Following percutaneous coronary intervention (PCI), short-term clopidogrel
therapy in addition to aspirin leads to greater protection from thrombotic
complications than aspirin alone. However, the optimal duration of combination
oral antiplatelet therapy is unknown. Also, although current clinical data
suggest a benefit for beginning therapy with a clopidogrel loading dose prior
to PCI, the practical application of this therapy has not been prospectively
To evaluate the benefit of long-term (12-month) treatment with clopidogrel
after PCI and to determine the benefit of initiating clopidogrel with a preprocedure
loading dose, both in addition to aspirin therapy.
Design, Setting, and Participants
The Clopidogrel for the Reduction of Events During Observation (CREDO)
trial, a randomized, double-blind, placebo-controlled trial conducted among
2116 patients who were to undergo elective PCI or were deemed at high likelihood
of undergoing PCI, enrolled at 99 centers in North America from June 1999
through April 2001.
Patients were randomly assigned to receive a 300-mg clopidogrel loading
dose (n = 1053) or placebo (n = 1063) 3 to 24 hours before PCI. Thereafter,
all patients received clopidogrel, 75 mg/d, through day 28. From day 29 through
12 months, patients in the loading-dose group received clopidogrel, 75 mg/d,
and those in the control group received placebo. Both groups received aspirin
throughout the study.
Main Outcome Measures
One-year incidence of the composite of death, myocardial infarction
(MI), or stroke in the intent-to-treat population; 28-day incidence of the
composite of death, MI, or urgent target vessel revascularization in the per-protocol
At 1 year, long-term clopidogrel therapy was associated with a 26.9%
relative reduction in the combined risk of death, MI, or stroke (95% confidence
interval [CI], 3.9%-44.4%; P = .02; absolute reduction,
3%). Clopidogrel pretreatment did not significantly reduce the combined risk
of death, MI, or urgent target vessel revascularization at 28 days (reduction,
18.5%; 95% CI, −14.2% to 41.8%; P = .23). However,
in a prespecified subgroup analysis, patients who received clopidogrel at
least 6 hours before PCI experienced a relative risk reduction of 38.6% (95%
CI, −1.6% to 62.9%; P = .051) for this end
point compared with no reduction with treatment less than 6 hours before PCI.
Risk of major bleeding at 1 year increased, but not significantly (8.8% with
clopidogrel vs 6.7% with placebo; P = .07).
Following PCI, long-term (1-year) clopidogrel therapy significantly
reduced the risk of adverse ischemic events. A loading dose of clopidogrel
given at least 3 hours before the procedure did not reduce events at 28 days,
but subgroup analyses suggest that longer intervals between the loading dose
and PCI may reduce events.