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.
Wada
Russ
R
Modeling and Simulation, Daiichi Sankyo, 399 Thornall St, Edison, NJ 08837, USA.
Rohatagi
Shashank
S
Small
David
D
Winters
Kenneth J
KJ
Salazar
Daniel E
DE
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