CREDO: Clopidogrel for the Reduction of Events During Observation - 1-year Follow-up Results

Luis Gruberg, MD, FACC

Disclosures

November 22, 2002

The 28-day results of the CREDO trial were previously published as part of Medscape Cardiology's Conference Coverage of TCT 2002. Click here for background information and study design.


Presenter: Steven R. Steinhubl, MD, Chapel Hill, North Carolina

Until recently, antiplatelet treatment following percutaneous coronary intervention (PCI) was recommended for 2-4 weeks. In October 2002, based on the results of such studies as CURE,[1] the ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction (MI)[2] were updated to increase antiplatelet therapy for at least 1 month and up to 9 months. The Clopidogrel for the Reduction of Events During Observation (CREDO)[3] trial marked the first study to assess the long-term (12 months) effects of antiplatelet therapy in patients following PCI. The study also sought to determine optimal timing for the initiation of therapy.

1-Year Results

Baseline clinical characteristics were well balanced between the 2 groups (Table 1), and both groups received similar treatments following baseline angiography (Table 2).

Table 1. CREDO: Baseline Clinical Characteristics
  Clopidogrel
(n = 1053)
Placebo
(n = 1063)
Age (yrs) 61.5 61.8
Female (%) 29.3 27.9
Prior infarction (%) 33.5 34.4
Diabetes (%) 27.5 25.4
Recent infarction (%) 14.3 13.1
Table 2. CREDO: Prescribed Treatment Following Angiography
  Clopidogrel
(n = 1053)
Placebo
(n = 1063)
PCI (%) 85.6 86.2
Coronary bypass surgery (%) 3.9 4.0
Medical treatment (%) 8.3 7.6


The principal result of CREDO was a 26.9% relative risk reduction (RRR) (8.5% vs 11.5%; P = .02) in the primary endpoint (composite death, MI, stroke) among patients on clopidogrel for 1 year following PCI vs those on placebo treatment. This significant reduction can be temporally separated into 2 intervals:

  1. Baseline to day 28

  2. Day 29 to 1 year

At 28-day follow-up, among the intent-to-treat population, compared with placebo, patients treated with clopidogrel plus aspirin had a 19.7% RRR in the clinical composite endpoint, but this reduction was not statistically significant (P = .21). The RRR, however, did reach statistical significance in an analysis comparing both groups between day 29 and 1 year. During this timeframe, patients treated with clopidogrel had an RRR of 37.4% in the primary endpoint (P = .04) (Figure 1).

Figure 1. CREDO: composite of death, MI, or stroke at varying time intervals.

Although nonsignificant, individual analysis of each component of the composite endpoint showed a positive trend in favor of clopidogrel treatment vs placebo (Figure 2), there was no difference between the 2 groups with respect to minor bleeding. However, patients randomized to clopidogrel had a significant increase in the number of major bleeding complications (Figure 3).

Figure 2. CREDO: individual components of primary endpoint at 1 year.
Figure 3. CREDO: bleeding complications between clopidogrel treatment and placebo.

When analysis was performed according to the timing of the loading dose (< 6 hours vs 6-24 hours prior to PCI), there was no difference in the outcome between the 2 groups if pretreatment was given < 6 hours prior to PCI. However, compared to no pretreatment, when administered between 6 and 24 hours before PCI, there was a 38.6% reduction in the composite endpoint (9.4% vs 5.8%, P = .05).

Conclusions

The CREDO trial demonstrated that following a PCI procedure, maintaining dual antiplatelet therapy with aspirin and clopidogrel for up to 1 year significantly reduces the risk of adverse thrombotic events by 26.9%. The time at which treatment is administered can also affect outcome, as initiating a loading dose of at least 300 mg clopidogrel is likely to be beneficial only if started more than 6 hours prior to a planned PCI procedure. Investigators believe that adherence to this dosing regimen in all planned PCI procedures may prevent over 50,000 cases of MI, stroke, or death annually. In addition, it can be speculated that even longer therapy with aspirin and clopidogrel may have a beneficial prophylactic effect.

CREDO: Background, trial design, and 28-day results, published as part of Medscape Cardiology's Conference Coverage of TCT 2002.
The thienopyridine, ticlopidine, and its more recently developed analogue, clopidogrel (Plavix, Bristol-Myers Squibb) are relatively new, potent platelet inhibitors that act upon the inhibition of the platelet P2T type ADP receptor at the adenyl cyclase-coupled receptor site. These agents are administered orally with maximal bioavailability when taken after meals, and are inactive in vitro, requiring endogenous liver metabolism to 1 or more unknown active metabolites. Ticlopidine, 250 mg twice a day, and clopidogrel, 75 mg/day, are rapidly absorbed after a single oral dose, with significant platelet inhibition achieved after 2-3 days of therapy and maximal inhibition attained 4-7 days thereafter. The antiplatelet action associated with the drugs is irreversible and persists for 7-10 days even after treatment cessation, which corresponds to the mature platelet lifespan.

 

Recently published data have shown that clopidogrel may be an effective substitute for ticlopidine after endovascular stenting, with the advantage of once-daily dosing, more rapid platelet inhibition, excellent tolerability, and a lower incidence of side effects. The benefit of starting therapy prior to intervention has been established from retrospective, nonrandomized, observational studies. In the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Trial (EPISTENT),[4] patients who did not receive abciximab and underwent thienopyridine pretreatment had better outcomes than those who did not undergo pretreatment. Conversely, patients who were treated with abciximab had similar outcomes regardless of whether they were pretreated with a thienopyridine. The Percutaneous Coronary Intervention in the Clopidogrel in Unstable angina to prevent Recurrent Events (PCI-CURE) trial[5] has shown that pretreatment with clopidogrel reduces the incidence of cardiovascular death, urgent target vessel revascularization (TVR), or myocardial infarction (MI) by 30% when compared with placebo.

Trial Design

The Clopidogrel for Reduction of Events During Observation (CREDO) trial was initiated to compare the efficacy of pretreatment with a loading dose of clopidogrel 300 mg given 3-24 hours prior to percutaneous coronary intervention (PCI) with 75 mg of clopidogrel given at the time of the procedure, on a background of aspirin, with or without the planned use of a glycoprotein (GP) IIb/IIIa inhibitor. The trial enrolled a total of 2116 patients planned for PCI who were randomized to either clopidogrel 300 mg and aspirin 325 mg as a loading dose (n = 1053) or placebo and aspirin 325 mg 3-24 hours prior to PCI (n = 1063) (Figure 4). All patients who underwent PCI and stenting (regardless of randomization), followed by clopidogrel 75 mg for 28 days. From day 28 up to 1 year, patients who were randomized to pretreatment with clopidogrel plus aspirin were continued on a daily dose of clopidogrel, while those patients randomized to placebo continued with placebo. Success of the trial was based on the primary principal composite endpoint of death, MI, or stroke at 1 year in the intention-to-treat (all randomized patients) population.

Figure 4. CREDO: trial design.

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