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Trial Shows Some Benefit of Genetically Guided Antiplatelet Therapy After Balloon Angioplasty

NEW YORK – Pharmacogenetic testing of patients undergoing balloon angioplasties may reduce the number of serious adverse events they experience during antiplatelet treatment, a new trial has found. 

After percutaneous coronary interventions (PCIs), which include balloon angioplasties and stent placements, patients are typically given dual antiplatelet therapy, a combination of aspirin and a P2Y12 inhibitor, to prevent blood clots. The most common P2Y12 inhibitor is clopidogrel, but about a third of patients have a CYP2C19 gene variant that affects clopidogrel activity. Patients with loss-of-function CYP2C19 gene variants are at increased risk of heart attack or stroke following PCIs.

While current guidelines do not recommend genetic testing when prescribing clopidogrel, the TAILOR-PCI clinical trial sought to examine whether testing before prescribing clopidogrel reduces adverse events following PCI. The researchers reported in the Journal of the American Medical Association on Tuesday that the trial did not meet its primary endpoint of showing a 50 percent reduction in adverse events in the year following the procedure in patients who underwent genetic testing prior to prescribing clopidogrel, but they did find for a smaller reduction in adverse events.

"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," first author Naveen Pereira from the Mayo Clinic said in a statement.

The researchers recruited 5,302 patients undergoing PCI and randomized them to either genotype-guided selection of P2Y12 inhibitor therapy or conventional therapy with clopidogrel. Within the genotype-guided group, the researchers identified 903 patients with CYP2C19 loss-of-function variants who then largely received the alternate therapy ticagrelor.

After a year, samples from patients from the conventional therapy arm of the study were genotyped. Of these, 946 were found to have CYP2C19 loss-of-function variants, and they mostly received clopidogrel.

The primary endpoint of the study — a composite endpoint of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia — was not statistically different between the genotype-guided and conventional arms of the study. These adverse events occurred in 4 percent of patients with CYP2C19 loss-of-function variants from the genotype-guided group and in 5.9 percent of patients with CYP2C19 loss-of-function variants from the conventional group after 12 months.

Despite not meeting their primary endpoint, the trial researchers noted that there was a 34 percent lower occurrence of adverse events within the genotype-guided group. 

They further reported that a post hoc analysis indicated an 80 percent reduction in adverse events among patients who received genetically guided treatment when that analysis was restricted to the first three months following PCI. In a related editorial appearing in JAMA, David Moliterno, Susan Smyth, and Ahmed Abdel-Latif, all from the University of Kentucky, noted that this finding is in line with studies that have suggested a shorter duration of dual antiplatelet therapy might be best as its effects are the most pronounced in the first few months of treatment.

The researchers also noted the primary event rate they observed in their trial was lower than what they had assumed when the trial was designed in 2012. Since then, there have been improvements in the standard of care, such as drug-coated stents, that may have reduced the rate of adverse events among patients, but also affected the trial's ability to meet its goal. 

Moliterno, Smyth, and Abdel-Latif added that the findings don't mean a personalized approach for guiding drug prescriptions shouldn't be pursued. "The broader question is how much the healthcare system should invest in integrating these strategies into daily practice and if the return on such an investment is clinically and financially rewarding," they wrote. "Clinicians and patients would argue that the clinical and financial cost of genotype testing would pale in comparison with the cost of an admission for stent thrombosis or a major bleeding complication."

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