CREDO 1-year results confirm benefit of long-term aspirin and clopidogrel therapy after PCI

Susan Jeffrey

November 18, 2002

Chicago, IL - One-year results of the Clopidogrel for the Reduction of Events During Observation (CREDO) trial confirm that long-term therapy with clopidogrel and aspirin significantly reduced the risk of adverse ischemic events after elective PCI. Although the benefit of a loading dose of clopidogrel given 3 hours before the procedure did not reach statistical significance, the data suggest it may be worthwhile if the dose is given at least 6 hours ahead.

Final results of the study were presented here at the American Heart Association November 2002 meeting to coincide with their publication in the November 20, 2002 issue of the Journal of the American Medical Association.

"The CREDO trial is the first randomized trial to demonstrate the benefits of long-term improved dual antiplatelet therapy with clopidogrel and aspirin in the elective PCI population," said Dr Steven R Steinhubl (University of North Carolina, Chapel Hill). The results add to a growing body of evidence supporting the importance of long-term anti-platelet protection with clopidogrel and aspirinhighlighted in recent guidelines changes reflecting the results of the previous Clopidogrel in Unstable angina to Prevent Recurrent Events (CURE) trialand extend the benefit to a more acutely stable population, he said.

"We feel the clinical implications of this are enormous," Steinhubl told a press conference here. "If the results of the trial were to be applied to the 1.5 million patients who are anticipated to undergo percutaneous intervention worldwide this year, more than 50000 patients who otherwise would have suffered a heart attack, stroke, or death would not."

Long-term risk requires long-term therapy

Long-term data such as those reported from follow-up of patients undergoing PCI in the EPIC trial show that the risk of events after the procedure is high and remains high over the life of the patient, Steinhubl said. To date, therapy for preventing these events has typically been aspirin.

The CURE trial in patients with acute coronary syndromes was the first to show the combination of aspirin and clopidogrel was beneficial in reducing long-term thrombotic events. "Important to the PCI population, the PCI subset of the CURE trial (PCI-CURE) achieved similar benefit with long-term clopidogrel and aspirin," he said.

The aim of CREDO, then, was to define the optimal duration of therapy, both before and after elective PCI. Eligible patients who were either set to undergo PCI or were considered at high likelihood for the procedure enrolled from 99 centers in North America between June 1999 and April 2001.

A total of 2116 patients were randomized to receive a 300-mg clopidogrel loading dose or placebo anywhere from 3 to 24 hours before the procedure in addition to 81 to 325 mg/day of aspirin. After the procedure, all patients received aspirin and clopidogrel out to 28 days, at which time those who had received the loading dose received 75 mg/day of clopidogrel, and those in the control group received placebo out to 12 months. All patients continued on aspirin throughout the study.

Primary outcome measures were the incidence of a composite of death, MI, or stroke in the intent-to-treat population and the 28-day incidence of the composite of death, MI, or urgent target vessel revascularization in the per-protocol population.

The 28-day results were presented previously at the Transcatheter Cardiovascular Therapeutics 2002 meeting in September and reported at that time by heartwire .

Overall, patients pretreated with clopidogrel had a nonsignificant 18.5% relative reduction in the composite end point, nor was there a significant reduction in events for patients pretreated less than 6 hours before the procedure. However, those treated more than 6 hours before the procedure showed a 38.6% reduction in events, from 9.4% to 5.8% (p=0.05).

Significant risk reduction

At 1 year, long-term use of clopidogrel and aspirin was associated with a significant 26.9% reduction in the risk of death, MI, or stroke, Steinhubl reported, with an absolute risk reduction of 3%. Out to day 28, differences in events were not significant, but between day 29 and 1 year, there was a significant reduction in the composite end point.

CREDO: 1-year clinical outcomes with clopidogrel vs placebo




RRR (95% CI)

 Death, MI, stroke, overall 89 (8.5%) 122 (11.5%) 26.9 (3.9-44.4)*
 Death, MI, stroke at 28 days 5.5% 6.9% 19.7 (-13.3-43.1)
Death, MI, stroke from day 29 to 1 year 2.9% 4.6% 37.4 (1.8-60.1)**
* p=0.02

Similar results were seen in each component of the end point, but these findings did not reach statistical significance.

