An analysis of mortality rates with dual-antiplatelet therapy in the primary prevention population of the CHARISMA trial.
OBJECTIVE
To examine the unanticipated, excess mortality observed in patients randomized to clopidogrel and aspirin vs. aspirin alone in the prespecified 'asymptomatic' subgroup of CHARISMA, we investigated whether dual-antiplatelet therapy may be associated with adverse cardiovascular (CV) events in a primary prevention population.


RESULTS
Of 15 603 patients enrolled, 3284 were initially categorized as asymptomatic with CV risk factors, but 995 had a prior CV event, leaving 2289 patients to represent the primary prevention cohort. This subset was compared with 13 148 symptomatic patients with established vascular disease and both were evaluated for CV death and bleeding. A multivariate analysis analysed predictors of CV death in this group. No post mortem data were available. Compared with aspirin alone, a significant increase in CV death (P = 0.01) was observed in patients receiving dual-antiplatelet therapy in the asymptomatic population. Within the primary prevention cohort, this excess CV death was not significant (P = 0.07). Multivariate analysis of the primary prevention group showed a trend towards excess CV death (P = 0.054; HR 1.72; CI 0.99-2.97) with dual-antiplatelet therapy (aspirin plus clopidogrel). Other independent predictors of CV death included increasing age, hypertension, atrial fibrillation, and a history of heart failure. There was a non-significant increase in moderate or severe bleeding (P = 0.218) with dual-antiplatelet therapy; thus, bleeding was an unlikely explanation for the excess event rate.


CONCLUSIONS
These findings do not support the use of dual-antiplatelet therapy with clopidogrel and aspirin in a primary prevention population. In this subgroup analysis, CV death occurred more frequently than anticipated. The cause of this apparent harm is not elucidated, may represent play of chance, but requires further prospective evaluation.
Wang
Thomas H
TH
Cleveland Clinic, Cleveland, OH, USA.
Bhatt
Deepak L
DL
Fox
Keith A A
KA
Steinhubl
Steven R
SR
Brennan
Danielle M
DM
Hacke
Werner
W
Mak
Koon-Hou
KH
Pearson
Thomas A
TA
Boden
William E
WE
Steg
P Gabriel
PG
Flather
Marcus D
MD
Montalescot
Gilles
G
Topol
Eric J
EJ
D000368:Aged; D001241:Aspirin / Q000008:administration & dosage / Q000009:adverse effects*; D050197:Atherosclerosis / Q000401:mortality / Q000517:prevention & control; D002318:Cardiovascular Diseases / Q000401:mortality* / Q000517:prevention & control; D000077144:Clopidogrel; D018572:Disease-Free Survival; D004359:Drug Therapy, Combination; D004812:Epidemiologic Methods; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000401:mortality / Q000517:prevention & control; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D020521:Stroke / Q000401:mortality / Q000517:prevention & control; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*
D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin