Overall Study Question
Antithrombotic and antiplatelet agents have been major pharmacological advances in reducing the risk of death from cardiovascular causes, myocardial infarction, and recurrent ischemia in non-ST-elevation acute coronary syndromes (NSTEACS). While the use of aspirin, unfractionated heparin/low-molecular weight heparin (LMWH) and intravenous glycoprotein IIb/IIIa receptor inhibitors (GP IIb/IIIa inhibitors) have been shown to reduce the incidence of early cardiovascular events in specific patients with NSTEACS, a high rate of major vascular events in this patient population still persists. Although aspirin is recommended to be continued indefinitely, there is no convincing evidence to support the use of LMWH or GP IIb/IIIa antagonist beyond the acute period. It has been suggested that the thienopyridine antiplatelet clopidogrel may have added benefit when given with aspirin in reducing long-term risk of ischemic events.
The CURE trial was an international, multi-centre, randomized, double-blind, placebo-controlled trial comparing the efficacy and safety of clopidogrel, plus aspirin with those of aspirin alone in non-ST-elevation acute coronary syndromes.
Consenting patients were enrolled if they had been hospitalized within 24 hours after the onset of symptoms that were consistent with ischemia. Ischemia was defined as unstable angina or acute myocardial infarction (MI) without ST-segment elevation greater than 1 mm and had either electrocardiographic (ECG) changes or an elevation in serum cardiac enzymes or markers. Exclusion criteria included a contraindication to antithrombotic or antiplatelet therapy, the use of oral anticoagulants, a high risk for bleeding or severe heart failure, a coronary revascularization procedure within the previous three months, or receipt of a intravenous GP IIb/IIIa inhibitors within the previous three days.
Patients were immediately randomized to receive a 300 mg loading dose of clopidogrel (or matching placebo) followed by 75 mg of clopidogrel (or matching placebo) for 3 to 12 months. At the discretion of the physician in charge, patients concurrently received aspirin in a dose range of 75 mg to 325 mg daily . Follow-up assessments occurred at discharge from hospital, at one and three months, and then every three months until the end of the study.
The first primary outcome of this study was the composite of death from cardiovascular causes, nonfatal MI, or stroke. The second primary outcome was the composite of the first primary outcome plus refractory ischemia. The secondary outcomes for this study were severe ischemia, heart failure, the need for revascularization and bleeding complications.
Are the Results of the Study Valid?
1. Was assignment of patients randomized?
After informed consent was obtained, patients were randomly assigned to either the clopidogrel group or the placebo group by a central, 24-hour, computerized randomization service from the Canadian Cardiovascular Collaboration Project Office. Permuted-block randomization, stratified according to clinical centre was used.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
Patients were recruited between December 1998 and September 2000 at 482 centers in 28 countries. A total of 12, 562 patients were enrolled; 6,259 received clopidogrel and 6,303 received placebo. All analyses were based on the intention-to-treat principle. Six patients in the clopidogrel group and 7 patients in the placebo group were lost to follow-up.
3. Were patients, their clinicians, and study personnel ‘blind’ to treatment?
This was a double-blinded study. Two formal interim assessments were performed by a blinded independent data and safety monitoring board when approximately one-third and two-thirds of the expected events had occurred.
4. Were the groups similar at the start of the trial?
The baseline demographics and characteristics of the patients in both groups were similar including admitting diagnosis, medical history, time from onset of pain to randomization, ECG abnormalities and cardiovascular medication history. Unfortunately, the authors provided no information regarding the rates of significant family history of coronary artery disease or cholesterol profiles for the patient groups. This would have been useful to further define patient baseline characteristics. Considering the sample size and study design, it is reasonable to assume that these factors would likely be balanced across groups.
5. Aside from the experimental intervention, were the groups treated equally?
Subsequent to randomization there were no restrictions on the use of any therapy or interventions. More invasive management strategies were discouraged, however, and only 7.2% in the placebo group and 5.9% in the clopidogrel group received GP IIb/IIIa inhibitors. If the clinicians determined that angiography and revascularization were needed or that a thienopyridine derivative was indicated, the study medication could be stopped or open-label clopidogrel or ticlopidine could be used. Overall, 43.7% of patients underwent angiography, 16.5% underwent coronary artery bypass graft (CABG) and 21.2% underwent percutaneous transluminal coronary angioplasty (PTCA). A similar proportion of patients in both arms underwent revascularization (36.9% in the placebo group vs. 36% in the clopidogrel group). In both groups the study medication was recommended to be temporarily stopped for more than 5 days if patients underwent PTCA or CABG, and the majority of patients with PTCA received a thienopyridine-type agent for about two to four weeks after.
