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Adding pre-procedural and long term clopidogrel to aspirin may reduce cardiovascular events in people scheduled for percutaneous coronary intervention
TREATMENT
Adding pre-procedural clopidogrel to aspirin may reduce cardiovascular events in people scheduled for percutaneous coronary intervention Abstracted from: Steinhubl S, Berger P, MannTet al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention.J Am Med Assoc 2002; 288: 2411^2422.
BACKGROUND Adding a short course of clopidogrel to aspirin following percutaneous coronary intervention (PCI) may reduce the risk of thrombotic complications compared to aspirin alone. There may also be some bene¢t from administering clopidogrel prior to PCI. The optimal duration of combination oral antiplatelet therapy remains uncertain. OBJECTIVE To assess the e¡ect of (i) a loading dose of clopidogrel prior to PCI, and (ii) adding clopidogrel to aspirin for 12 months following PCI. SETTING Ninety-nine centres in the United States and Canada; June 1999 to April 2001. METHOD Double-blind randomised trial. PARTICIPANTS 2116 people aged over 21years with symptomatic coronary artery disease and evidence of ischaemia. All were assigned to elective PCI or had a high probability of undergoing PCI. Mean age 62 years; 89% white; 28% women. Exclusion criteria were contraindications to antiplatelet therapy or stenting; greater than 50% stenosis of the left main coronary artery; failed coronary intervention within 2 weeks; persistent ST-elevation within 24 hours; planned staged interventional procedure; GPIIb^IIIa inhibitor within 7 days; clopidogrel within 10 days, or thrombolytics within 24 hours. INTERVENTION Participants received a 300 mg loading dose of clopidogrel or placebo 3 to 24 hours before PCI. All participants also received 325 mg aspirin. Following PCI, all participants received 75 mg per day clopidogrel for 28 days. From day 29 to 12 months, those who received the pre-PCI loading dose were given 75 mg per day clopidogrel. Those who received placebo in the pre-PCI phase continued to receive placebo from day 29 to 12 months. All
1361-2611/03/$ - see front matter & 2003 Published by Elsevier Science Ltd. doi:10.1016/S1361-2611(03)00034- 4
participants received 81 to 325 mg per day aspirin during the follow-up year, at the discretion of the clinician. OUTCOMES Composite endpoint of myocardial infarction or stroke at 1 year intention-to-treat analysis; 28-day incidence of myocardial infarction or urgent target revascularisation using per protocol analysis.
death, using death, vessel
MAIN RESULTS There was no signi¢cant di¡erence in the combined risk of death, myocardial infarction or urgent target vessel revascularisation at 28 days among those who received clopidogrel versus placebo before PCI (risk reduction with clopidogrel 18.5%, 95% CI 14.2% to 41.8%, p ¼ 0:23). There was a trend towards improved outcomes in people who received clopidogrel at least 6 hours before PCI (relative risk reduction 38.6%, 95% CI 1.6% to 62.9%, p ¼ 0:05). At 1 year, long-term clopidogrel therapy was associated with a 3% absolute reduction in death, myocardial infarction or stroke (relative risk reduction 26.9%, 95% CI 3.9% to 44.4%, p ¼ 0:02). AUTHORS’ CONCLUSIONS A loading dose of clopidogrel before PCI had no e¡ect on adverse events at 28 days, but subgroup analyses suggest that administering clopidogrel more than 6 hours before PCI may have some bene¢t. Long-term clopidogrel may reduce the risk of adverse ischaemic events following PCI. Sources offunding: Bristol-Myers Squibb/Sano¢-Synthelabo partnership. Correspondence to: SR Steinhubl, Division of Cardiology, University of North Carolina, Chapel Hill, North Carolina, USA. Abstract provided by Bazian Ltd, London.
Evidence-based Cardiovascular Medicine (2003) 7, 87^ 88
87
Commentary
Caveats: long-term clopidogrel treatment
Percutaneous coronary intervention (PCI) is one of the most common procedures in the world. Any study that may contribute to a safer intervention is, therefore, important.The optimal antiplatelet therapy before and after PCI remains unclear.The Clopidogrel for the Reduction of Events During Observation (CREDO) trial is therefore highly relevant.
