Aspirin and Clopidogrel in Patients with ACS Undergoing PCI: CURE and PCI-CURE

Design and protocol of CURE. CURE is a large trial involving 12,562 patients with non-ST elevation acute coronary syndrome with either positive biomarkers myocardial injury or new ECG changes.¹ The trial thus involves at least a moderate-risk group of patients. These patients were randomized to receive either an immediate loading dose of 300 mg of clopidogrel, administered in the emergency room as soon as the diagnosis was made, followed by 75 mg/day for up to one year, or they were randomized to matching placebo. The trial was double-blind, and the study personnel, investigators, and patients had no knowledge of treatment allocation. With a very large sample size of 12,562 patients, the CURE trial has not only substantial power to answer the primary study questions, but also has power to explore important, pre-specified subgroup analyses. The primary endpoint of the CURE study is the composite of myocardial infarction, stroke, and cardiovascular death from the time of randomization until one-year follow-up.¹ The co-primary outcome was the above, plus refractory ischemia. The safety outcome was life-threatening and major bleeding. Primary results of CURE. The primary outcome of CURE was highly statistically and clinically significant. The time to event curves separate very early and continue to diverge all the way out until twelve months. Overall, there was a 20% relative risk reduction in the triple outcome of myocardial infarction, stroke, or cardiovascular death, which was highly statistically significant. Within this composite, the most pronounced benefit was observed in the reduction of myocardial infarctions, with the largest reductions (40%) in the Q-wave or ST-elevation myocardial infarctions — also highly statistically significant. Tracking with the reduction in large myocardial infarction was a 43% reduction in the use of thrombolytic therapy after randomization and an 18% reduction in new, radiologically confirmed heart failure, also significant. Thus, the reduction in myocardial infarctions in the CURE trial were not small enzyme increases, rather, they were large myocardial infarctions, which were clinically very relevant. Many of these myocardial infarctions required thrombolytic therapy and resulted in new onset, radiologically confirmed heart failure. Both of these latter endpoints were also reduced with the use of clopidogrel. Early benefit. The benefit began to emerge very early in the CURE study (Figure 1). Within two hours after administration of the 300 mg loading dose of clopidogrel, the time to event curves separate. By 24 hours post-randomization, there is already a one-third reduction in the composite of cardiovascular death, myocardial infarction, stroke, or severe ischemia, which is highly statistically significant. Thus, the effects of a 300 mg loading dose of clopidogrel appears to be very rapid. This observation is consistent with what is observed in vitro in terms of platelet inhibition with clopidogrel. Approximately six hours after administration of the 300 mg loading dose of clopidogrel, nearly the maximal platelet inhibition possible with this agent is achieved. Late benefit. From > 30 days to one year after randomization, there was an additional 20% relative risk reduction, which again is highly significant (Figure 2). Thus, there were clear benefits with the use of clopidogrel long-term, which is in addition to the early benefit observed. Our group currently has a manuscript in review with Circulation and some of these data will be presented in further detail at the 2002 AHA meeting. U.S. cohort of CURE patients. The U.S. patients enrolled in the CURE study did just as well as non-U.S. patients. The overall CURE population showed a 20% relative risk reduction for the primary outcome, while the U.S. cohort of CURE patients had a consistent 22% relative risk reduction. There was no significant interaction between the overall population and the patients in the U.S. cohort. Thus, U.S. patients experienced a similar benefit with clopidogrel compared with the overall cohort of CURE patients. TIMI risk score. While most antithrombotic agents have shown benefit primarily in moderate- and high-risk patients, some new data show the effects of clopidogrel in low-, moderate-, and high-risk patients according to the TIMI risk score.² The TIMI risk score was a good predictor of events in the CURE trial, once again validating the usefulness of this score. The event rates in the low-risk to high-risk groups in the placebo arm range from 5.7% to 11.4% to 20.7%. When the treatment effect of clopidogrel was examined in each of these time periods, significant and consistent reductions occurred at all three levels of risk. Interestingly, the highest risk patients had the greatest absolute reduction (approximately 5%) in major events (myocardial infarction, stroke, and cardiovascular death). Thus, clopidogrel is effective in low-, moderate-, and high-risk patients (Figure 3). Benefit-risk ratio. In the early phase of clopidogrel treatment ( 30 days to one year), there were only 10 cardiovascular death, myocardial infarction, or stroke events prevented per 1,000 patients — again, a statistically significant figure. There was only one additional life-threatening bleed per 1,000 patients. Thus, the benefit-risk profile of clopidogrel, both in the acute and long-term settings, is highly favorable for the use of clopidogrel (Figure 4). Revascularization. The CURE trial was the single largest experience in the world in terms of number and proportion of patients undergoing revascularization for acute coronary syndrome. More than 4,500 interventions were performed in the CURE trial, with 2,662 percutaneous coronary interventions (21% of procedures). As a comparison, the PURSUIT trial had 2,253 PCIs (24% of procedures); GUSTO IV had 1,509 PCIs (19%); PRISM had 698 PCIs (21%); and PRISM-PLUS had 475 PCI procedures (69%). PCI-CURE substudy. PCI-CURE was a prospectively designed substudy of patients undergoing PCI In the CURE trial.