Results
of
the
CREDO
study
(AHA Chicago, 18 November 2002)
The 75th scientific sessions of the American Heart Association took place in Chicago from 17 to 20 November 2002. In the first plenary session of Late Breaking Clinical Trials, the results of the CREDO study were presented. In this study, entitled Clopidogrel for Reduction of Events During Observation, long-term treatment (one year) ofclopidogrel (an ADPreceptor antagonist) combined with aspirin was compared with aspirin alone in patients who underwent a percutaneous coronary intervention (PCI). Long-term follow-up data of patients undergoing PCI from for example the EPIC (Evaluation of 7E3 for the Prevention of Ischaemic Complications) trial, showed that the risk of events after PCI is high and remains high during life. The CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) trial was the first to show that the combination of aspirin and clopidogrel (for the maximum duration of one year) was beneficial in reducing long-term thrombotic events in patients who were hospitalised for angina. In a subset of the CURE trial, PCI-CURE, similar benefit with long-term clopidogrel and aspirin was observed in patients who underwent a PCI procedure. The aim of CREDO was to define the optimal duration of this dual antiplatelet therapy both before and after PCI.
study. CREDO was a double-blind, randomised study including 2116 patients, which was carried out in 99 centres, 88 in the United States, and 11 in Canada. The study was designed to evaluate the efficacy and safety of long-term treatment with clopidogrel and the effect of pretreatment with a clopidogrel loading dose 3 to 24 hours before PCI, both on a background of aspirin therapy. Patients could be included in the study if they had symptomatic coronary artery disease with objective evidence of ischaemia, for which they were referred for PCI or thought to be at high likelihood of requiring PCI. One of the major exclusion criteria was a predisposition to bleeding disorders. Following randomisation, patients received either a 300 mg loading dose of clopidogrel or matching placebo. During the 28 days following PCI, all patients in the study received 75 mg clopidogrel and 325 mg aspirin once daily in addition to other standard therapies. After 28 days and up to 12 months, patients in the loading-dose group received clopidogrel 75 mg/day, and those in the control group received placebo, both in addition to aspirin (81-325 mg/day) and other standard therapies received (figure 1). The primary outcome measures were the incidence at 28 days of the composite of death, myocardial
Steven Steinhubl (Associate Professor ofMedicine at the University of North Carolina at Chapel Hill), principal investigator of the CREDO study, presented the results of this
P. KI&s. Leiden University Medical Centre, P0 Box 2900, 2300 RC Leiden. E-mail: [email protected]
104
infarction (MI) or urgent target vessel revascularisation (UTVR) and the incidence at one year of the composite of death, MI or stroke in the per-protocol population. Of all 2116 patients, 694 (33%) were referred for coronary angiography because of stable angina pectoris and 1117 (53%) were referred because of unstable angina. Based on the angiography, 1818 patients (86%) underwent PCI, 83 (4%) underwent a CABG and 168 (8%) were treated with medication. Overall, patients pretreated with clopidogrel had a non-significant 18.5 % relative risk reduction (RRR) (p=0.23) in the composite endpoint, death, MI or UTVR at 28 days. However, patients who had received the loading dose at least six hours prior to PCI showed a 38.6% reduction in events, from 9.4% to 5.8% (p=0.05). From randomisation to the end of long-term treatment, the clopidogrel-treated group demonstrated a statistically significant 26.9% reduction in the relative risk of the combined endpoint of death, MI or stroke (8.5% versus 11.5% respectively, p=0.02) This benefit was consistent in all the evaluated subgroups, both women and men, patients with and without acute coronary syndromes, with and without diabetes, and with and without the administration of glycoprotein IIb/IIIa inhibitors at the time of the intervention. Treatment did not appear to affect the need for target vessel revascularisation or any other revascularisation over follow-up. The complication most feared with the use of a dual antiplatelet therapy, such as aspirin and
Netherlands Heart Journal, Volume 11, Number 2, February 2003
clopidogrel, was the risk of bleeding. Patients who received clopidogrel and aspirin for a year had no statistically significant increase in bleeding compared with patients receiving aspirin alone, although there was a trend towards an increase in major bleeding defined by TIMI criteria (8.8% clopidogrel plus aspirin versus 6.7% placebo plus aspirin, p=0.07). Almost all major bleedings were associated with an invasive procedure, the majority of which was CABG related. Since clopidogrel is administered before coronary angiography and PCI, a consequent high risk of bleeding was experienced in patients requiring CABG within five days of clopidogrel administration. In this study more than half of all patients undergoing CABG were defined as having major bleeding, both in the treatment and in the control group. There were no fatal bleeds or intracranial haemorrhages nor any differences in the incidence of minor bleeding between both groups. A total of 831 patients (39%, 411 in the treatment group and 420
in the placebo group) did not complete the fill year on their assigned study drug. Most common reasons for withdrawal were patient choice or the occurrence of an adverse event. This implies that if everyone had stayed on therapy for the whole period of time, the benefits might have even been greater. Implications and future trials Dr Valentin Fuster (Mount Siani Medical School, New York) was the invited discussant of the CREDO trial in this late breaking trials session. The benefits observed by combining clopidogrel and aspirin will impact on the way we manage coronary artery disease in all different phases, Dr Fuster said. This dual antiplatelet therapy will probably become standard care for at least one year following PCI as well as in patients not undergoing intervention, as was shown by the CURE trial. He emphasised that great care should be taken in patients who have an increased risk of bleeding, and certainly in those patients who might undergo CABG.
