1. lopidogrel in nstable Angina to Prevent ecurrent vents
CURE or the Clopidogrel in Unstable angina to prevent Recurrent Events was a Phase III double-blind clinical trial designed to evaluate the early and long term efficacy and safety of clopidogrel versus placebo, both in addition to aspirin and other standard therapy in patients with acute coronary syndrome without ST-segment elevation (unstable angina or non–ST-segment elevation MI (NSTEMI) also known as non-Q-wave MI).

2. Disclaimer
This slide kit presents new data to support the rationale for the use of ADP receptor antagonists for approved and unapproved indications.
The slide kit has been prepared for medical and scientific purposes. It contains information on a use that is not approved by the FDA and should not be construed as an inducement to use clopidogrel for unapproved indications. Neither Sanofi-Synthelabo Inc., Bristol-Myers Squibb nor the partnership recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.
Disclaimer
This slide kit presents new data to support the rationale for the use of ADP receptor antagonists for approved and unapproved indications.
The slide kit has been prepared for medical and scientific purposes. It contains information on a use that is not approved by the FDA and should not be construed as an inducement to use clopidogrel in unapproved indications. Neither Sanofi-Synthelabo Inc., Bristol- Myers Squibb nor the partnership recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.

3. Rationale
Despite treatment with aspirin and heparin, the incidence of MI and CV death during hospitalization remains high, 6-8%
Long term, the incidence of these events remain high at 6-8% per year
The majority of patients (80%) who enter the hospital with acute coronary syndrome (ACS) are already on aspirin therapy
The negative findings of the oral GP IIb/IIIa’s underscores the need for alternative strategies to treat ACS
Despite treatment with aspirin and intravenous heparin, the incidence of another myocardial infarction and cardiovascular death remains substantial at 6-8% during the acute phase of hospitalization in patients with acute coronary syndrome (ACS).
In addition, the incidence of these events continues to remain high during long-term follow-up, at 6-8% per year over at least the next 2 years.
Furthermore, a large number of patients, up to 80%, who enter the hospital with ACS are already receiving aspirin therapy.
The negative findings of the oral GP IIb/IIIa receptor antagonists underscores the need to develop alternative strategies to reduce both the early and late ischemic events in patients with ACS.
CURE Study Investigators. Eur Heart J. 2000;21:
PURSUIT Investigators. Am J Cardiol. 1999;83:

4. Study Objectives Primary
Evaluate the early and long-term efficacy of clopidogrel vs placebo, both given in addition to aspirin and other standard therapy in preventing ischemic complications in patients with ACS without ST-segment elevation (unstable angina or non-ST-segment elevation MI)
Secondary
Evaluate the safety of clopidogrel in combination with ASA therapy in patients with ACS
The primary objective of this trial was to evaluate the early and long term efficacy of clopidogrel vs placebo, both given in addition to aspirin and other standard therapy in preventing ischemic complications in patients with ACS without ST-segment elevation (unstable angina and non-ST elevation myocardial infarction).
The secondary objective of this study was to evaluate the safety of clopidogrel in combination with ASA therapy in patients with ACS.
CURE Study Investigators. Eur Heart J. 2000; 21:

5. Study Design R 3 months £ double-blind treatment £ 12 months
Clopidogrel 300 mg loading dose
Clopidogrel 75mg q.d. + ASA mg q.d.*
(6259 patients)
Patients with
Acute Coronary Syndrome R
3 months £ double-blind treatment £ 12 months
(unstable angina or
non-ST-segment elevation MI)
Placebo + ASA mg q.d.*
(6303 patients)
Patients were eligible for CURE if they were admitted to the hospital within 24 hours of an episode of chest pain suggestive of unstable angina or non–ST-segment elevation MI. The average time between onset of pain and admission was 14 hours.
Patients were randomized to one of two treatment arms: either clopidogrel (300 mg loading dose followed by 75 mg/day) or placebo, both in addition to aspirin ( mg/day) and other standard therapy.
Medications at time of randomization may include heparin or low–molecular weight heparin, beta-blockers, ACE inhibitors, lipid-lowering agents, calcium channel blockers, and/or other therapies or interventions (PTCA, CABG) at physician’s discretion.
Treatment duration was for up to 1 year. The average duration of treatment was 9 months.
Follow-up assessments were conducted at 1 and 3 months for all patients and at 6, 9 and 12 months for patients randomized early in the study.
Day 1
1 m. Visit
3 m. Visit
6 m. Visit
9 m. Visit
12 m. or Final Visit
Discharge Visit
Placebo loading dose
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R = Randomization * In combination with other standard therapy

