Clopidogrel optimal loading dose Usage to Reduce Recurrent EveNTs-Organization to Assess Strategies in Ischemic Syndromes - CURRENT OASIS 7 — Presented at ESC and TCT 2009
The goal of the trial was to evaluate the efficacy and safety of a high daily dose of aspirin compared to a low dose of aspirin, and to compare standard dose clopidogrel with double dose clopidogrel, among patients with ST-elevation myocardial infarction (STEMI) or non–ST-segment elevation acute coronary syndrome (NSTE-ACS).
Patients Enrolled: 25,087
Mean Follow Up: 30 days
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="">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).
Percutaneous coronary intervention (PCI) was performed in 70% of patients in the trial. The reason no PCI was performed was 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%.
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 = 0.043). 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%, relative risk 0.83, 95% confidence interval 0.70-0.99, p = 0.036). 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%, RR 1.07, 95% CI 0.91-1.27, p = 0.42). The interaction between aspirin dose and clopidogrel dose did not reach statistical significance for the composite endpoint of myocardial infarction (MI)/stent thrombosis (p = 0.19) or major bleeding (p = 0.099).
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 0.96, 95% CI 0.85-1.08, p = 0.76). The lack of difference was consistent in the PCI cohort (4.2% for low-dose aspirin vs 4.1% for the high-dose group, HR 0.98, 95% CI 0.84-1.13, p = 0.76) and the no PCI cohort (4.7% vs 4.4%, HR 0.92, 95% CI 0.75-1.14, p = 0.44). Likewise, there was no difference in stent thrombosis between low-dose aspirin (2.1%) and high-dose aspirin (1.9%, HR 0.91, 95% CI 0.73-1.12, p = 0.37).
The primary safety endpoint of trial-defined major bleeding occurred in 2.3% of patients in both aspirin groups, and severe bleeding occurred in 1.7% of each group. Gastrointestinal bleeding was slightly more frequent in the high-dose group (0.24% vs. 0.38%, p = 0.051).
For the standard- versus double-dose clopidogrel comparison, when pooling the two aspirin strata together, there was no difference in the primary endpoint of cardiovascular death, MI, or stroke at 30 days (4.4% for standard-dose vs. 4.2% for double-dose, HR 0.95, 95% CI 0.84-1.07, p = 0.37). There was a significant interaction with performance of PCI (p-interaction = 0.016), with a lower rate of the primary endpoint with double-dose clopidogrel versus standard-dose clopidogrel in the PCI cohort (4.5% vs. 3.9%, HR 0.85, 95% CI 0.74-0.99) and a numerically higher rate of the primary endpoint with double-dose clopidogrel in the no PCI cohort (4.2% vs. 4.9%, HR 1.17, 95% CI 0.95-1.44). There was also no difference overall in the individual components of the composite endpoint of cardiovascular death (2.2% vs. 2.1%, HR 0.96, 95% CI 0.81-1.14, p = 0.63), MI (2.2% vs. 1.9%, HR 0.86, 95% CI 0.73-1.03, p = 0.097), or stroke (0.5% each, p = 0.95) for standard- versus double-dose clopidogrel, respectively. In the PCI cohort, definite or probable stent thrombosis was significantly lower in the double-dose clopidogrel group (2.3% vs. 1.6%, HR 0.71, 95% CI 0.57-0.89, p = 0.002), as was definite stent thrombosis (1.2% vs. 0.7%, HR 0.58, 95% CI 0.42-0.79, p = 0.001). This was noted in patients receiving both bare-metal and drug-eluting stents. The primary safety endpoint of trial-defined major bleeding was significantly higher in the double- versus standard dose-clopidogrel group (2.0% vs. 2.5%, HR 1.25, 95% CI 1.05-1.47, p = 0.01), as was trial-defined severe bleeding (1.5% vs. 1.9%, HR 1.23, 95% CI 1.02-1.49, p = 0.03). There was no significant difference in TIMI defined major bleeding (0.95% vs. 1.04%, HR 1.09, 95% CI 0.85-1.40, p = 0.50) or in CABG-related major bleeding (0.9% vs. 1.0%, HR 1.10, 95% CI 0.85-1.42, p = 0.48). In the PCI cohort, trial-defined major bleeding was more frequent with double- versus standard-dose clopidogrel (1.1% vs. 1.6%, HR 1.44, 95% CI 1.11-1.86, p = 0.006), whereas TIMI major bleeding occurred in 0.5% of each group (p = 0.79).
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, 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. When the factorial data were pooled, treatment with high-dose aspirin was not associated with a difference in the composite endpoint of cardiovascular death, MI, or stroke at 30 days compared with low-dose aspirin. Likewise, a double dose of clopidogrel was also not associated with a reduction in the primary endpoint compared with standard-dose clopidogrel.
While the results were negative overall for the clopidogrel comparison when the aspirin data were pooled, there was an interaction with the performance of PCI, with a reduction in the primary endpoint with double-dose clopidogrel in the PCI cohort, but no difference in the no PCI cohort. This represents an important finding, but the results should be interpreted in the context of the overall trial findings. Trial-defined major bleeding, the primary safety endpoint of the trial per the design manuscript, was more frequent with double-dose clopidogrel compared with standard-dose clopidogrel both overall and in the PCI cohort, but presumably not in the no PCI cohort (data not reported). Conversely, TIMI-defined major bleeding did not differ between the dose groups in the overall cohort or in the PCI cohort. 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.
For the aspirin dose comparison when the clopidogrel data were pooled, no difference was seen between the high- and low-dose groups in either the efficacy or in the bleeding. Clinically, aspirin dosing varies widely, with lower doses generally used in Europe and higher doses generally used in the United States.
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.
Keywords: Random Allocation, Therapies, Investigational
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