The design of the second part of the study, examining long-term clopidogrel treatment following PCI, is confusing. In addition to the PCI population of 1815 participants, 301 people who were randomised, but who did not have a PCI were included in the long-term analysis. Since the objective was to evaluate long-term clopidogrel treatment after PCI, it does not seem relevant to include these patients. Long-term clopidogrel treatment irrespective of PCI is a different matter.This will be addressed in the CHARISMA trial. In the CREDO study, there was a 26.9% reduction of ischaemic events in the clopidogrel group, but this includes non-PCI patients. If only the PCI population is considered, the effect of clopidogrel is less pronounced. It is important to recognise that the long-term f|ndings include the effect of clopidogrel treatment before PCI, not just 11 months of treatment from day 29 after the procedure. Since participants were not re-randomised at day 29 following PCI, it is not possible to analyse the effect of long-term clopidogrel treatment following PCI separately. We can, however, examine data on death or myocardial infarction (MI) in the PCI population. After 28 days, there were 52 cases of death or MI in the clopidogrel group and 64 cases in the placebo group. Excluding events in the non-PCI group, by the end of the study there were 77 cases of death or MI in the clopidogrel group and 100 cases in the placebo group (8.6% v 10.9% placebo).These f|gures suggest that only about half of the long-term difference between groups was due to the 11 month clopidogrel treatment after day 28, the other half being the result of the loading dose of clopidogrel before PCI. A relatively modest effect of long-term clopidogrel treatment after PCI was also found in PCI-CURE.1 Cardiovascular death or MI within 30 days after PCI was 4.4% in the placebo group and 2.9% in the clopidogrel group.By the end of the study, with average follow-up of 8 months, the incidence had increased to 8% and 6%, respectively. Thus, the main difference between groups was already apparent after 30 days. To summarise, in the CREDO trial it is not possible to do an adequate analysis of the effect of long-term clopidogrel treatment after PCI due to study design. Any effect that does exist may be considerably smaller than the long-term result reported.This suggests that the investigators’ main conclusion is not justif|ed. Longterm clopidogrel treatment cannot be recommended after PCI based on the CREDO study.
This study’s contribution This study’s main contribution involves f|ndings about pre-PCI administration of clopidogrel. Overall, 300 mg clopidogrel given 3 to 24 hours before the procedure made no signif|cant difference to the composite endpoint of death, myocardial infarction and urgent revascularisation at 28 days. The investigators undertook a pre-specif|ed subgroup analysis of the time between drug administration and the procedure. In the group that received the loading dose 6 to 12 hours before the intervention, the primary endpoint was reduced by 35.5%. The reduction was 40.1% for those who received clopidogrel 12 to 24 hours before PCI. There was no effect if clopidogrel was given less than 6 hours before the procedure. Although the study was not powered to draw f|rm conclusions from this subgroup analysis, the f|nding is striking. Other evidence In the subgroup of 2658 people undergoing PCI in the randomised CURE study, clopidogrel reduced the composite endpoint of cardiovascular death, myocardial infarction or need for urgent revascularisation within 30 days by 30% (6.4% v 4.5% control).1 About 25% of participants in both groups received open label clopidogrel before the intervention. When these participants were excluded, clopidogrel reduced the composite endpoint by 42%. In our own‘real world’ study, 706 consecutive patients received 375 mg clopidogrel in addition to aspirin the day before PCI.2 Compared to 724 consecutive patients treated with aspirin alone, pre-treatment with clopidogrel reduced the composite of death, myocardial infarction or urgent revascularisation by 41% (8.2% v 4.8%, p=0.01). In another study with consecutive patients, 600 mg clopidogrel was given to 864 people 2 to 4 hours before coronary stenting.3 Compared to 870 patients receiving conventional ticlopidine treatment, clopidogrel reduced the composite of death, myocardial infarction or need for urgent revascularisation by 35% (6.8% v 4.5%, po0.05).
Clinical implications In the CREDO trial summarised above, administering clopidogrel more than 6 hours before PCI had similar benef|ts to these other three studies.Taken together, these f|ndings suggest administering a loading dose of clopidogrel before scheduled PCI. The CREDO study suggests that if a loading dose of 300 mg is used, it is wise to administer it at least 6 hours before the procedure.The optimal size and timing of the clopidogrel loading dose remains unclear.
88
Evidence-based Cardiovascular Medicine (2003) 7, 87^ 88
Ulf Berglund, MD Department of Cardiology University Hospital Linkoºping, Sweden Literature cited 1. Mehta SR, Yusuf S, Peters RJG et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527^533. 2. Berglund U, Richter A. Clopidogrel treatment before percutaneous coronary intervention reduces adverse cardiac events. J Invas Cardiol 2002; 14: 243^246. 3. Pache J, Kastrati A, Mehilli J et al. Clopidogrel therapy in patients undergoing coronary stenting, value of a high loading dose regimen.Catheter Cardiovasc Interv. 2002; 55: 436^ 441.