6. Key Inclusion Criteria
Age ³ 21 years1
Suspected UA or NSTEMI (no ST  ³ 1.0 mm)2
Presentation £ 24 hours after onset of symptoms2
ECG changes compatible with ischemia or elevated cardiac enzymes or troponin I or T ³ 2 x ULN2
Patients at least 21 years of age were eligible for the CURE trial if they presented to the hospital with chest pain suggestive of acute coronary syndrome without ST-segment elevation greater than 1 mm within 24 hours on onset.
Patients must also have had ECG evidence of new ischemia or had an elevation in cardiac enzymes (CK-MB) or troponin I or T at least twice the upper limit of normal.
1 CURE Study Protocol (Data on file, Sanofi-Synthelabo, Inc.)
2 CURE Study Investigators. Eur Heart J. 2000; 21:

7. Key Exclusion Criteria
NYHA Class IV heart failure1
Uncontrolled hypertension2
Current use of anticoagulants1, clopidogrel, ticlopidine, or NSAIDS2, or GP IIb/IIIa inhibitor within 3 days1
PCI or CABG within 3 months1
History of severe thrombocytopenia or neutropenia2
At high risk for bleeding1
Contraindications to antithrombotic or antiplatelet therapy1
Patients were excluded from the CURE trial if they had any of the above conditions.
1 CURE Study Investigators. Eur Heart J. 2000; 21:
2 CURE Study Protocol (Data on file, Sanofi-Synthelabo, Inc.)

8. Outcome Definitions MI: Stroke: CV Death: Refractory Ischemia:
At least two of the following criteria: chest pain, ECG changes, elevation of cardiac markers or enzymes (Troponin, CK, CK-MB)
Stroke:
Neurological deficit ³ 24 hrs (CT/MRI encouraged)
CV Death:
Excludes any death for which there was no clearly documented non-CV cause
Refractory Ischemia:
In-hosp: recurrent ischemia on max med Rx + ECG changes + intervention £ 1 day
After discharge: Rehosp for UA with ECG changes
Severe Ischemia:
Changes similar to in-hospital refractory ischemia, but no intervention
Recurrent Angina:
All other ischemic chest pain in hospital
MI was defined as presence of at least two of the following criteria: (1) ischemic chest pain, (2) elevation of cardiac markers to at least twice the upper limit of normal and (3) ECG changes compatible with infarction.
Stroke was defined as new focal neurologic deficit of vascular origin; lasting > 24 hours. Stroke was further classified as due to intracranial hemorrhage, ischemia, or of uncertain origin
Cardiovascular death included all deaths for which there was no clearly documented non- vascular cause (eg, car accident).
Refractory ischemia was defined in two ways:
Refractory ischemia in hospital was defined as recurrent chest pain lasting more than 5 minutes with new ECG changes indicative of myocardial ischemia while on optimal medical therapy (2 antianginal medications, one of which was IV nitrates unless contraindicated) and leading to additional intervention (thrombolytics, cardiac catheterization, insertion of intra-aortic balloon pump, revascularization or transfer to a referral hospital for an invasive procedure) by midnight of the next calendar day.
Refractory ischemia after discharge was defined as rehospitalization lasting > 24 hours for unstable angina with ECG changes consistent with ischemia.
Severe ischemia was defined as similar to in-hospital refractory ischemia, but for which no urgent intervention was performed.
Recurrent angina was also defined as in-hospital refractory ischemia, without the ECG changes.
The CURE Trial Investigators. N Engl J Med. 2001;345:

9. Efficacy Analyses
First Primary End Point First occurrence of any component of the cluster of:
Myocardial Infarction
Stroke (ischemic, hemorrhagic, or of uncertain type)
Cardiovascular death
Second Primary End Point First occurrence of any component of the cluster of:
Refractory ischemia
The primary analysis was based on intention-to-treat population and captured the occurrence of the first ischemic event.
The primary end point of CURE was the composite of MI, stroke or cardiovascular death.
MI was defined as presence of at least two of the following criteria: (1) ischemic chest pain, (2) elevation of cardiac markers to at least twice the upper limit of normal, and (3) ECG changes compatible with infarction
Stroke was defined as new focal neurologic deficit of vascular origin; lasting > 24 hours. Stroke was further classified as due to intracranial hemorrhage, ischemia, or uncertain
Cardiovascular death included all deaths for which there was no clearly documented non-vascular cause
The second primary end point was the above plus refractory ischemia.
Refractory ischemia was defined in two ways:
Refractory ischemia in hospital was defined as recurrent chest pain lasting more than 5 minutes with new ECG changes indicative of myocardial ischemia while on optimal medical therapy (2 antianginal medications, one of which was IV nitrates unless contraindicated) and leading to additional intervention (thrombolytics, cardiac catheterization, insertion of intra-aortic balloon pump , revascularization or transfer to a referral hospital for an invasive procedure) by midnight the next calendar day.
Refractory ischemia after discharge was defined as rehospitalization lasting > 24 hours for unstable angina with ECG changes consistent with ischemia.
The CURE Trial Investigators. N Engl J Med. 2001;345:

