Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events−Seventh Organization to Assess Strategies in Ischemic Syndromes - CURRENT–OASIS 7
CURRENT–OASIS 7 was a 2 × 2 factorial trial that aimed to evaluate the efficacy and safety of a high daily dose of aspirin compared with a low dose of aspirin, and standard-dose clopidogrel compared with double-dose clopidogrel, among patients with ST-elevation myocardial infarction (STEMI) or non–ST-segment elevation acute coronary syndrome (NSTE-ACS).
High-dose aspirin would be superior to low-dose aspirin, and high-dose clopidogrel would be superior to standard-dose clopidogrel in patients with STEMI or NSTE-ACS.
Patients Enrolled: 25,086
Mean Follow Up: 30 days
Mean Patient Age: 61.3 years
- Patients with unstable angina, NSTEMI, or STEMI randomized within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischemia/infarction
- Age <18 years
- Use of oral anticoagulants in ≤10 days with an INR of >1.5, or planned use during the hospitalization
- Use of clopidogrel >75 mg within 24 hours before randomization
- Contraindication to clopidogrel and/or aspirin
- Active bleeding or significant increased risk of bleeding
- History of severe systemic bleeding or history of bleeding diathesis or coagulopathy
- Uncontrolled hypertension
- Investigational treatment (drug or device) within the previous 30 days
- Medical, geographic, or social factors making study participation impractical, or inability to provide written informed consent and to understand the full meaning of the informed consent
- Efficacy: Cardiovascular death, myocardial (re)infarction, or stroke up to day 30
- Safety: Major bleeding, using the CURRENT trial definition per the design paper (Am Heart J 2008;156:1080-8)
- Cardiovascular death, MI, stroke, or refractory ischemia up to day 30
- Individual efficacy outcomes up to day 30: Cardiovascular death, total death, MI, periprocedural MI, stroke, recurrent ischemia, urgent revascularization, and stent thrombosis
- Rates of occluded (TIMI 0 or 1 flow) versus open (TIMI 2 or 3 flow) infarct-related artery at the start of coronary angiography or at hospital discharge, whichever comes first (STEMI population only)
Patients were randomized in an open-label manner to a high daily dose of aspirin (300-325 mg) or to a low dose of aspirin (75-100 mg), and were followed for 30 days. Patients were also randomized in 2 × 2 factorial design to a clopidogrel high-dose regimen (600 mg loading dose on day 1 followed by 150 mg once daily on days 2-7, followed by 75 mg once daily on days 8-30) compared with the standard-dose regimen (300 mg loading dose on day 1, followed by 75 mg once daily on days 2-30).
A total of 25,086 patients were enrolled. Of these, 12,520 received high-dose clopidogrel and 12,566 received standard-dose clopidogrel, while 12,507 received high-dose aspirin and 12,579 received low-dose aspirin. Baseline characteristics were fairly similar between the two arms. Percutaneous coronary intervention (PCI) was performed in about 70% of patients in the trial. The reason no PCI was performed was due to no significant coronary artery disease (15%), coronary artery bypass grafting (CABG) (7%), and other reasons despite presence of coronary artery disease (10%). Type of ACS was unstable angina/NSTEMI in 70.8% of patients and STEMI in 29.2%. About 23% of the patients had diabetes mellitus, and 18% had a history of prior MI. Elevated cardiac biomarkers were noted in about 65% of the patients.
High-dose clopidogrel vs. standard-dose clopidogrel: There was no difference in the primary endpoint of cardiovascular death, MI, or stroke at 30 days between the two arms (4.2% for double-dose vs. 4.4% for standard-dose, hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.83-1.06, p = 0.30). There was also no difference overall in the individual components of the composite endpoint of cardiovascular death (2.1% vs. 2.2%, p = 0.57), MI (1.9% vs. 2.2%, p = 0.09), or stroke (0.5% each, p = 0.95) for double- versus standard-dose clopidogrel, respectively. The primary safety endpoint of trial-defined major bleeding was significantly higher in the double- versus standard dose-clopidogrel group (2.5% vs. 2.0%, HR 1.24, 95% CI 1.05-1.46, p = 0.01), as was trial-defined severe bleeding (1.9% vs. 1.6%, p = 0.04). There was also a significant difference in TIMI-defined major bleeding (1.7% vs. 1.3%, p = 0.03), but not in CABG-related major bleeding (1.0% vs. 0.9%, p = 0.53).
There was a significant interaction with performance of PCI (p-interaction = 0.03), with a lower rate of the primary endpoint with double-dose clopidogrel versus standard-dose clopidogrel in the PCI cohort (3.9% vs. 4.5%, HR 0.85, 95% CI 0.74-0.99, p = 0.04) and a numerically higher rate of the primary endpoint with double-dose clopidogrel in the no PCI cohort (4.3% vs. 4.9%, p = 0.22). In the PCI cohort, definite stent thrombosis was significantly lower in the double-dose clopidogrel group (0.7% vs. 1.3%, HR 0.54, 95% CI 0.39-0.74, p = 0.0001). This was noted in patients receiving both bare-metal and drug-eluting stents. In the PCI cohort, trial-defined major bleeding was more frequent with double- versus standard-dose clopidogrel (1.6% vs. 1.1%, HR 1.41, 95% CI 1.09-1.83, p = 0.009), whereas TIMI major bleeding occurred in 0.5% of each group (p = 0.79)
High-dose aspirin vs. low-dose aspirin: There was no difference in the primary endpoint of cardiovascular death, MI, or stroke at 30 days between the low- and high-dose aspirin groups (4.4% vs 4.2%, HR 0.97, 95% CI 0.86-1.09, p = 0.61). There was also no difference overall in the individual components of the composite endpoint of cardiovascular death (2.3% vs. 2.1%, p = 0.22), MI (2.1% vs. 2.0%, p = 0.76), or stroke (0.5% vs. 0.6%, p = 0.32), respectively. The primary safety endpoint of trial-defined major bleeding occurred in 2.3% of patients in both aspirin groups (p = 0.9), and severe bleeding occurred in 1.7% of each group (p = 0.93). CABG-related and TIMI severe bleeding were also similar between the two arms.
