Pereira in a prepared statement released by ACC. “This finding suggests that the lion’s share of the benefit of genetically guided therapy may occur during this high-risk period. Because this wasn’t a preplanned analysis, we can’t draw firm conclusions from it, but it merits further study.”
A prespecified sensitivity analysis that included multiple events per patient within the 12-month study period demonstrated a 40% reduction in ischemic events in favor of the genotyping-guided strategy, which was statistically significant (P = 0.011).
No significant difference in major and minor bleeding was observed between the two groups.
“They just missed the primary end point unfortunately,” commented Roxana Mehran, MD, from Mount Sinai School of Medicine, New York City, who was not involved in the study. “Maybe we should be looking beyond that P value. The investigators looked for a 50% reduction; they found a 34% reduction. Is that not good enough? To me it is; clinically it makes a great deal of sense in my mind.”
The absolute risk reduction of 1.8% was “pretty good,” she added. “In the important vulnerable period up to 3 months, up to 6 months even, there was an important early benefit with genotyping, and that’s when it really counts.”
TAILOR-PCI was funded by the Mayo Clinic in collaboration with the National Heart, Lung, and Blood Institute. Spartan Bioscience, Inc, supplied the genetic tests used. Naveen L. Pereira, MD, reported no disclosures.