What were the Results?
1. How large was the treatment effect?
Patients were treated for 3 to 12 months (mean duration of treatment 9 months). The first primary outcome (death from cardiovascular causes, nonfatal MI, or stroke) occurred in 9.3% of the clopidogrel group and 11.4% of the placebo group (p < 0.001, ARR = 2.1%, RRR = 18.4%, NNT = 48). There was no significant reduction in cardiovascular death or stroke, only nonfatal myocardial infarction was reduced significant from 6.7% to 5.2% (p<0.001). The second primary outcome (first primary outcome or refractory ischemia) occurred in 16.5% of the clopidogrel group and 18.8% of the placebo group (p < 0.001, ARR = 2.3%, RRR = 12.2%, NNT = 43). The rate of other in-hospital outcomes (severe ischemia, recurrent angina, need for coronary revascularization) also tended to be lower in the clopidogrel group. The benefits were consistent among various subgroup analyses including both high-risk and low-risk features, in those receiving different doses of aspirin, and various proven therapies such as angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, lipid-lowering drugs prior to study enrollment. Further analysis indicated that the benefit of clopidogrel was apparent within a few hours after randomization and significantly lower in the clopidogrel group by 24 hours.
Clopidogrel was associated with a significant increase in major and minor bleeding. Major bleeding occurred in 3.7% in the clopidogrel group and 2.7% in the placebo group (p = 0.001, ARI = 1.0%, RRI = 38%, NNH = 100). Minor bleeding episodes were significantly increased in the clopidogrel group at 5.1% compared with the placebo group at 2.4% (p < 0.001, ARI = 2.7%, RRI = 113%, NNH = 37). There was no significant increase in the risk of life-threatening bleeding which occurred in 2.2% in the clopidogrel group and 1.8% in the placebo group (p = 0.13, ARI = 0.4%, RRI = 22%, NNH = 250). The excess major bleeding episodes were gastrointestinal hemorrhages and bleeding at the sites of arterial punctures. The number of patients who required transfusions of greater than or equal to 2 units of blood was 2.8% in the clopidogrel group and 2.2% in the placebo group (p = 0.02). Overall, there was no significant increase of major bleeding episodes after CABG (8.3% in the clopidogrel group vs. 6.6% in the placebo group)(7). However there was a trend towards a higher bleeding rate in those receiving clopidogrel within five days of surgery, with major bleeding rates of 9.6% in clopidogrel group and 6.3% in placebo group (p = 0.06, RR = 1.53). The incidence of thrombocytopenia or neutropenia was similar in both groups.
A total of 46.2% of patients in the clopidogrel group temporarily stopped the study medication (for more than five days) and 45.4% of patients in the placebo group. The study medication was permanently discontinued in 21.1% of the clopidogrel group and 18.8% of the placebo group. The use of other medications was similar in both groups.
2. How precise was the estimate of the treatment effect?
The relative risk 95% confidence intervals for the first primary outcome was 0.72 to 0.90 and for the second primary outcome was 0.70 to 0.94. These confidence intervals are narrow and do not cross one (i.e. the point of unity) supporting the statistically significant result.
Will the Results Help Me in Caring for My Patients?
1. Can the results be applied to my patient care?
This international study involving 28 countries had a large representation of patients from Europe, Canada and U.S. The inclusion and exclusion criteria are consistent with other NSTEACS trials and would suggest general applicability to patients in centres that do not routinely conduct early invasive interventions as those who had received early coronary intervention or GP IIb/IIIa antagonists were excluded from the study.
Although patients were excluded if they had received coronary revascularization in the previous three months, once a patient was randomized to a treatment group, there were no restrictions on the use of any therapy or interventions that was believed to be necessary. In patients who underwent PTCA or CABG, the study medication was recommended to be temporarily interrupted for more than five days and the majority of the patients who underwent PTCA received open-label thienopyridine antiplatelet agent for two to four weeks. The study medication was restarted after a median of 11 days in the patients who underwent CABG.
