Double dose Clopidogrel associated with improved cardiac outcomes in patients undergoing PCI: Results of CURRENT/OASIS-7 Trial

September 3,2009 by Smita Kohli, M.D.

Dr. Mehta from the CURRENT investigators team presented the results of the CURRENT OASIS 7(Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent EveNTs/Optimal Antiplatelet Strategy for InterventionS) trial at the European Society of Cardiology ESC, 2009 which showed a significant reduction in cardiovascular death, MI, stent thombosis and stroke with higher dose of Clopidogrel in PCI group at the end of 30 days. There was no difference in outcomes between low Vs Higher dose of Aspirin. Prior studies have shown that Clopidogrel 300mg loading dose followed by 75mg maintenance dose has been shown to reduce cardiovascular events in ACS and PCI patients. Recent data has also shown that doubling these dosages results in higher and more rapid antiplatelet effect . Dose of Aspirin varies between North America and Europe. There have been no large scale RCTs to compare low dose Vs higher dose aspirin in patients with ACS undergoing PCI. With this background, investigators from CURRENT designed this study to evaluate the efficacy and safety of (1) a higher loading and initial maintenance dose of clopidogrel compared with the standard-dose regimen and (2) high-dose ASA compared with low-dose ASA in patients with ST or non–ST-segment-elevation ACS managed with an early invasive strategy.

This was a multicenter, multinational, randomized, parallel group trial which enrolled a total of 25,087 patients with acute coronary syndrome(which included UA/NSTEMI and STEMI) who underwent early invasive management with intended PCI. Patients were then randomized to receive(2 X 2 factorial)

• Clopidogrel : Double dose(600mg loading dose followed by 150mg x7d, then 75mg/day) Vs standard dose(300mg loading dose followed by 75 mg daily
• Aspirin: High dose(300-325mg/day) vs low dose(75-100mg/day)

Patients were then followed at the end of 30 days. Primary outcome was first occurence of any component of cardiovascular death, myocardial (re)infarction and stroke up to 30 days. Safety outcome was major bleeding at day 30.

Out of 25087 patients, 24769(99%) underwent cardiac catheterization out of which 70% had PCI. Type of ACS was UA/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 vs the standard dose clopidogrel group (4.6% vs 3.8%, RR 0.83, 95% CI 0.70-0.99, p=0.036) However, there was no difference between the double dose clopidogrel vs 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 MI/stent thrombosis (p=0.19) or major bleeding (p=0.099) There was no difference in the primary endpoint of CV 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). For the standard vs double dose clopidogrel comparison, when pooling the two aspirin strata together, there was no difference in the primary endpoint of CV 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 vs 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 CV 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 vs 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). The primary safety endpoint of trial-defined major bleeding was significantly higher in the double vs 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 vs standard dose clopidogrel (1.1% vs 1.6%, HR 1.44, 95% CI 1.11-1.86, p=0.006), while TIMI major bleeding occurred in 0.5% of each group (p=0.79).

This can be interpreted as follows: Among the PCI patients, the risk of stent thrombosis was reduced by 30% and the risk of MI was reduced by 22% in the group that received the high dose Clopidogrel compared to the group that received the standard dose. The high dose group had more major bleeding, but there was no increase in intracerebral or fatal bleeds. No benefit of the higher dose was found in the group of patients who did not have PCI. In a second randomization, patients received either high-dose (300-325 mg once daily) or low-dose (75-100 mg once daily) aspirin. There were no significant differences in outcome between these two groups.

The present study represents the first large-scale clinical outcomes trial to evaluate standard vs 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. 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. Although trial defined major bleeds was higher overall and in PCI cohort with higher dose clopidogrel as compared to standard dose group, TIMI defined major bleeds, intra-cranial hemorrhage, fatal bleeds or CABG related bleeds were not different between the two groups. Results presented do not mention the type and number of stents patient received and the length of the stents; factors which are known to affect the incidence of stent thrombosis. Report also did not include the data on bleeding in no PCI group.

This study implies that the combination of high-dose clopidogrel combined with usual doses of aspirin may be the optimal treatment strategy in PCI patients. High dose clopidogrel is effective in decreasing the incidence of stent thrombosis. This study may also open doors for further evaluation of high dose clopidogrel for late stent thrombosis.

PowerPoint Presentation

Media:CURRENT_OASIS_7_without_supplementary_slides.ppt

Sources

• Mehta SR, Bassand JP, Chrolavicius S, Diaz R, Fox KAA, Granger CB, Jolly S, Rupprecht HJ, Widimsky P, Yusuf S. 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. Results as presented at ESC 2009.
• Learn more about this trial at Clinicaltrials.gov