Clopidogrel for the treatment of adult patients following acute coronary syndrome

22 Apr 2009 Clopidogrel for the treatment of adult patients following acute coronary syndrome

Introduction: this is an update of the November 2004 Therapeutics Initiative systematic review report.

Research questions:

1. “Are there any clinical advantages to the use of clopidogrel, in combination with ASA, for twelve months as compared to thirty days in medically treated patients following ACS (unstable angina or non-ST elevation myocardial infarction)?”
2. “Are there any incremental risks or potential harms associated with the use of clopidogrel, in combination with ASA, in medically treated patients following ACS?”

Drug

Clopidogrel (Oral inhibitor of platelet aggregation)

Indication

(see Product Monograph ¹)

Acute Coronary Syndrome

1. “PLAVIX, in combination with acetylsalicylic acid (ASA), is indicated for the early and long-term secondary prevention of atherothrombotic events (myocardial infarction, ischemic stroke, cardiovascular death and/or refractory ischemia) in patients with acute coronary syndromes- without ST segment elevation (ie. unstable angina or non-Q-wave myocardial infarction). These benefits of PLAVIX have been shown only when these patients were concomitantly treated with ASA in addition to other standard therapies. These benefits were also seen in patients who were managed medically and those who were managed with percutaneous coronary intervention (with or without stent) or CABG (coronary artery bypass graft)”.
2. “For patients with ST-segment elevation acute myocardial infarction, PLAVIX has been shown to reduce the rate of an endpoint of all-cause mortality and the rate of a combined endpoint of death, re-infarction or stroke.”

Assessment principles:

Double blind randomized controlled trials in adult patients with acute coronary syndrome (unstable angina or non-ST elevation myocardial infarction) comparing [clopidogrel plus ASA] vs. ASA alone will be critically appraised. Health outcomes will be evaluated according to the following hierarchy – all cause mortality; non-fatal serious adverse events, including non-fatal myocardial infarction, non-fatal stroke, revascularization procedures, major bleeding, central nervous system bleeding, thrombotic thrombocytopenic purpura; other adverse events including withdrawal due to adverse events; and functional quality of life.

Search strategy and findings: MEDLINE (1966-March 2009), EMBASE (1980- March 2009), and Cochrane database of systematic reviews and CENTRAL (issue 1, 2009) were searched. The updated search did not identify any new RCT published since the March 2004 report. Additional publications of the three previously identified RCTs (CURE, PCI-CURE and CREDO trial) were appraised.

Results and overall summary:

Additional publications of CURE, PCI-CURE and CREDO trial did not provide information regarding optimal duration of clopidogrel therapy. ^2,3,4

Summary of the November 2004 systematic review report

1. For the treatment of patients hospitalized with acute coronary syndrome without ST segment elevation

One DBRCT (CURE trial) compared clopidogrel plus aspirin with placebo plus aspirin therapy in patients hospitalized within 24 hours after the onset of symptoms of acute coronary syndrome without ST segment elevation. ² The mean duration of treatment was 9 months. Total serious adverse events were not reported. There was no significant difference in total mortality.

Compared with placebo plus aspirin, clopidogrel plus aspirin significantly reduced the absolute risk of the first primary outcome, which was defined as the composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (9.3% vs. 11.4%, ARR =2.1%, NNT =48). About half of the total absolute risk reduction in the first primary outcome was already achieved after 1 month of therapy (4.3% vs. 5.4%, ARR =1.1%, NNT=91). The number of pills needed to prevent 1 event in the first month was 3003 (Calculated based on 91 patients needed to treat for 30 days and taking into consideration the recommended dose (300 mg = 4 pills the first day of therapy, and 75 mg = 1 pill for each day afterwards). An average of 8 more months of combined therapy with clopidogrel plus aspirin was required to achieve the additional half of the absolute risk reduction. The number of pills needed to prevent 1 event during the duration of the entire trial was 13,104 (Calculated based on 48 patients needed to treat for a mean of 9 months and taking into consideration the recommended dose (300 mg = 4 pills the first day of therapy, and 75 mg = 1 pill for each day afterwards).