There was no evidence of interaction with PCI (p = 0.93), with no difference in the primary endpoint in the PCI cohort (4.2% for low-dose aspirin vs. 4.1% for the high-dose group, p = 0.76) and the no PCI cohort (4.7% vs. 4.5%, p = 0.96). There was no difference in the incidence of definite stent thrombosis between the low-dose and high-dose aspirin arms (1.0% vs. 0.9%).
For the primary efficacy endpoint of the trial, there was a significant interaction with the factorial randomization in the trial between low-dose and high-dose aspirin and standard-dose and double-dose clopidogrel (p = 0.04). In the high-dose aspirin group, the primary efficacy event rate was lower in the double-dose clopidogrel versus the standard-dose clopidogrel group (4.6% vs. 3.8%, HR 0.82, 95% CI 0.69-0.98, p = 0.03). However, there was no difference between the double-dose clopidogrel versus the standard-dose clopidogrel group in the low-dose aspirin cohort (4.2% vs 4.5%, HR 1.07, 95% CI 0.90-1.26, p = 0.46). The interaction between aspirin dose and clopidogrel dose did not reach statistical significance for the composite endpoint of MI/stent thrombosis (p = 0.19) or major bleeding (p = 0.099).
In the 6,346 patients presenting with STEMI who underwent PCI, there was a significant reduction in the incidence of stent thrombosis (2.5% vs. 3.5%, p = 0.024), MI (1.2% vs. 1.9%, p = 0.025), in the double-dose clopidogrel arm compared with standard-dose clopidogrel, with no difference in cardiovascular death (3.1% vs. 3.2%, p = 0.73) or stroke (0.4% vs. 0.5%, p = 0.58). The highest risk of stent thrombosis seemed to be in the cohort that received low-dose aspirin and standard-dose clopidogrel. There was, however, no difference in the incidence of CURRENT major (1.4% vs. 1.2%, p = 0.50) or severe (1.1% vs. 0.9%, p = 0.52) bleeding.
Among patients with STEMI or NSTE-ACS, high-dose clopidogrel and high-dose aspirin are not superior to standard-dose clopidogrel and low-dose aspirin, respectively, in reducing cardiovascular events at 30 days. Moreover, high-dose clopidogrel results in a significant increase in major and severe bleeding, as compared with standard-dose clopidogrel; high-dose aspirin results in similar major bleeding rates as low-dose aspirin. There was a significant interaction between aspirin dose and clopidogrel dose in the composite endpoint of cardiovascular death, MI, or stroke at 30 days, with no difference seen between double- and standard-dose clopidogrel in the low-dose aspirin cohort, and a significant reduction with double-dose clopidogrel in the high-dose aspirin cohort. Further, there was a significant interaction between clopidogrel dose and PCI, with patients receiving PCI showing a reduction in composite cardiovascular events and stent thrombosis at 30 days with high-dose clopidogrel, as compared with standard-dose clopidogrel. Such an interaction was not noted with aspirin dose.
The present study represents the first large-scale clinical outcomes trial to evaluate standard- versus double-dose clopidogrel, with previous studies primarily platelet function trials. However, double-dose clopidogrel, particularly with the loading dose, is often given in clinical practice for ACS patients undergoing PCI. The benefit noted with high-dose clopidogrel in the PCI arm is interesting, and potentially very important, but the results should be interpreted in the context of the overall trial findings. These will need to be carefully evaluated in future trials. The findings for aspirin indicate that high-dose aspirin may not be beneficial, other than in patients also getting high-dose clopidogrel. This interaction will also need to be tested in future trials.
The CURRENT-OASIS 7 Investigators. Dose comparisons of clopidogel and aspirin in acute coronary syndromes. N Engl J Med 2010;363:930-42.
Mehta SR, Tanguay JF, Eikelboom JW, et al., on behalf of the CURRENT-OASIS 7 trial investigators. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 2010;Sep 1:[Epub ahead of print].
Presented by Dr. Shamir R. Mehta at the ESC Congress, Barcelona, Spain, August 2009, and at TCT 2009, San Francisco, CA, September 24, 2009.
Mehta SR, Bassand JP, Chrolavicius S, et al. Design and rationale of CURRENT-OASIS 7: A randomized, 2 × 2 factorial trial evaluating optimal dosing strategies for clopidogrel and aspirin in patients with ST and non–ST-elevation acute coronary syndromes managed with an early invasive strategy. Am Heart J 2008;156:1080-8.
Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Atherosclerotic Disease (CAD/PAD), ACS and Cardiac Biomarkers, Aortic Surgery, Interventions and ACS, Interventions and Coronary Artery Disease
Keywords: Coronary Artery Disease, Myocardial Infarction, Stroke, Acute Coronary Syndrome, Platelet Aggregation Inhibitors, Drug-Eluting Stents, Ticlopidine, Blood Platelets, Purinergic P2Y Receptor Antagonists, Percutaneous Coronary Intervention, Biological Markers, Metals, Thrombosis, Confidence Intervals, Coronary Artery Bypass, Diabetes Mellitus
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