³ In this study, the treatments (clopidogrel or placebo) were randomized and the decision to perform PCI was left to the discretion of the investigator. The PCI-CURE study data, from the time of randomization to one year, show a large relative risk reduction of 31% in the double endpoint of cardiovascular death or myocardial infarction, which is highly statistically significant.⁴ The time to event curves separated very early and continued to diverge all the way out to one year. Even prior to PCI, there was a 32% reduction in major events in this trial. Then from the time of PCI to 30 days after the procedure, there was an additional 34% reduction. From 30 days after PCI to the end of follow-up, there was a consistent 21% reduction in cardiovascular death and myocardial infarction. The primary reduction again occurred in large Q-wave myocardial infarctions. Small peri-procedural enzymes rises were not measured after the study. In the period of > 30 days after PCI to the end of the study, there was a significant 14% reduction in cardiovascular death, myocardial infarction, and re-hospitalization. Thus, clopidogrel pretreatment was clearly beneficial and should be standard therapy for all patients undergoing PCI. The continuation of clopidogrel long-term, for up to one year, resulted in incremental benefits. Thus, PCI-CURE is the first study to demonstrate that ACS patients undergoing PCI will derive substantial benefit from long-term treatment with clopidogrel (Figures 5 and 6). Bleeding outcomes in CURE. Bleeding in clinical trials is dependent upon the definition used, thus standardized definitions are important. The TIMI criteria for bleeding are used in many acute coronary syndrome trials. As we reported in The New England Journal of Medicine,¹ if the TIMI bleeding criteria are applied to the CURE trial, there is no apparent excess bleeding. The CURE major bleeding criteria are actually much broader: only two units of blood transfusion qualified as major bleeding (Figure 7). Bleeding that the investigator considered the cause of a severe disability also qualified as major bleeding in the CURE trial. Thus, these criteria were not as conservative as those defined in other trials. Applying this definition, an increase in the relative risk of bleeding of 1.38 (statistically significant) was observed. This increased bleeding appeared to be largely influenced by the dose of aspirin (Figure 8). The CURE data looked at three different doses of aspirin: 200 mg. In the placebo group, there was a dose-dependent increase in bleeding with aspirin from 1.9% up to 3.4% at the highest level. A similar pattern was observed for clopidogrel, which started at 3% and ended at 4.5%. Interestingly, if low-dose aspirin plus clopidogrel was used, the bleeding risk was 3% versus high-dose aspirin alone (325 mg), which was 3.7%. There was no significant increase in life-threatening bleeding in the CURE study (1.8% to 2.2%).¹ Fatal bleeding rates in the trial were identical between the placebo and clopidogrel groups (0.2%), as were a 5 g/dL drop in hemoglobin (0.9%); hypotension requiring inotropic therapy (0.5%); surgical intervention or re-operation (0.7%); and hemorrhagic stroke (0.1%). The only apparent difference in life-threatening bleeding rates occurred in the category of > 4 blood transfusion units between the placebo and clopidogrel groups, but the numbers are very small. In terms of major and life-threatening bleeding rates in patients undergoing CABG surgery, there was no significant increase in major or life-threatening bleeding overall. The majority of patients actually had aspirin and study drug stopped at some point prior to surgery. The data can be divided into those patients who stopped medication 5 days prior to CABG. Five days is the approximate biological half-life of clopidogrel. If study drug was stopped > 5 days prior to CABG, there was no excess in major bleeding. However, if aspirin was continued to within 5 days of surgery, there was a relative risk increase of 1.53 (p-value of 0.06). If the TIMI definition of bleeding had been used in this evaluation, there again would have been no apparent increase in bleeding with clopidogrel versus placebo. Benefit of clopidogrel for CABG patients. The other side of the question is whether patients who underwent CABG derived any benefit from clopidogrel therapy. Professor Fox presented data at the recent ESC meeting showing that, in fact, there was a consistent 22% reduction in cardiovascular death, myocardial infarction, and stroke with the use of clopidogrel versus placebo in patients who underwent CABG surgery during the initial hospitalization (Figure 9). This is entirely consistent with those patients who did not undergo CABG surgery. Thus, even if the