The observational extended study of the previously reported 12-month randomized TAILOR-PCI trial shows genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI) did not significantly reduce ischemic events compared with conventional therapy, after a median of 39 months. This was the same finding as in the original trial.
However, there is more to this than meets the eye, according to lead investigator Naveen L. Pereira, MD, professor of medicine at Mayo Clinic, Rochester, Minnesota, who recently presented the findings at the virtual American College of Cardiology 2021 Scientific Session.
In the randomized trial, half of the 5302 patients received conventional therapy with clopidogrel, while the other half had a point-of-care genotyping test (Spartan Rx, Spartan Bioscience) to guide therapy, he said.
Patients who carried at least one of two CYP2C19 loss-of-function alleles that are associated with a diminished response to clopidogrel were given ticagrelor (or prasugrel, if ticagrelor was not tolerated), and noncarriers received clopidogrel.
Patients in the genotype-guided therapy group had a 34% lower risk of cardiovascular events than those in the conventional therapy group, but this did not meet the primary endpoint of a 50% reduction in events and was not statistically significant (P = .056).
Nevertheless, the result was “clinically meaningful with a high likelihood of genotype testing benefit,” Pereira told theheart.org | Medscape Cardiology in an interview.
The researchers hypothesized that in the extended follow-up study, ischemic outcomes would be significantly better in the genotype-guided therapy group, but this was not the case, he reported. “But please note there was a corresponding decrease in P2Y12 inhibitor use over time,” he stressed.
That is, beyond 12 months, when therapy type was not specified by protocol, patients in the genotype-guided therapy group were much less likely to continue ticagrelor, whereas there was a much smaller drop in clopidogrel use in the conventional therapy group.
The other outcomes in the extended observational study were similar to those in the original randomized trial. There was no significant between-group difference in bleeding events, and the benefit of genotype-guided therapy was strongest in the first 3 months after PCI. The researchers also did not find any significant differences in the primary outcome in prespecified subgroups.
Panelist Judith S. Hochman, MD, senior associate dean of clinical sciences at New York University School of Medicine, New York City, complimented Pereira on this “tough study to conduct,” a trial that investigated “a very controversial question — to use genotype-testing guided therapy or not for patients undergo PCI.”
She noted that ACC and the American Heart Association (AHA) don’t recommend a genotype-guided strategy for antiplatelet therapy selection, but instead they recommend giving any P2Y12 inhibitor, and, for patients with acute coronary syndrome, giving ticagrelor or prasugrel (a class 2A recommendation).
“Should we have a personalized strategy” she asked, based on patient characteristics such as race and procedure characteristics including ST-segment elevation myocardial infarction (STEMI), to select which patients should receive genotype testing?
Pereira replied that the findings from the extended TAILOR-PCI study, plus results from two recently published meta-analyses, one by Galli et al in The Lancet and one by his own group in JACC: Cardiovascular Interventions, “point to the fact that we could have an intermediate step right now that could change our clinical practice.”
“I feel we could get more precise,” he continued. “We should start thinking now based on all these results that have been published.”
He suggests that if a patient is not a loss-of-function carrier, clinicians can safely give clopidogrel, whereas if a patient is a loss-of-function carrier — as 30% of patients are — clinicians can give ticagrelor or prasugrel.
“Mind-Boggling” Impact of Loss-of-Function Status
Pereira pointed out that in their group’s meta-analysis of seven randomized clinical trials of P2Y12 inhibitor therapy after PCI, ticagrelor/prasugrel therapy significantly reduced the risk of ischemic outcomes compared with clopidogrel therapy in CYP2C19 loss-of-function carriers (hazard ratio, 0.70) but not in noncarriers (HR 1.0).
This means that in these large trials, including PLATO and TRITON TIMI 48, which showed that ticagrelor/prasugrel was superior to clopidogrel, “most of the benefit comes from the patients’ loss-of-function status — which is mind-boggling — and the [noncarriers] did fine with clopidogrel,” he said.
“The data for genetic testing in P2Y12 inhibitors should be interpreted in the totality of evidence,” Pereira concluded.
This should consider pharmacokinetic studies, which have shown that patients with loss of function have decreased clopidogrel active metabolite levels and less inhibition of platelet aggregation.
And observational studies have all shown that patients who carry loss-of-function alleles have an increased risk of ischemic events when treated with clopidogrel.
Moreover, a prespecified analysis of TAILOR-PCI, allowing for multiple events per patient, demonstrated a 40% reduction in ischemic events in patients with loss-of-function variants who received genotype-guided vs conventional therapy (P = .01), “which no one talks about,” he said.
And the meta-analysis that their group performed, which included the negative PLATO genetic substudy, also demonstrated that the benefit of ticagrelor/prasugrel primarily emerges because of loss-of-function status of patients receiving clopidogrel, Pereira noted.
TAILOR-PCI Observational Study Design
The primary efficacy analysis for the TAILOR-PCI extended observational study was conducted in the same 1849 loss-of-function carriers from the randomized clinical trial; 946 of these patients had received conventional therapy and 903 patients had received genotype-guided therapy.
The patients in both groups had similar baseline characteristics. They had a median age of 62 years and about 75% were male; 47% were White and 45% were Asian. They had similar comorbidities and about 85% of patients had presented with ACS and 15% with stable coronary artery disease (CAD).
During the 12-month TAILOR-PCI study, while therapy was protocol-driven, dual antiplatelet therapy (DAPT) use was 98% of person-days in both the genotype-guided therapy group and the conventional therapy group.
However, during follow-up, when therapy was not protocol-driven, DAPT use fell to 43% in the genotype-guided therapy group and 57% in the conventional therapy group.
Ticagrelor use in the genotype-guided therapy group dropped “dramatically” from 75% to 23%, from the first 12 months to the time beyond 12 months, whereas clopidogrel use in the conventional therapy arm fell from 97% to 63%.
The study was funded by the National Heart, Lung, and Blood Institute. Spartan Bioscience provided the point-of-care genotyping platform and assays. Pereira has disclosed no relevant financial relationships. Hochman discloses having financial relationships with Abbott Vascular (previously St. Jude Medical), Amgen, Espero, Medtronic, Merck, Omron Healthcare, Phillips (previously Volcano Corp), and Sunovion, and receiving research grants from Arbor Pharmaceuticals and AstraZeneca.
American College of Cardiology (ACC) 2021 Annual Scientific Session: Session 412-04. Presented May 17, 2021.