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.

The results of the CURRENT OASIS 7(Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent EveNTs/Optimal Antiplatelet Strategy for InterventionS) trial were presented at the 2009 European Society of Cardiology ESC meeting. Overall, there was no efficacy benefit for either high dose aspirin or high dose clopidogrel in the trial. There was, however, a significant interaction term indicating that the results were significantly different among patients who were treated with both high dose aspirin and high dose clopidogrel. There was also a positive interaction term with respect to the prospectively-defined PCI subgroup in which there was 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 high dose of aspirin.

Background
Prior studies have demonstrated that a 300 mg loading dose of Clopidogrel  followed by a 75 mg maintenance dose is associated with a reduction in cardiovascular events in ACS and PCI patients compared to aspirin alone. Despite these benefits, approxiately 27% of the population is resistant to clopidogrel due to a variant in the Cyp 2C19 allele that diminishes the ability of these patients to metabolize clopidogrel from the pro drug into the active metabolite. Higher doses of clopidogrel have therefore been tested to assess whether clinical outcomes could be further improved. Indeed, a 600 mg loading dose has been associated with greater and more rapid antiplatelet effects.

The optimal dose of aspirin following PCI has not been defined in randomized trials and the dose of aspirin varies between North America and Europe. The CURRENT trial was undertaken 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.

Design
CURRENT 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 in a 2 X 2 factorial design one of the 4 following regimens:
 * 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 through 30 days. The pre-specified primary outcome was first occurrence of any component of cardiovascular death, myocardial (re)infarction and stroke up to 30 days. The primary safety outcome was major bleeding through day 30.

WikiDoc contacted Dr. Shamir Mehta who indicated that the PCI-subgroup was a "pre-specified post randomization subgroup and documented in the statistical analysis plan finalized by the operations committee prior to unblinding, together with a pre-specified hypothesis that there would be a significant interaction with greater relative benefit in those undergoing PCI."

Results
Out of 25,087 patients randomized in the trial, 24,769(99%) underwent cardiac catheterization out of which 70% underwent PCI. The breakdown in the type of ACS was UA/NSTEMI in 70.8% of patients and STEMI in 29.2%.

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). However, 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). Given the 2 X 2 factorial design and the positive interaction term, evaluation of the 4 subgroups is valid. 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). 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 with respect to 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 homogenous in those patients who did and did not undergo PCI (i.e. the interaction term was negative). Event rates 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) were similar. 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).

There was a significant interaction with performance of PCI (p-interaction=0.016), a pre-specified post randomization subgroup. There was 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) but no significant difference in 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).

Interpretation
Overall, among all ACS patients undergoing cardiac catheterization, there were no differences in clinical outcomes among patients randomized to either high or low dose clopidogrel or aspirin. However, there was a positive interaction term meaning the results varied significantly depending upon the combination of high vs low dose clopidogrel with high vs low dose aspirin as well as among patients who did and did not undergo PCI. There was a benefit in the risk of the primary efficacy endpoint among patients in the high dose clopidogrel / high dose aspirin group. 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 protocol defined major bleeding, but there was no increase in intracerebral or fatal bleeds. No benefit of the higher dose of clopidogrel or aspirin was found in the group of patients who did not undergo 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.

CURRENT is 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.

Comparison with Results from TRITON-TIMI 38
The design of the two trials differed in important ways. The patients in CURRENT were pre-treated with clopidogrel prior to cardiac catheterization and PCI while pre-treatment was not undertaken in TRITON-TIMI 38. The dose of clopidgrel in TRITON-TIMI 38 was a 300 mg load followed by a maintenance dose of 75 mg per day (the FDA approved dose). Follow-up was only through 30 days in CURRENT, but was over a year in TRITON. While the benefits of high dose clopidogrel were confined to the PCI group in CURRENT, it should be noted that the benefits of prasugrel were likewise observed among PCI patients (medically managed patients were not studied in TRITON-TIMI 38). While there was no excess risk of TIMI major bleeding associated with double dose clopidogrel in the 30 days of follow-up in CURRENT, it should be noted that there was also no excess risk of TIMI major bleeding or fatal bleeding associated with prasugrel administration in the first 30 days of follow-up in TRITON-TIMI 38.

The data and conclusions from CURRENT are confined to the first 30 days after PCI. After 30 days, the dose regimen of clopidogrel is the same as that studied in TRITON-TIMI 38. Landmark analyses from 30 days onward do show some benefits of prasugrel over clopidogrel (a reduction in spontaneous MI and stent thrombosis). However, there was also an excess risk of TIMI major bleeding after 30 days with prasugrel. Unlike pre-treatment with 600 mg of clopidogrel as studied in CURRENT, treatment with 60 mg of prasugrel at the time of the PCI procedure allows the cardiologist to define the coronary anatomy first, to determine if the patient needs coronary artery bypass grafting (CABG). There are no comparisons of the clinical outcomes of double dose clopidogrel vs prasugrel, but data from the PRINCIPLE study suggests better platelet inhibition with prasugrel compared with double dose clopidogrel. Again whether this would lead to better clinical outcomes has not been studied.

While prasugrel at a loading dose of 60 mg and a maintenance dose of 10 mg is FDA approved, the 600 mg loading dose and 150 mg dose per day for the first week in CURRENT is not FDA approved at this time. This double dose dose clopidogrel regimen is, however, mentioned in the ACC / AHA and ESC guidelines.

PowerPoint Presentation
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