Genetic substudy shows fewer major cardiovascular events with ticagrelor, regardless of relevant genetic variability in ACS patients

A new genetic substudy of PLATO (A Study of PLATelet Inhibition and Patient Outcomes) showed that the effects on a combined primary end point of cardiovascular death, myocardial infarction, or stroke seen in patients with acute coronary syndromes (ACS) who received the investigational oral antiplatelet treatment, ticagrelor (Brilinta, AstraZeneca), were maintained, whether or not they had the genetic variability that has been previously shown to affect a patient’s response to clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi Pharmaceuticals).

The substudy is the first to look at both efficacy and bleeding end points of ACS patients treated with ticagrelor who carry variations in the CYP2C19 and ABCB1 genes. The data were presented Aug. 29 at the European Society of Cardiology (ESC) Congress in Stockholm, Sweden, and simultaneously published in The Lancet.

Regardless of the CYP2C19 genotype, the primary outcome occurred less often with ticagrelor vs clopidogrel (interaction P=.46). Ticagrelor event rates were 8.6% per year in carriers and 8.8% per year in non-carriers of CYP2C19 loss-of-function genotype. For clopidogrel patients that carried the CYP2C19 loss-of-function alleles, there was an 11.2% per year event rate, compared with 10.0% per year for patients without the loss of function allele.

Similar to the overall PLATO study, total major bleeding did not significantly differ between ticagrelor and clopidogrel regardless of CYP2C19 genotype.

The genetic substudy also investigated ticagrelor and clopidogrel treatment outcomes in the 3 genetic groupings of the ABCB1 gene group; these were defined as high, intermediate, and low expressions of ABCB1, respectively. The primary efficacy event rates for ticagrelor were 9.5% per year for low, 8.5% per year for intermediate, and 8.8% per year for high expression groups. Primary efficacy event rates for clopidogrel were 10.5% per year for low, 9.8% per year for intermediate, and 11.9% per year for high expression groups. There was no relationship between the ABCB1 genotype and bleeding.

“This substudy is the largest database of ACS patients to date to examine the impact of genetic make-up on response to oral antiplatelet treatment,” said Lars Wallentin, MD, PhD, primary investigator of the PLATO genetic substudy and professor of Cardiology and Research Director at the Uppsala University in Sweden. “As this substudy showed, the effects seen with ticagrelor were independent of genetic variability in CYP2C19 or ABCB1.”

The substudy was designed to explore the interaction of CYP2C19 and ABCB1 genes on ticagrelor and clopidogrel efficacy and safety. More than 10,200 ACS patients were genotyped for CYP2C19 and ABCB1 status. On a background of aspirin, patients in the ticagrelor group were given a 180-mg loading dose and a 90-mg twice-daily maintenance dose, while patients in the clopidogrel group were given a 300-mg to 600-mg loading dose and 75-mg once-daily maintenance dose, for 6 to 12 months.

Ticagrelor has yet to be approved by FDA, though the agency’s Cardiovascular and Renal Drugs Advisory Committee voted to recommend its approval in July.