Adding pre-procedural clopidogrel to aspirin may reduce cardiovascular events in people scheduled for percutaneous coronary intervention Abstracted from: Steinhubl S, Berger P, MannTet al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention.J Am Med Assoc 2002; 288: 2411^2422.
BACKGROUND Adding a short course of clopidogrel to aspirin following percutaneous coronary intervention (PCI) may reduce the risk of thrombotic complications compared to aspirin alone. There may also be some bene¢t from administering clopidogrel prior to PCI. The optimal duration of combination oral antiplatelet therapy remains uncertain. OBJECTIVE To assess the e¡ect of (i) a loading dose of clopidogrel prior to PCI, and (ii) adding clopidogrel to aspirin for 12 months following PCI. SETTING Ninety-nine centres in the United States and Canada; June 1999 to April 2001. METHOD Double-blind randomised trial. PARTICIPANTS 2116 people aged over 21years with symptomatic coronary artery disease and evidence of ischaemia. All were assigned to elective PCI or had a high probability of undergoing PCI. Mean age 62 years; 89% white; 28% women. Exclusion criteria were contraindications to antiplatelet therapy or stenting; greater than 50% stenosis of the left main coronary artery; failed coronary intervention within 2 weeks; persistent ST-elevation within 24 hours; planned staged interventional procedure; GPIIb^IIIa inhibitor within 7 days; clopidogrel within 10 days, or thrombolytics within 24 hours. INTERVENTION Participants received a 300 mg loading dose of clopidogrel or placebo 3 to 24 hours before PCI. All participants also received 325 mg aspirin. Following PCI, all participants received 75 mg per day clopidogrel for 28 days. From day 29 to 12 months, those who received the pre-PCI loading dose were given 75 mg per day clopidogrel. Those who received placebo in the pre-PCI phase continued to receive placebo from day 29 to 12 months. All
1361-2611/03/$ - see front matter & 2003 Published by Elsevier Science Ltd. doi:10.1016/S1361-2611(03)00034- 4
participants received 81 to 325 mg per day aspirin during the follow-up year, at the discretion of the clinician. OUTCOMES Composite endpoint of myocardial infarction or stroke at 1 year intention-to-treat analysis; 28-day incidence of myocardial infarction or urgent target revascularisation using per protocol analysis.
death, using death, vessel
MAIN RESULTS There was no signi¢cant di¡erence in the combined risk of death, myocardial infarction or urgent target vessel revascularisation at 28 days among those who received clopidogrel versus placebo before PCI (risk reduction with clopidogrel 18.5%, 95% CI 14.2% to 41.8%, p ¼ 0:23). There was a trend towards improved outcomes in people who received clopidogrel at least 6 hours before PCI (relative risk reduction 38.6%, 95% CI 1.6% to 62.9%, p ¼ 0:05). At 1 year, long-term clopidogrel therapy was associated with a 3% absolute reduction in death, myocardial infarction or stroke (relative risk reduction 26.9%, 95% CI 3.9% to 44.4%, p ¼ 0:02). AUTHORS’ CONCLUSIONS A loading dose of clopidogrel before PCI had no e¡ect on adverse events at 28 days, but subgroup analyses suggest that administering clopidogrel more than 6 hours before PCI may have some bene¢t. Long-term clopidogrel may reduce the risk of adverse ischaemic events following PCI. Sources offunding: Bristol-Myers Squibb/Sano¢-Synthelabo partnership. Correspondence to: SR Steinhubl, Division of Cardiology, University of North Carolina, Chapel Hill, North Carolina, USA. Abstract provided by Bazian Ltd, London.
Evidence-based Cardiovascular Medicine (2003) 7, 87^ 88
87
Commentary
Caveats: long-term clopidogrel treatment
Percutaneous coronary intervention (PCI) is one of the most common procedures in the world. Any study that may contribute to a safer intervention is, therefore, important.The optimal antiplatelet therapy before and after PCI remains unclear.The Clopidogrel for the Reduction of Events During Observation (CREDO) trial is therefore highly relevant.
