Correlation of inhibition of platelet aggregation with cardiovascular and bleeding outcomes in acute coronary syndromes.

Inhibition of platelet aggregation (IPA) has been a drug development target in acute coronary syndrome (ACS) for almost 2 decades. The relationship between IPA and cardiovascular (CV) events has not been quantified. Cardiovascular (non fatal myocardial infarction, death) and major bleeding events were extracted from phase 2 or 3 randomized, double-blind trials that evaluated oral and intravenous glycoprotein 2b/3a (GP2b/3a) antagonists and thienopyridines. IPA was extracted from different sources that studied a similar regimen in a similar population. Events were correlated to IPA using a linear relative-risk mixed-effects model. Covariates included type of drug, mean age, gender percentage, and ADP. Clinical trial simulations were conducted to evaluate the relationship between IPA and the likelihood of observing a CV event in a 6-month end point trial. Data from 81918 subjects in 20 studies were extracted from the literature. To achieve a 20% relative reduction in CV events would require a further 77% (56%-100%) absolute increase in IPA for IV GP2b/3a antagonists or a further 27%(20%-41%) absolute increase for thienopyridines. CV risk reduction was less in studies with older subjects and greater in studies with greater percentages of male subjects. Assuming a 3% major bleeding rate in the control group, these drugs had a 1% increase in absolute risk as absolute platelet inhibition increases by 60% (range, 40%-80%). This relationship in intrinsic bleeding may be different in different population subtypes. Assuming a 12% event rate, a 6-month active-controlled thienopyridine trial with 3000 subjects could detect a relationship between CV events and IPA with 80% likelihood. Target IPA increases in ACS are an absolute increase of 80% for IV GP2b/3a antagonists and 30% for thienopyridines. Quantitative models using literature data on IPA and CV events can be used to select dose regimens in early stages of drug development.