A new genetic substudy of PLATO (A Study of PLATelet Inhibition and Patient Outcomes) showed that the effects on a combined primary endpoint of cardiovascular death, myocardial infarction, or stroke seen in Acute Coronary Syndromes (ACS) patients who received the investigational oral antiplatelet treatment, ticagrelor (BRILINTA™), were maintained, whether or not they had the genetic variability that has been previously shown to affect a patient's response to clopidogrel. The substudy is the first to look at both efficacy and bleeding endpoints of ACS patients treated with ticagrelor who carry variations in the CYP2C19 and ABCB1 genes. The data were presented today at the European Society of Cardiology (ESC) congress in Stockholm, Sweden and simultaneously published in The Lancet.

CYP2C19
Regardless of the CYP2C19 genotype, the primary outcome occurred less often with ticagrelor versus clopidogrel (interaction p=0.46). 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 allele, there was a 11.2% per year event rate, compared to 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.

ABCB1
The genetic substudy also investigated ticagrelor and clopidogrel treatment outcomes in the three 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. As this substudy showed, the effects seen with ticagrelor were independent of genetic variability in CYP2C19 or ABCB1," said Professor Lars Wallentin, primary investigator of the PLATO genetic substudy and Professor of Cardiology and Research Director at the Uppsala University, Sweden.

The substudy was designed to explore the interaction of CYP2C19 and ABCB1 genes on ticagrelor and clopidogrel efficacy and safety. 10,285 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.

About ACS
ACS is an umbrella term for conditions that result from a reduction in blood flow to the heart muscle. These conditions range from unstable angina (UA/chest pain) to myocardial infarction (MI/heart attack):

• STEMI is a type of heart attack in which the coronary artery is generally blocked off by a blood clot, and as a result virtually all the heart muscle being supplied by the affected artery starts to die.
• UA/NSTEMI is a type of heart attack in which a blood clot partly occludes an artery and as a result only a portion of the heart muscle being supplied by the affected artery dies. UA is one of the types of ACS, a series of conditions most commonly produced by the rupture of a plaque in a coronary artery. UA is "unstable" not only because a plaque has potentially ruptured (a situation which threatens to progress to a myocardial infarction), but also because the symptoms it produces - the angina - generally occurs more frequently, often at rest, and lasts longer.

About the PLATO study
PLATO was a large (18,624 patients in 43 countries) head-to-head patient outcomes study of ticagrelor versus clopidogrel, designed to establish whether ticagrelor could achieve clinically meaningful CV and safety end points in ACS patients. PLATO was designed to reflect current clinical management of ACS patients and included and represented all types of ACS patients (STEMI, NSTEMI & UA) whether they underwent invasive procedures or were medically managed.

About BRILINTA™/BRILIQUE™
Ticagrelor (BRILINTA/BRILIQUE) is an investigational oral antiplatelet treatment for ACS. Ticagrelor is a direct-acting P2Y12 receptor antagonist in a chemical class called cyclo-pentyl-triazolo-pyrimidines (CPTPs). Ticagrelor is the first reversibly-binding oral ADP receptor antagonist.

BRILINTA and BRILIQUE are trademarks of the AstraZeneca group of companies.

About AstraZeneca
AstraZeneca is a global, innovation-driven biopharmaceutical business with a primary focus on the discovery, development and commercialisation of prescription medicines. As a leader in gastrointestinal, cardiovascular, neuroscience, respiratory and inflammation, oncology and infectious disease medicines, AstraZeneca generated global revenues of US $32.8 billion in 2009. For more information please visit: www.astrazeneca.com.