The reduction in the first primary outcome was mainly due to a decreased rate of myocardial infarction (5.2% v. 6.7%, ARR= 1.5%, NNT= 67) which was  most likely seen in patients considered to have a high risk of future cardiovascular events (ARR =4.8%, NNT =21), compared with patients with either low or intermediate risk (ARR =1.6%, NNT =63), according to a modification of the TIMI risk score. A decrease in refractory ischemia (1.4% vs. 2.0%, ARR= 0.6%, NNT= 167), and in revascularization procedures (20.8% vs. 22.7%, ARR= 1.9%, NNT= 53) also occurred during the initial hospitalization, but not during the entire trial.

Adding clopidogrel to aspirin was also associated with a significantly increased incidence of bleeding episodes (8.5% vs. 5.0%, ARI= 3.5%, NNH= 29), despite exclusion of patients judged “at high risk of bleeding”. There was an increase in both, major (3.7% vs. 2.7%, ARI= 1%, NNH= 100) and minor bleeding episodes (5.1% vs. 2.4%, ARI= 2.7%, NNH= 37). Approximately half of the total excessive major bleeds in the clopidogrel plus aspirin group occurred during the first month of therapy (2.0% vs. 1.5%, ARI= 0.5%, NNH= 200).

For the treatment of patients undergoing a percutaneous coronary intervention:

1. Two DBRCTs (PCI-CURE study and CREDO trial) compared clopidogrel plus aspirin with placebo plus aspirin therapy in patients undergoing a percutaneous coronary intervention. (3, 4) The conclusions for the management of patients undergoing a percutaneous coronary intervention are confounded by the differences in the 2 available studies in terms of type of patients included, study design and definition of outcomes:
2. The CREDO trial included patients with a more stable, less acute baseline status than the PCI-CURE study. The PCI-CURE study included only patients hospitalized with acute coronary syndrome without ST-segment elevation who eventually underwent a percutaneous coronary intervention.
3. In the PCI-CURE study, when PCI was performed patients randomized to clopidogrel had received the drug for a mean of 10 days, compared with a mean of 9.8 hours for patients treated in the CREDO trial.
4. Routine periodic determinations of cardiac enzymes were performed in the CREDO trial, but not in the PCI-CURE study, leading to a higher detection of asymptomatic myocardial infarctions in the former trial.
5. Urgent target vessel revascularization was defined different in both trials.
6. Major bleeding episodes were defined different in both trials.

The PCI-CURE study

There was no difference in mortality when clopidogrel was added to aspirin in patients undergoing a PCI. There was a decrease in cardiovascular morbidity. Treatment with clopidogrel plus aspirin was associated with a reduction in the first primary outcome, which was defined as the composite of cardiovascular death, myocardial infarction; or urgent revascularization procedures by 30 days after PCI (4.5% v. 6.4%, ARR= 1.9%, NNT= 53) which was almost entirely due to a decreased rate of myocardial infarctions by 30 days after PCI (2.1% vs. 3.8%, ARR= 1.7%, NNT= 59). Furthermore, since most patients received open-label thienopyridines after PCI for several weeks, the difference observed at 30 days after PCI was mainly due to the effects of clopidogrel treatment prior to PCI.

At the end of follow-up (mean 9 months), patients treated with clopidogrel plus aspirin had a lower incidence of myocardial infarction (8.1% vs. 11.4%, ARR= 3.3%, NNT= 30). However, almost the entire total absolute risk reduction in myocardial infarction was achieved by 1 month after PCI. The same group also had a reduction in the need for any revascularization procedure (14.2% vs. 17.1%, ARR= 2.9%, NNT= 34). There was no difference in major bleeding episodes, but patients receiving clopidogrel plus aspirin had a higher incidence of minor bleeds (3.5% vs. 2.1%, ARI= 1.4%, NNH= 71).

The CREDO trial

In the CREDO trial, there was no difference in mortality. Treatment with clopidogrel plus aspirin was associated with a non-significant reduction in the primary outcome, which was defined as the composite of death, myocardial infarction, or urgent target vessel revascularization at 28 days after PCI (6.8% vs. 8.3%, p=0.23). When considered separately, neither of the components of the primary outcome was significantly different between the groups.

The group assigned to clopidogrel plus aspirin had a reduction in the primary outcome at 1 year, which was defined as the composite of death, myocardial infarction, or stroke (8.5% vs. 11.5%, ARR= 3.0%, NNT= 33). However, there was no difference if each component was analyzed individually. Furthermore, the same group also had non-statistically significant excess in major bleeding episodes, which numerically counteracted the total number of myocardial infarctions or revascularization procedures prevented.