The design of the second part of the study, examining long-term clopidogrel treatment following PCI, is confusing. In addition to the PCI population of 1815 participants, 301 people who were randomised, but who did not have a PCI were included in the long-term analysis. Since the objective was to evaluate long-term clopidogrel treatment after PCI, it does not seem relevant to include these patients. Long-term clopidogrel treatment irrespective of PCI is a different matter.This will be addressed in the CHARISMA trial. In the CREDO study, there was a 26.9% reduction of ischaemic events in the clopidogrel group, but this includes non-PCI patients. If only the PCI population is considered, the effect of clopidogrel is less pronounced. It is important to recognise that the long-term f|ndings include the effect of clopidogrel treatment before PCI, not just 11 months of treatment from day 29 after the procedure. Since participants were not re-randomised at day 29 following PCI, it is not possible to analyse the effect of long-term clopidogrel treatment following PCI separately. We can, however, examine data on death or myocardial infarction (MI) in the PCI population. After 28 days, there were 52 cases of death or MI in the clopidogrel group and 64 cases in the placebo group. Excluding events in the non-PCI group, by the end of the study there were 77 cases of death or MI in the clopidogrel group and 100 cases in the placebo group (8.6% v 10.9% placebo).These f|gures suggest that only about half of the long-term difference between groups was due to the 11 month clopidogrel treatment after day 28, the other half being the result of the loading dose of clopidogrel before PCI. A relatively modest effect of long-term clopidogrel treatment after PCI was also found in PCI-CURE.1 Cardiovascular death or MI within 30 days after PCI was 4.4% in the placebo group and 2.9% in the clopidogrel group.By the end of the study, with average follow-up of 8 months, the incidence had increased to 8% and 6%, respectively. Thus, the main difference between groups was already apparent after 30 days. To summarise, in the CREDO trial it is not possible to do an adequate analysis of the effect of long-term clopidogrel treatment after PCI due to study design. Any effect that does exist may be considerably smaller than the long-term result reported.This suggests that the investigators’ main conclusion is not justif|ed. Longterm clopidogrel treatment cannot be recommended after PCI based on the CREDO study.
This study’s contribution This study’s main contribution involves f|ndings about pre-PCI administration of clopidogrel. Overall, 300 mg clopidogrel given 3 to 24 hours before the procedure made no signif|cant difference to the composite endpoint of death, myocardial infarction and urgent revascularisation at 28 days. The investigators undertook a pre-specif|ed subgroup analysis of the time between drug administration and the procedure. In the group that received the loading dose 6 to 12 hours before the intervention, the primary endpoint was reduced by 35.5%. The reduction was 40.1% for those who received clopidogrel 12 to 24 hours before PCI. There was no effect if clopidogrel was given less than 6 hours before the procedure. Although the study was not powered to draw f|rm conclusions from this subgroup analysis, the f|nding is striking. Other evidence In the subgroup of 2658 people undergoing PCI in the randomised CURE study, clopidogrel reduced the composite endpoint of cardiovascular death, myocardial infarction or need for urgent revascularisation within 30 days by 30% (6.4% v 4.5% control).1 About 25% of participants in both groups received open label clopidogrel before the intervention. When these participants were excluded, clopidogrel reduced the composite endpoint by 42%. In our own‘real world’ study, 706 consecutive patients received 375 mg clopidogrel in addition to aspirin the day before PCI.2 Compared to 724 consecutive patients treated with aspirin alone, pre-treatment with clopidogrel reduced the composite of death, myocardial infarction or urgent revascularisation by 41% (8.2% v 4.8%, p=0.01). In another study with consecutive patients, 600 mg clopidogrel was given to 864 people 2 to 4 hours before coronary stenting.3 Compared to 870 patients receiving conventional ticlopidine treatment, clopidogrel reduced the composite of death, myocardial infarction or need for urgent revascularisation by 35% (6.8% v 4.5%, po0.05).
Clinical implications In the CREDO trial summarised above, administering clopidogrel more than 6 hours before PCI had similar benef|ts to these other three studies.Taken together, these f|ndings suggest administering a loading dose of clopidogrel before scheduled PCI. The CREDO study suggests that if a loading dose of 300 mg is used, it is wise to administer it at least 6 hours before the procedure.The optimal size and timing of the clopidogrel loading dose remains unclear.
88
Evidence-based Cardiovascular Medicine (2003) 7, 87^ 88
Ulf Berglund, MD Department of Cardiology University Hospital Linkoºping, Sweden Literature cited 1. Mehta SR, Yusuf S, Peters RJG et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527^533. 2. Berglund U, Richter A. Clopidogrel treatment before percutaneous coronary intervention reduces adverse cardiac events. J Invas Cardiol 2002; 14: 243^246. 3. Pache J, Kastrati A, Mehilli J et al. Clopidogrel therapy in patients undergoing coronary stenting, value of a high loading dose regimen.Catheter Cardiovasc Interv. 2002; 55: 436^ 441.