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.
Modeling and Simulation, Daiichi Sankyo, 399 Thornall St, Edison, NJ 08837, USA.
Russ
R
Wada
Shashank
S
Rohatagi
David
D
Small
Kenneth J
KJ
Winters
Daniel E
DE
Salazar
D054058:Acute Coronary Syndrome / Q000401:mortality / Q000517:prevention & control*; D000367:Age Factors; D015415:Biomarkers / Q000097:blood; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D006470:Hemorrhage / Q000139:chemically induced / Q000453:epidemiology*; D006801:Humans; D008954:Models, Biological; D009203:Myocardial Infarction / Q000453:epidemiology*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D012737:Sex Factors
D015415:Biomarkers; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011725:Pyridines; C446540:thienopyridine