Critical appraisal of included RCTs

1. Several currently recommended strategies for the treatment of acute coronary syndromes without ST-segment elevation include the use of an intravenous glycoprotein IIb/IIIa receptor antagonist for high-risk patients, or for patients in whom a PCI is planned ^12-14. However, in the CURE trial only 369 patients (5.9%) in the clopidogrel group, and 454 patients (7.2%) in the placebo group received such treatment, even though more than 15% of the patients in each group were eventually classified as high risk ², and around 21% of patients in each group underwent a PCI ⁶. This is probably because the CURE trial was performed before the routine use of Gp IIb/IIIa receptor antagonist became commonplace in “high risk” patients.The more extensive use of the combination of a glycoprotein IIb/IIIa receptor antagonist with clopidogrel plus aspirin in current clinical practice could result in different benefits and adverse outcome rates compared with the results of the CURE and CREDO trials. ¹² For example, in a retrospective study of 299 patients undergoing percutaneous coronary intervention and all treated with clopidogrel in addition to a glycoprotein (GP) IIb/IIIa receptor antagonist, the incidence of hemorrhage was 11% ¹⁶. Although the severity of bleeds was not described, the incidence was considerably higher than the combined incidence of major and minor bleeding events reported in either the PCI-CURE or the CREDO trials.
2. For patients undergoing PCI, the study design for both available trials (PCI-CURE and CREDO) cannot answer the question of whether the long-term reduction in events achieved with clopidogrel plus aspirin therapy was due entirely to the prolonged treatment or was due at least partially to a delayed benefit derived from acute treatment. Neither of the trials re-randomized patients to clopidogrel or placebo after the open label thienopyridine/ASA treatment following PCI. This is especially important for the PCI-CURE trial, in which patients received the study drug for a mean of 10 days before the open label period: when long term treatment with either clopidogrel or placebo started after the open label period, the baseline conditions for both groups were no longer the same. This long-term benefit from an early treatment effect appears less important in the CREDO trial since patients received only 1 dose of clopidogrel before the open label period and there was no significant acute events reduction (the difference in the primary outcome at 28 days was not significant).
3. In the PCI-CURE study, the main benefit was a reduction in myocardial infarction. The greater reduction occurred early, during the first month of therapy. Since most patients received open-label thienopyridines after PCI for several weeks, the reduction in myocardial infarctions observed at 30 days after PCI was mainly due to the effects of clopidogrel treatment prior to PCI.
4. In the CREDO trial, there was a non-significant trend toward a lower incidence of myocardial infarction and urgent revascularization procedures at 28 days after PCI. It is possible that the less acute population included and the shorter duration of treatment before PCI could explain the failure to demonstrate a statistically significant short-term benefit (compared with the results in PCI-CURE). However, the more frequent use of a GpIIb/IIIa receptor antagonist in CREDO can also be involved in some of the differences.
5. Unstable angina, one of the most important non-ST segment elevation acute coronary syndromes, was the reason to perform a PCI in 53% of patients included in the CREDO trial. Given that combined treatment with clopidogrel and aspirin reduced the cardiovascular morbidity in patients with acute coronary syndromes without ST-segment elevation in the PCI-CURE study, it would be interesting to know the segregated results in the group of patients with more stable coronary conditions included in the CREDO trial. The benefits and risks of treatment with clopidogrel plus aspirin are unknown in patients undergoing a PCI for reasons other than acute coronary syndrome.
6. Incomplete reporting of total and specific serious adverse events limits understanding of the overall health impact of clopidogrel plus aspirin treatment. Clarity is also needed on the clinical significance of the outcome events. For example, although both are considered as major bleeds, there is a great difference in clinical significance between a hemorrhagic stroke and a bleed requiring transfusion but which leaves no important sequelae. The same could be true for a large myocardial infarction leading to congestive heart failure, compared with a periprocedural small asymptomatic infarction diagnosed by an increase in cardiac enzymes. This missing information is needed to define the overall benefit/harm ratio derived from the long-term use of clopidogrel in addition to aspirin.