patient underwent early CABG surgery in the trial, there was still a relative 22% benefit with clopidogrel (Figure 10). Invasive strategy. One question that arises relates to the issue of holding clopidogrel treatment for a few days if catheterization reveals surgical disease. This is usually not a major issue. In fact, the invasive strategy group in the TACTICS-TIMI 18 study waited for a median of 5.8 days prior to surgery (in the U.S., that number was 5.5 days). Thus, even in a protocol-mandated invasive strategy, in the context of a randomized trial, there were still delays to CABG. In the real world, the delays are likely to be longer. TACTICS-TIMI 18 data and CURE bleeding rates. In the TACTICS-TIMI 18 trial, 3.6% of patients in the invasive arm underwent CABG (36/1,000 patients). In the CURE study, there was an incidence of 2.8 life-threatening bleeds per 100 patients post-CABG surgery with clopidogrel. Thus, 2.8% of 36 per 1,000 actually works out to only one extra bleed per 1,000 acute coronary syndrome patients treated with an invasive strategy. The benefit-risk ratio of clopidogrel in patients undergoing CABG is thus about 22 fewer deaths, myocardial infarctions, and strokes, versus 1 in 1,000 life-threatening bleeds with clopidogrel. Clearly, the benefits of clopidogrel far outweigh the associated risks, even when an invasive strategy is used. ACC/AHA guideline recommendations. The Class 1 recommendations for antiplatelet therapy in patients with acute coronary syndromes undergoing PCI take into account the benefits of clopidogrel demonstrated in CURE and PCI-CURE. Prior to PCI, the recommendation calls for aspirin, clopidogrel, and heparin, as well as a GP IIb/IIIa antagonist for moderate- to high-risk patients. During PCI, the guidelines recommend aspirin, clopidogrel, and heparin, as well as an intravenous GP IIb/IIIa antagonist. After PCI, the guidelines recommend the double combination of aspirin and clopidogrel for a nine-month period — because this was the mean duration of therapy in the trial.⁸ The longest duration of treatment in CURE was out to one year. It is biologically plausible that there are benefits of chronic clopidogrel therapy well beyond this point. DISCUSSION Stephen Ellis: Can you give us the PCI-CURE data stratified by IIb/IIIa use versus no GP IIb/IIIa use? Shamir Mehta: Yes. Both the placebo and the clopidogrel groups showed identical bleeding rates of 2.2%. No excess in bleeding was observed in patients who received clopidogrel compared with placebo on a background of GP IIb/IIIa antagonist use. Elliot Rapaport: These data are very impressive. As I understood it, among all of the secondary outcomes, there was no benefit of rehospitalization for unstable angina. Do you think that it is due to the play of chance, or do you have another explanation for this? Also, in today’s practice, GP IIb/IIIa inhibitors are so often used — not just in the PCI environment, but also in the high-risk and even moderate-risk patients who do not go to the catheterization laboratory. What is your judgment on the role of clopidogrel under those circumstances, since so very few of the CURE patients actually received a GP IIb/IIIa inhibitor? Shamir Mehta: Yes, that is true. Approximately 25% of the CURE patients underwent an interventional procedure. As for your first question, we don’t know why there was no impact of clopidogrel on re-hospitalization for unstable angina — it’s a very soft endpoint. It may be related to the fact that some of those cases were actually myocardial infarctions, since patients who presented with recurrent ischemia serious enough to admit to the hospital, often have a troponin rise and thus may have met the new ACC/AHA guidelines definition for myocardial infarction. If the marker or enzyme rise was greater than two times the upper limit of normal, it would have met the definition of myocardial infarction. That may have been the reason, but I can’t say for certain. The trial data showed that patients who did not undergo revascularization after randomization derived a 20% risk reduction benefit with clopidogrel — a highly significant figure in and of itself. Thus, the addition of clopidogrel definitely should be standard therapy in patients not undergoing revascularization. If the patient is at moderate to high risk, one should consider adding an intravenous GP IIb/IIIa inhibitor on top of that. Elliot Rapaport: Is your recommendation based on any data? Shamir Mehta: There are no large randomized studies using quadruple therapy (aspirin, clopidogrel, intravenous GP IIb/IIIa inhibitor, heparin). The TOPSTAR study did show a benefit of quadruple therapy, however, the study was quite small. Nevertheless, quadruple therapy has a clear biological rationale and is an ACC/AHA Class IIa recommendation for management of non-ST elevation ACS. In the PCI setting, retrospective data from the TARGET study and from the work that Steve has done in the EPISTENT trial show an incremental benefit to adding a thienopyridine on to a GP IIb/IIIa antagonist, at least for patients undergoing intervention. Steve Steinhubl: Tomorrow afternoon we will see the prospective data from CREDO involving 1,000 patients who received GP IIb/IIIa agents with or without clopidogrel pre-treatment. Chris Cannon: We are slightly hampered by the fact that this evening’s round table discussion is taking place the day before the CREDO results are being presented!