2. Were all clinically important outcomes considered?
All important outcomes were considered and clearly defined. It is interesting to note that the CURE study involved two primary outcomes (see above). It is not expected that this would have affected the significance of the study results as the authors described appropriate statistical adjustments.
3. Are the likely treatment benefits worth the potential harms and costs?
Clopidogrel in addition to aspirin significantly decreased the incidence of the first and second primary outcomes. However this occurred at the expense of an increase in major and minor bleeding, although there was no increase in the risk of life-threatening bleeding. (7)
Finally, it is important to consider whether the benefit of therapy outweighs the financial cost. Clopidogrel costs approximately $3 per day in the U.S. and $2.90 per day in Canada (for a total of $783 CDN for 9 months excluding dispensing fee). Although this will not be an issue for in-hospital costs, it may be a barrier to long-term treatment for elderly patients (who are the majority of ACS patients) on government assistance plans that do not readily cover the cost of clopidogrel outside the hospital. A full cost-effectiveness economic analysis of the study is expected to be presented later.
Although there are now many treatments for the acute management of non-ST-elevation acute coronary syndrome, only aspirin is used long-term. (6) The benefit of a short-term combination of aspirin plus a thienopyridine derivative in lowering the rates of myocardial infarction is established in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) with stenting. (8) The CURE trial demonstrates the benefit of adding clopidogrel to the treatment regimens for patients with NSTEACS who are receiving aspirin and other medications but with an increased risk for bleeding.
The baseline characteristics of the patients in the CURE trial are consistent with the patient population seen in other NSTEACS studies. It can be argued that the patients in CURE are of a moderate to high-risk category as a large number of patients (93.8%) presented with ECG positive changes at entry. This is consistent with the patient population seen in the PURSUIT and PRISM-PLUS trials where greater than 99% and 94% respectively had positive ECG changes while only over 55% of the patients in ESSENCE had reported ECG changes at baseline. (3-5) However, there were more patients who had positive enzymes and ST depression in the GP IIb/IIIa inhibitor trials than either the ESSENCE or CURE trials (enzymes: 45% (4,5) vs. 21% (3) and 25% (CURE) ; ST depression: 49-58% (4,5) vs. 24% (3) & 42% (CURE)). This would suggest that there are some similarities in the level of risk of patients in the CURE trial and the GP IIb/IIIa inhibitor trials and that the CURE patients might also have been considered candidates for GP IIb/IIIa inhibitor therapy +/- invasive interventions. However, the event rates in the placebo group in the CURE trial suggest an intermediate risk population when compared with other NSTEACS trials. In CURE, 12.1% of the placebo group experienced death or MI at 9 months compared to 13.5% in the ESSENCE study at 1 year and 15.7% in the PURSUIT4 study at 30 days and 15.4% in the PRISM-PLUS5 study at 6 months.
It is important to note that the bleeding definitions used in the CURE trial were different from the standard GUSTO and TIMI bleeding scales more commonly used in other NSTEACS trials. The bleeding definitions used in the CURE trial were more stringent than either GUSTO or TIMI bleeding scales and resulted in higher bleeding rates. When analyzed by the GUSTO and TIMI scales, no differences between groups was found.
The CURE trial excluded patients who had received a GP IIb/IIIa inhibitor within the previous 3 days or those who had received a revascularization within the previous 3 months. Therefore, the role of clopidogrel is still unknown in this patient population.
With respect to risk versus benefit, the results from the CURE trial indicate that treating 1000 patients for 9 months prevents 20 events (cardiovascular death, nonfatal MI, or stroke) at a cost of 10 major bleeds. The risk of major bleeding in CURE is comparable to the GP IIb/IIIa inhibitor trials, but higher than the major bleeding rates in the ESSENCE study with enoxaparin. It is difficult to make definitive comments regarding the risk versus benefit of clopidogrel compared with current antithrombotic and antiplatelet agents used in NSTEACS management due to the different primary endpoints that are evaluated in each study. This fact emphasizes the importance of early risk-stratification of NSTEACS patients to target therapy at the appropriate level to maximize benefit.
Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.