Virtual ACC: Genotype-guided therapy after PCI does not hit study target

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Naveen Pereira
Naveen Pereira

Today, during the Virtual American College of Cardiology (ACC) event (28–30 March, Central Time), Naveen L Pereira (Mayo Clinic, Rochester, USA) told the online audience that using genetic testing to guide antiplatelet therapy after percutaneous coronary intervention (PCI) does not reduce the 12-month incidence of ischaemic events by 50%—the prespecified goal of the TAILOR PCI (Tailored antiplatelet initiation to lessen outcomes due to decreased clopidogrel response after PCI) trial—compared with usual therapy (no genetic testing). However, genotype-guided therapy was associated with a 34% reduction at one year.

Speaking via video, Pereira said that clopidogrel, following a PCI procedure, was “the most widely prescribed P2Y12 inhibitor” but added its effectiveness may be reduced in patients who are CYP2C19 loss of function carriers. He explained that patients with this genotype are not able to fully metabolise clopidogrel, which potentially means they may not receive any benefit from the drug and, thus, may be at increased risk of ischaemic events. Furthermore, Pereira observed that up to 30% of people—rising to 50% in people of Asian heritage—in the USA may have this genotype and, therefore, may be suitable candidates for an alternative antiplatelet agent (such a ticagrelor). Indeed, the US Food and Drug Administration (FDA) labelling for clopidogrel has a black box warning to highlight the need for alternative therapy for patients with the genotype.

Therefore, the aim of TAILOR PCI was to provide an answer to the question “does identifying loss of function of CYP2C19 carriers and altering P2Y12 inhibitor therapy based on CYP2C19 genotype reduce ischaemic outcomes in the first 12 months after PCI?”.

Patients, including those with acute coronary syndromes and stable disease, scheduled for PCI were randomised to undergo genotype-guided therapy or conventional therapy. In the genotype group (2,641), those who tested positive for CYP2C19 *2/3* carrier were prescribed ticagrelor after PCI whereas those tested negatively were prescribed clopidogrel. All patients in the conventional therapy group (2,635) were prescribed clopidogrel. At 12 months, both groups underwent TaqMan genotyping. Pereira et al then compared (in the primary analysis cohort) outcomes of CYP2C19 *2/3* carrier patients (903) in the genotype-guided therapy group with those in the conventional therapy group (946).

The primary endpoint of the study was the composite of cardiovascular death, myocardial infarction, stroke, definite or probable stent thrombosis, and severe recurrent ischaemia within one year of the index PCI. Pereira commented that, in the statistical analysis, he and his colleagues assumed an event rate of 6% in the conventional therapy patients (who received clopidogrel) and an event rate of 6% in the genotype-guided therapy group (who received ticagrelor) “with a minimum detectable hazard ratio of 0.5 with 85% power”.

At one year, the primary endpoint occurred in 4% of patients in the genotype-guided therapy group vs. 5.9% in the conventional therapy group. This meant that genotype-guided therapy was associated with a non-significant 34% relative risk reduction in ischaemic events—meaning that TAILOR PCI did not meet its primary endpoint (which hypothesised that there would be a 50% reduction). However, a prespecified sensitivity analysis showed a statistically significant 40% reduction in the total number of events per patient receiving genotype-guided treatment compared with patients who received standard treatment. Additionally, a post-hoc analysis suggested that the benefit of genotyope-guided therapy is greatest within the first three months, with a nearly 80% reduction in ischaemic events compared with conventional therapy. The rates of bleeding were similar between groups.

Pereira commented: “Although these results fell short of the effect size that we predicted, they nevertheless provide a signal that offers support for the benefit of genetically guided therapy, with approximately one-third fewer adverse events in the patients who received genetically guided treatment compared with those who did not.” He added that, as the first three months after PCI is when patients are most at risk of ischaemic events, the observed 80% reduction “suggests that the lion’s share of the benefit of genetically guided therapy may occur during this high-risk period. Because this was not a pre-planned analysis, we cannot draw firm conclusions from it, but it merits further study.”

Panellist Roxana Mehran (The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, USA), again via video, commented: “This trial once again shows us that these guided treatments do give us guidance but still they could be a marker of higher risk patient population.” She added that TAILOR PCI was an “excellent study” and a “very informative” one.

The COVID-19 pandemic led to the ACC Annual Scientific Session Together with World Congress of Cardiology (ACC.20/WCC) being cancelled. The Virtual ACC is a free online event that streams the educational material, including late-breaking trials, that would have been presented at the ACC.20/WCC. 


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