Variability in platelet responsiveness to clopidogrel among 544 individuals.
OBJECTIVE
We sought to describe the responses of patients to clopidogrel using ex vivo measures of platelet aggregation and activation in a large, heterogeneous population.


BACKGROUND
Recently, a number of reports, using various definitions, have dichotomized patients who are treated with clopidogrel into a minority of "non-responders" and a majority of "responders." Such classifications imply that treatment leads to an all-or-none response, with potentially important clinical implications.


METHODS
We conducted secondary post-hoc analyses of a dataset consisting of volunteers (n = 94) and patients after coronary stenting (n = 405), with heart failure (n = 25), and after stroke (n = 20).


RESULTS
The response of subjects to clopidogrel followed a normal, bell-shaped distribution, with a mean and standard deviation of 41.9 +/- 20.8% when aggregation was induced by 5 mumol/l of adenosine diphosphate. When hyporesponsiveness and hyper-responsiveness to clopidogrel were considered to be two standard deviations less than and greater than the mean, respectively, the prevalence of hyporesponsiveness and hyper-responsiveness in these patients was 4.2% and 4.8%, respectively. Pretreatment platelet activity and clinical characteristics were not associated with responsiveness to clopidogrel.


CONCLUSIONS
Individuals receiving clopidogrel exhibit a wide variability in response that follows a normal distribution. The clinical implications of this variability are unknown but potentially are important. Clinical trials are needed to define whether hyporesponders to clopidogrel are at increased risk for thrombotic events and whether hyper-responders are at increased risk for bleeding. If so, the individualization of antiplatelet therapy, including clopidogrel dosing, may be possible in the future but will require the ability to easily and reproducibly measure responsiveness by a method that has been proven to be predictive of clinical events.
Serebruany
Victor L
VL
HeartDrug Research Laboratories, Osler Medical Building, 7600 Osler Drive, Towson, MD 21204, USA. heartdrug@aol.com
Steinhubl
Steven R
SR
Berger
Peter B
PB
Malinin
Alex I
AI
Bhatt
Deepak L
DL
Topol
Eric J
EJ
D000368:Aged; D015703:Antigens, CD / Q000097:blood / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000503:physiopathology; D000077144:Clopidogrel; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D012189:Retrospective Studies; D012307:Risk Factors; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013997:Time Factors
D015703:Antigens, CD; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D000077144:Clopidogrel; D013988:Ticlopidine