Conclusions

1. Based on one double blind randomized controlled trial in patients hospitalized within 24 hours after the onset of symptoms of acute coronary syndromes without ST-segment elevation and not being judged as “at high risk of bleeding”, adding clopidogrel to aspirin resulted in an absolute risk reduction of the primary outcome, which was defined as the composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (9.3% vs. 11.4%, ARR =2.1%, NNT =48). About half of the total absolute risk reduction in the first primary outcome was already achieved after 1 month of therapy (4.3% vs. 5.4%, ARR =1.1%, NNT=91 and the number of pills needed to prevent 1 event was 3003). An average of 8 more months of combined therapy with clopidogrel plus aspirin was required to achieve the additional half of the total absolute risk reduction. The number of pills needed to prevent 1 event during the duration of the entire trial was 13,104. The reduction in the primary outcome was most likely seen in patients considered to have a high risk of future cardiovascular events (ARR =4.8%, NNT =21), compared with patients with either low or intermediate risk (ARR =1.6%, NNT =63), according to a modification of the TIMI risk score. A decrease in refractory ischemia (1.4% vs. 2.0%, ARR= 0.6%, NNT= 167), and in revascularization procedures (20.8% vs. 22.7%, ARR= 1.9%, NNT= 53) also occurred during the initial hospitalization, but not during the entire trial. Adding clopidogrel to aspirin was also associated with a significantly increased incidence of bleeding episodes (8.5% vs. 5.0%, ARI= 3.5%, NNH= 29), despite exclusion of patients judged “at high risk of bleeding”. There was an increase in both, major (3.7% vs. 2.7%, ARI= 1%, NNH= 100) and minor bleeding episodes (5.1% vs. 2.4%, ARI= 2.7%, NNH= 37). Approximately half of the absolute risk increase in total excessive major bleeds in the clopidogrel plus aspirin group occurred during the first month of therapy (2.0% vs. 1.5%, ARI= 0.5%, NNH= 200).
2. Two DBRCTs (PCI-CURE study and CREDO trial) compared clopidogrel plus aspirin with placebo plus aspirin therapy in patients undergoing a percutaneous coronary intervention. The CREDO trial included patients with a more stable, less acute baseline status than the PCI-CURE study. The PCI-CURE study included only patients hospitalized with acute coronary syndrome without ST-segment elevation who eventually underwent a percutaneous coronary intervention.
   • In the PCI-CURE trial treatment with clopidogrel plus aspirin was associated with a reduction in the first primary outcome, which was defined as the composite of cardiovascular death, myocardial infarction; or urgent revascularization procedures by 30 days after PCI (4.5% vs. 6.4%, ARR= 1.9%, NNT= 53). The reduction was almost entirely due to a decreased rate of myocardial infarctions by 30 days after PCI (2.1% vs. 3.8%, ARR= 1.7%, NNT= 59). Furthermore, since most patients received open-label thienopyridines after PCI for several weeks, the difference observed at 30 days after PCI was mainly due to the effects of clopidogrel treatment prior to PCI. At the end of follow-up (mean 9 months), patients treated with clopidogrel plus aspirin had a lower incidence of myocardial infarction (8.1% vs. 11.4%, ARR= 3.3%, NNT= 30). However, almost the entire total absolute risk reduction in myocardial infarction was achieved by 1 month after PCI. The same group also had a reduction in the need for any revascularization procedure (14.2% vs. 17.1%, ARR= 2.9%, NNT= 34). There was no difference in major bleeding episodes, but patients receiving clopidogrel plus aspirin had a higher incidence of minor bleeds (3.5% vs. 2.1%, ARI= 1.4%, NNH= 71).
   • In the CREDO trial, treatment with clopidogrel plus aspirin was associated with a non-significant reduction in the primary outcome, which was defined as the composite of death, myocardial infarction, or urgent target vessel revascularization at 28 days after PCI (6.8% vs. 8.3%, p=0.23).  A reduction in the primary outcome was observed at 1 year, which was defined as the composite of death, myocardial infarction, or stroke (8.5% vs. 11.5%, ARR= 3.0%, NNT= 33). Furthermore, non-statistically significant excess in major bleeding episodes was seen, which numerically counteracted the total number of myocardial infarctions or revascularization procedures prevented.
3. Several currently recommended strategies for the treatment of acute coronary syndromes without ST-segment elevation include the use of an intravenous glycoprotein IIb/IIIa receptor antagonist for high-risk patients, or for patients in whom a PCI is planned. The more extensive use of the combination of a glycoprotein IIb/IIIa receptor antagonist with clopidogrel plus aspirin in current clinical practice could result in different benefits and adverse outcome rates compared with the results of the CURE and CREDO trials. Incomplete reporting of total and specific serious adverse events limits understanding of the overall health impact of clopidogrel plus aspirin treatment.

References

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