Genotype-Based P2Y12 Prescribing Post-PCI Falls Short in TAILOR-PCI

(UPDATED) The much-awaited TAILOR-PCI trial did not meet its primary outcome to show that, in loss-of-function carriers with ACS or stable CAD post-PCI patients, using a genotype-guided oral P2Y12 inhibitor strategy compared with conventional clopidogrel treatment decreased the risk of ischemic events at 12 months. However, the randomized trial’s results show a statistically significant benefit of genotyping over 3 months and in reducing multiple ischemic events per patient.

Many were expecting this trial to give a definitive answer regarding the effectiveness of a genotype-guided strategy given that last year’s POPular Genetics study showed noninferiority compared to a blanket approach of giving prasugrel or ticagrelor to STEMI patients in terms of thrombotic events and superiority for bleeding.

“We set a high standard for ourselves, but we observed a 34% risk reduction and hence we were statistically not significant,” said Naveen Pereira, MD (Mayo Clinic, Rochester, MN), who presented TAILOR-PCI today during the virtual American College of Cardiology 2020 Scientific Session. “I think the frustration here was it was almost positive.”

The researchers revised their statistical goal to achieve a 50% risk reduction with a genotype-guided strategy after observing event rates of 4-5% a few years into the study. At 1 year post-PCI, they observed a 34% reduction in the primary endpoint—a composite of cardiovascular death, MI, stroke, definite or probable stent thrombosis, and severe recurrent ischemia—with a genotype-guided strategy among patients with a CYP2C19 loss-of-function allele compared with conventional clopidogrel therapy (4.0% vs 5.9%; adjusted HR 0.66; 95% CI 0.43-1.02).

“I think the probability of our results being true is very high,” Pereira said during a press conference. “People should pay close attention to that, and I hope it changes guidelines. But for sure I think if genetic information is made available to the physician, if someone is a poor metabolizer, not changing therapy would be very difficult to do.”

Roxana Mehran, MD (Icahn School of Medicine at Mount Sinai, New York, NY), who discussed the study following its presentation suggested that physicians “look beyond” the 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 very, very great deal of sense in my mind. They were looking for an absolute risk reduction of 3%. They got 1.8%, that's pretty good.”

The fact that the results did show a statistically significant reduction in events “in that very important vulnerable period” of 3 months after PCI indicates success, she added. “In my mind, congratulations. You did show for the first time even though you did not meet your primary endpoint, that tailoring our therapy using genotype reduces events and [that] understanding the CYP2C19 gene and then treating those patients appropriately by uptitrating their P2Y12 inhibitor was beneficial in this patient population.”

Similarly, Dominick Angiolillo, MD, PhD (University of Florida College of Medicine, Jacksonville), who commented on the study for TCTMD, said while “it would have been nice to see a study formally positive for its primary endpoint, . . . the data are very encouraging for the use of genetic testing.”

Difference Seen at 3 Months

For the study, Pereira and colleagues randomized 5,302 patients from 40 institutions in four countries to received genotype-guided (ticagrelor 90 mg BID for loss-of-function carriers and clopidogrel 75 mg daily for noncarriers) or conventional clopidogrel therapy (75 mg daily) following PCI between May 2013 and October 2018. In total, 903 and 946 patients in each arm, respectively, were found to be CYP2C19 *2/*3 loss-of-function carriers, and these made up the primary analysis cohort. The median patient age was 62 years, 25% were female, and 82% were treated for ACS. The average time to randomization following PCI was just under 5 hours.

In a post hoc analysis, the researchers found a significant absolute 2.1% benefit in using the genotype-guided strategy at 3 months (HR 0.21; P = 0.001).

There were no differences in TIMI major or minor bleeding between the study arms, and there were no differences in the primary endpoint according to any prespecified subgroup analyses.

In a prespecified sensitivity analysis for the primary endpoint looking at multiple recurrent events, though, they did find a benefit for genotyping (HR 0.60; 95% CI 0.41-0.89; P = 0.011).

Comparison With POPular Genetics

In discussion following the presentation, Patrick T. O’Gara, MD (Harvard Medical School, Boston, MA), asked how these results should be interpreted given the positive results seen with POPular Genetics.

“It certainly seems that this trial as well as many others have continued to chip away with what we have all embraced as the biologic appropriateness of trying to target therapies based on genetic risk,” he said. “We’ve fallen short. I would hate for people to focus unnecessarily on the fact that you missed your primary endpoint by a hundredth of a percentage point and not sort of speak to the big picture about how we can make this genetic testing more widely available at the point of care in a more accurate way that actually informs clinical decision making among our interventional and general cardiology colleagues. It just makes too makes too much sense to ignore this potential.”

Pereira clarified that TAILOR-PCI was designed to show superiority of genotyping while POPular Genetics compared a genotyping strategy to no-genotyping strategy in which everyone in the latter group was given ticagrelor. “If you just piece out the ischemic event rate, which is what TAILOR-PCI was looking at, . . . the ischemic event rate in POPular Genetics in the genotyping guided group was in the mid 4% range, which was very similar to the ticagrelor arm [in TAILOR-PCI] without genetic testing,” he said. “So hence it was not inferior.” O’Gara followed up by questioning if the fact that 15% of the patients in the genotype-guided strategy arm received clopidogrel “hurt” the eventual study results.

“We addressed that in two ways,” Pereira said, explaining that the prespecified time-sensitivity analysis showed a “very, very similar” hazard ratio. “We also then had a prespecified analysis where we examined only those patients who were in the on-treatment protocol—so the ones who were getting ticagrelor only and excluding the patients who got clopidogrel. When you look at the outcomes of the on-treatment protocol cohorts, again the point estimate was very similar. So, it didn’t hurt us a whole lot actually.”

More Data Ahead

Because so many in the field were expecting a definitive answer from TAILOR-PCI, Angiolillo acknowledged the valid desire for another trial. “When we have a trial that does not fully answer the question, obviously there is a need for more study,” he said. “I think studies conducted in more homogeneous patient cohorts would be ideal.”

For example, he explained, many clinicians think ACS patients should be treated with prasugrel, which they did not receive here. Still, the current data do “show that there is room for individualizing treatment, that there is not a one-size-fits-all, and I look forward to . . . the era of personalized medicine and using genetic testing,” Angiolillo said.

Pereira noted that these patients will be followed out to 24 months, and the next set of results could potentially change perspective further. “Beyond 12 months, you get more events, it's an intention-to-treat analysis, and as you get more events, we may even be powered to look at a risk reduction of what we originally sought out with 35%,” he said, explaining that at this point “patients do not know their genotype yet so it remains kind of blinded.”