CREDO: Individual components of the combined end point



No. (%)


No. (%)

RRR (95% CI)

Death 18 (1.7) 24 (2.3) 24.6 (38.9-59.1)
MI 70 (6.7) 89 (8.4) 20.8 (-8.4-42.1)
Stroke 9 (0.9) 10 (0.9) 10.0 (-21.3-24.0)

Results were also similar across subgroups studied: in women and men, those with and without acute coronary syndromes, with and without diabetes, as well as those patients who received glycoprotein IIb/IIIa inhibitors at the time of the intervention and those who did not. Treatment did not appear to affect the need for target vessel revascularization or any other revascularization over follow-up.

Patients treated with clopidogrel for 1 year did show a trend toward increased major bleeding defined by TIMI criteria, occurring in 8.8% vs 6.7% in the placebo group (p=0.07). "Importantly, virtually all of this major bleeding was associated with an invasive procedure, and the majority of this was CABG-related, with more than one half of all patients undergoing CABG in this CREDO trial being defined as having a major bleed, both in the treatment and control groups," Steinhubl said.

There was no difference in the incidence of minor bleeding between the groups, he noted.

A total of 63% of patients in the clopidogrel group and 61% in the control group completed the full year on their assigned study drug. The most common reasons for withdrawal were patient choice or the occurrence of an adverse event, many of which had not been previously reported with either aspirin or clopidogrel.

Steinhubl told heartwire they were disappointed with these results. "You really have to maintain enthusiasm among the patients, among the study sites, and say it's really important to do this," he said. But the results imply that if everyone had stayed on therapy for the whole [time], the benefits might have been better, he said, "so the 27% may actually underestimate the true benefit."

Questions remain

The mechanism of the benefit they saw is still in question, Steinhubl added. It's clear that the dual antiplatelet protection of aspirin and clopidogrel is preventing not only platelet aggregation but also platelet activation, he said. "The platelet I think is a very underappreciated inflammatory cell, and by preventing that activation and really aggressively preventing it, I think we prevent the inflammation associated with that."

If the only mechanism were prevention of platelet aggregation, he added, it would probably have been overwhelmed by the addition of a GP IIb/IIIa inhibitor. "In fact, the benefit was just as good, even better, in patients who received a GP IIb/IIIa inhibitor, he said.

Some preliminary data suggest marked benefit of clopidogrel in patients with elevated C-reactive protein, he added, and other studies show the combination of aspirin and clopidogrel decrease inflammatory markers such as CRP and CD-40 ligand.

Ongoing trials will provide answers to some of the questions not addressed by CREDO. The Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT) trial is studying patients pretreated with 600 mg of clopidogrel, then randomized to receive either abciximab or placebo to see whether there is any concomitant benefit of adding a IIb/IIIa inhibitor to patients who have already received adequate pretreatment with clopidogrel.

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial is assessing the benefit of continuing clopidogrel and aspirin treatment out to an anticipated follow-up of 42 months in 15200 high-risk but stable patients.

The risk of thrombotic events is long-term, even life-long, he said, and will be most affected not by interventions but by the individual atherosclerotic burden and the stability of that condition, he said. "So we would suspect and anticipate that longer-term clopidogrel and aspirin would be having a greater benefit."

Changing the standard of care

Dr Valentin Fuster

Dr Valentin Fuster (Mount Sinai Medical School, New York) was the invited discussant for the CREDO trial. "The benefits observed by combining clopidogrel and aspirin I'm sure will impact on the way we manage coronary artery disease in all the different phases," Fuster told the meeting here. Long-term use of clopidogrel plus aspirin will "probably become the standard of care, for at least the first year following PCI," he added, as well as in patients not undergoing intervention, as was shown by the CURE results.

No information is currently available on the use of the combination for more than 1 year, Fuster noted. "Perhaps this might be tested or considered, particularly in patients with coronary artery disease at high risk for vascular events and low risk of bleeding."

However, he added, "I would emphasize, short-term and also long-term, the issue of bleeding; to be very, very cautious in patients who are predisposed to such problems, and certainly in particular, in those patients that we feel at the time of the intervention may undergo coronary artery bypass grafting."

In addition, because of the cost of clopidogrel, and based on the recent long-term data provided by ASPECT 2 and WARIS II, a long-term comparison study between clopidogrel and aspirin with other oral anticoagulants should probably be "urgently considered," he noted.

Pre-PCI, he said, use of a 600-mg loading dose will probably also become a standard of care for these patients, and it is possible that even higher loading doses should be tested. However, based on data from PCI-CURE and now from CREDO, "pre-PCI administration of clopidogrel should be recognized as probably conveying a high risk of bleeding in patients requiring coronary artery bypass grafting within 5 days of clopidogrel administration," Fuster said.


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