The largest cardiology trial to examine the effectiveness of using genetic testing for CYP2C19 to guide treatment choice, TAILOR-PCI, did not meet its primary endpoint of demonstrating a 50% reduction at one year in the combined rate of cardiovascular death, myocardial infarction, stroke, severe recurrent ischemia and stent thrombosis. The results of this Late-Breaking Clinical Trial were presented March 28 during ACC.20/WCC.

Current guidelines from the ACC and American Heart Association do not recommend testing patients for the CYP2C19 genetic abnormality before prescribing clopidogrel. No prospective clinical trials have shown that outcomes are better for patients who have the abnormality when the test is used to guide their treatment.

The NHLBI-funded international trial enrolled 5,302 patients who had PCI with at least one stent for acute coronary syndrome or stable coronary artery disease and requiring 12 months of dual antiplatelet therapy. Patients were randomly assigned either to conventional therapy (clopidogrel 75 mg daily) or genotype-guided therapy (ticagrelor 90 mg twice daily for carriers and clopidogrel 75 mg daily for noncarriers).

The primary analysis cohort, based on the prespecified analysis plan, consisted of 946 patients in the conventional group and 903 patients in the genotype-guided group as being carriers using TaqMan genotyping at 12 months. Their median age was 62 years and 75% were men.

Among patients who carried the genetic variant, the primary endpoint occurred in 4% of the genotype-guided group, compared with 5.9% in the conventional group (hazard ratio, 0.66; 95% confidence interval [CI], 0.43-1.02; p=0.056). No difference was seen in the safety endpoint of TIMI major bleeding or minor bleeding (1.9% vs. 1.6%, respectively).

A prespecified sensitivity analysis for the primary endpoint found a 40% reduction for cumulative primary endpoint events that occurred during the study period (95% CI, 0.41-0.89; p=0.011).

“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,” says Naveen L. Pereira, MD, FACC, co-principal investigator of the study.

A post hoc analysis found a nearly 80% reduction in the rate of adverse events in the first three months of treatment among patients who received genetically guided therapy compared with those who did not. Pereira explains, “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.” Extended follow-up funded by the NHLBI is ongoing.

ACC.org Editor-in-Chief Kim A. Eagle, MD, MACC, notes: “Interpreting trials like this where the prespecified target was not met but a potential effect was seen is very challenging. The purist will say that either another trial is needed or longer follow-up showing that the treatment target is reached  before adopting this strategy in practice. This practice area is further complicated by rapid changes in stent design, new antiplatelet agents, and other modifications in care including variable insurance coverage of newer antiplatelet agents. My own view is that we need more data.”

Clinical Topics: Acute Coronary Syndromes, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Stable Ischemic Heart Disease, Acute Heart Failure, Interventions and ACS, Chronic Angina

Keywords: ACC Annual Scientific Session, acc20, Percutaneous Coronary Intervention, Acute Coronary Syndrome, Heart Failure, Angina, Stable

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