Pretreatment
PCI
LD Clopidogrel #
Clopidogrel #
Clopidogrel *
LD Placebo #
Clopidogrel #
Placebo *
28 days
22 months
R
LD=loading dose, R=randomisation, #=including ASA (325 mg once daily) and other standard therapies, *=including ASA (81-325 mg once daily) and other standard therapies. - Clopidogrel loading dose of 300 - From PCI to 28 days all patients
mg given 3-24 hrs before PCI. received 75 mg clopidogrel once daily. - From day 29 to 1 year patients received 75 mg clopidogrel or matching placebo once daily.
Because of the costs of clopidogrel a long-term comparison study between the combination of clopidogrel and aspirin and other oral anticoagulants should be considered, according to Dr Fuster. Two upcoming trials will hopefully answer some ofthe remaining questions on the amount and timing of the loading dose, the concomitant use of GP IIb/AIIa receptor blockers, and the effects of continuing clopidogrel for more than one year. In the Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT) trial patients pretreated with 600 mg of clopidogrel, and then randomised to receive either abciximab or placebo, are studied to evaluate whether there is any concomitant benefit of adding a GP IIb/lIla inhibitor to patients who have already received adequate pre-treatment with clopidogrel. The Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilisation, Management, and Avoidance (CHARISMA) trial aimed to assess the benefit of continuing clopidogrel and aspirin treatment for an anticipated followup of42 months in 15,200 high-risk but stable patients. For now, we know that in patients undergoing PCI, the continuation of clopidogrel and aspirin therapy for one year leads to a significant reduction in irreversible atherothrombotic events compared with treatment for only four weeks. Pre-treatment administered at least six hours before PCI leads to a significant reduction in periprocedural major adverse cardiac events, with or without the concomitant use of a glycoprotein 1Ib/IIIa antagonist. i
Figure 1. Operall study design.
Netherlands Heart Jounal, Volume 11, Number 2, February 2003
105
of
the
CREDO
study
(AHA Chicago, 18 November 2002)
The 75th scientific sessions of the American Heart Association took place in Chicago from 17 to 20 November 2002. In the first plenary session of Late Breaking Clinical Trials, the results of the CREDO study were presented. In this study, entitled Clopidogrel for Reduction of Events During Observation, long-term treatment (one year) ofclopidogrel (an ADPreceptor antagonist) combined with aspirin was compared with aspirin alone in patients who underwent a percutaneous coronary intervention (PCI). Long-term follow-up data of patients undergoing PCI from for example the EPIC (Evaluation of 7E3 for the Prevention of Ischaemic Complications) trial, showed that the risk of events after PCI is high and remains high during life. The CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) trial was the first to show that the combination of aspirin and clopidogrel (for the maximum duration of one year) was beneficial in reducing long-term thrombotic events in patients who were hospitalised for angina. In a subset of the CURE trial, PCI-CURE, similar benefit with long-term clopidogrel and aspirin was observed in patients who underwent a PCI procedure. The aim of CREDO was to define the optimal duration of this dual antiplatelet therapy both before and after PCI.
study. CREDO was a double-blind, randomised study including 2116 patients, which was carried out in 99 centres, 88 in the United States, and 11 in Canada. The study was designed to evaluate the efficacy and safety of long-term treatment with clopidogrel and the effect of pretreatment with a clopidogrel loading dose 3 to 24 hours before PCI, both on a background of aspirin therapy. Patients could be included in the study if they had symptomatic coronary artery disease with objective evidence of ischaemia, for which they were referred for PCI or thought to be at high likelihood of requiring PCI. One of the major exclusion criteria was a predisposition to bleeding disorders. Following randomisation, patients received either a 300 mg loading dose of clopidogrel or matching placebo. During the 28 days following PCI, all patients in the study received 75 mg clopidogrel and 325 mg aspirin once daily in addition to other standard therapies. After 28 days and up to 12 months, patients in the loading-dose group received clopidogrel 75 mg/day, and those in the control group received placebo, both in addition to aspirin (81-325 mg/day) and other standard therapies received (figure 1). The primary outcome measures were the incidence at 28 days of the composite of death, myocardial
Steven Steinhubl (Associate Professor ofMedicine at the University of North Carolina at Chapel Hill), principal investigator of the CREDO study, presented the results of this
P. KI&s. Leiden University Medical Centre, P0 Box 2900, 2300 RC Leiden. E-mail: [email protected]
104
infarction (MI) or urgent target vessel revascularisation (UTVR) and the incidence at one year of the composite of death, MI or stroke in the per-protocol population. Of all 2116 patients, 694 (33%) were referred for coronary angiography because of stable angina pectoris and 1117 (53%) were referred because of unstable angina. Based on the angiography, 1818 patients (86%) underwent PCI, 83 (4%) underwent a CABG and 168 (8%) were treated with medication. Overall, patients pretreated with clopidogrel had a non-significant 18.5 % relative risk reduction (RRR) (p=0.23) in the composite endpoint, death, MI or UTVR at 28 days. However, patients who had received the loading dose at least six hours prior to PCI showed a 38.6% reduction in events, from 9.4% to 5.8% (p=0.05). From randomisation to the end of long-term treatment, the clopidogrel-treated group demonstrated a statistically significant 26.9% reduction in the relative risk of the combined endpoint of death, MI or stroke (8.5% versus 11.5% respectively, p=0.02) This benefit was consistent in all the evaluated subgroups, both women and men, patients with and without acute coronary syndromes, with and without diabetes, and with and without the administration of glycoprotein IIb/IIIa inhibitors at the time of the intervention. Treatment did not appear to affect the need for target vessel revascularisation or any other revascularisation over follow-up. The complication most feared with the use of a dual antiplatelet therapy, such as aspirin and
Netherlands Heart Journal, Volume 11, Number 2, February 2003
clopidogrel, was the risk of bleeding. Patients who received clopidogrel and aspirin for a year had no statistically significant increase in bleeding compared with patients receiving aspirin alone, although there was a trend towards an increase in major bleeding defined by TIMI criteria (8.8% clopidogrel plus aspirin versus 6.7% placebo plus aspirin, p=0.07). Almost all major bleedings were associated with an invasive procedure, the majority of which was CABG related. Since clopidogrel is administered before coronary angiography and PCI, a consequent high risk of bleeding was experienced in patients requiring CABG within five days of clopidogrel administration. In this study more than half of all patients undergoing CABG were defined as having major bleeding, both in the treatment and in the control group. There were no fatal bleeds or intracranial haemorrhages nor any differences in the incidence of minor bleeding between both groups. A total of 831 patients (39%, 411 in the treatment group and 420
in the placebo group) did not complete the fill year on their assigned study drug. Most common reasons for withdrawal were patient choice or the occurrence of an adverse event. This implies that if everyone had stayed on therapy for the whole period of time, the benefits might have even been greater. Implications and future trials Dr Valentin Fuster (Mount Siani Medical School, New York) was the invited discussant of the CREDO trial in this late breaking trials session. The benefits observed by combining clopidogrel and aspirin will impact on the way we manage coronary artery disease in all different phases, Dr Fuster said. This dual antiplatelet therapy will probably become standard care for at least one year following PCI as well as in patients not undergoing intervention, as was shown by the CURE trial. He emphasised that great care should be taken in patients who have an increased risk of bleeding, and certainly in those patients who might undergo CABG.
Pretreatment
PCI
LD Clopidogrel #
Clopidogrel #
Clopidogrel *
LD Placebo #
Clopidogrel #
Placebo *
28 days
22 months
R
LD=loading dose, R=randomisation, #=including ASA (325 mg once daily) and other standard therapies, *=including ASA (81-325 mg once daily) and other standard therapies. - Clopidogrel loading dose of 300 - From PCI to 28 days all patients
mg given 3-24 hrs before PCI. received 75 mg clopidogrel once daily. - From day 29 to 1 year patients received 75 mg clopidogrel or matching placebo once daily.
Because of the costs of clopidogrel a long-term comparison study between the combination of clopidogrel and aspirin and other oral anticoagulants should be considered, according to Dr Fuster. Two upcoming trials will hopefully answer some ofthe remaining questions on the amount and timing of the loading dose, the concomitant use of GP IIb/AIIa receptor blockers, and the effects of continuing clopidogrel for more than one year. In the Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT) trial patients pretreated with 600 mg of clopidogrel, and then randomised to receive either abciximab or placebo, are studied to evaluate whether there is any concomitant benefit of adding a GP IIb/lIla inhibitor to patients who have already received adequate pre-treatment with clopidogrel. The Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilisation, Management, and Avoidance (CHARISMA) trial aimed to assess the benefit of continuing clopidogrel and aspirin treatment for an anticipated followup of42 months in 15,200 high-risk but stable patients. For now, we know that in patients undergoing PCI, the continuation of clopidogrel and aspirin therapy for one year leads to a significant reduction in irreversible atherothrombotic events compared with treatment for only four weeks. Pre-treatment administered at least six hours before PCI leads to a significant reduction in periprocedural major adverse cardiac events, with or without the concomitant use of a glycoprotein 1Ib/IIIa antagonist. i
Figure 1. Operall study design.
Netherlands Heart Jounal, Volume 11, Number 2, February 2003
105