10. Baseline Characteristics
Placebo
N = 6303
Clopidogrel
N = 6259
Age (mean)
Mean time from pain onset to randomization (hrs)
Mean heart rate (beats/min)
Mean systolic BP (mm Hg)
Female (%)
Diagnosis at Entry
Unstable Angina (%)
Non–ST-segment elevation MI (%)
ECG abnormalities (%)
NEJM
The baseline patient characteristics, seen above, were comparable between the two treatment groups. Approximately 38% were female and the mean age was 64 years. Seventy-five percent had unstable angina, while 25% had an acute MI without ST-segment elevation. Approximately 94% of patients had ECG abnormalities.
The CURE Trial Investigators. N Engl J Med. 2001;345:

11. Patient History Placebo N = 6303 (%) Clopidogrel N = 6259 (%)
History of MI
CABG Surgery/PTCA
Stroke
Heart Failure
Hypertension
Diabetes
Current or former smoker
NEJM
The two groups had similar patient histories. Thirty-two percent had a previous MI,18% had either CABG or PTCA, 4% had a previous stroke, and approximately 7% had heart failure. Note that 22% of the total population had diabetes.
The CURE Trial Investigators. N Engl J Med. 2001;345:

12. ECG Abnormality Type Placebo (%) Clopidogrel (%)
History Abnormal ECG
ST-segment Dep > 1 mm
ST-segment elevation < 1 mm
Major T-wave inversion
Other T-wave inversion
Other abnormalities
NEJM
Nearly 94% of patients had an abnormal ECG at study entry, with ST-segment depression  1 mm being the most common abnormality. Overall, the baseline demographic data indicate that this is at least an intermediate risk group of patients with unstable angina or non–ST-segment elevation MI.
The CURE Trial Investigators. N Engl J Med. 2001;345:

13. Primary End Point - MI/Stroke/CV Death
11.4%
Placebo + ASA*
9.3%
Clopidogrel + ASA*
Clopidogrel provided a 20% relative risk reduction in the composite outcome of MI, stroke or CV death (95% CI , P < 0.001). Overall there were 719 (11.4%) first events in the placebo group and 582 (9.3%) in the clopidogrel group. The hazard rate curves began to separate within the first few hours after therapy initiation and continued to diverge over the remainder of the trial.
20% RRR
P < 0.001
N = 12,562 3 6 9 12
Months of Follow-Up
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:

14. MI/Stroke/CV Death within 30 Days
Placebo + ASA*
Clopidogrel + ASA*
Clopidogrel provided a 21% relative risk reduction in the primary end point of MI, stroke or CV death within 30 days (95% CI , P = 0.003). Beneficial effects were reported within a few hours, with the rate of cardiovascular death, nonfatal stroke, or refractory or severe ischemia significantly reduced by 24 hours in the clopidogrel treated group vs the placebo group (1.4% vs 2.1%, RRR 34% 95% CI of 0.51 to 0.86).
21% RRR
P = 0.003
N = 12,562 10 20 30
Days of Follow-Up
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:

15. Main Efficacy Results - Primary Endpoint
Placebo + ASA* N = 6303
Clopidogrel + ASA* N = 6259
Relative Risk Reduction
Outcome
P value
CV death, MI, stroke (Primary 11.4% 9.3% 20% < end point)
MI 6.7% 5.2% 23%
Stroke 1.4% 1.2% 14%
CV death 5.5% 5.1% 7%
NEJM
Clopidogrel in addition to aspirin provided a 20% relative risk reduction in the composite end point of CV death, MI, and stroke (11.4% vs 9.3%, 95% CI , P < 0.001).
Each component of the composite outcome was reduced with the greatest benefit seen in the MI outcome (RRR 23%). There was also a 14% relative risk reduction in strokes and a 7% relative risk reduction in cardiovascular death.
TO BE RESOLVED
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:

16. Main Efficacy Results - Second Primary End Point
Placebo + ASA*
Clopidogrel + ASA*
RRR
P value
Second Primary End Point 18.8% 16.5% 14% < 0.001
Refractory Ischemia 9.3% 8.7% 7% NS**
Refractory Ischemia in hospital 2.0% 1.4% 32% P < 0.001
Refractory Ischemia after discharge 7.6% 7.6% 1% NS**
Severe Ischemia 3.8% 2.8% 26% P = 0.003
Recurrent Ischemia 22.9% 20.9% 9% P = 0.01
Heart Failure† 4.4% 3.7% 18% P = 0.03
NEJM
This slide summarizes the other efficacy results. The addition of clopidogrel significantly reduced the second primary end point of MI, stroke, cardiovascular death or refractory ischemia (16.5% vs 18.8%, RR 0.86, 95% CI , P < 0.001). Clopidogrel also provided a 32% relative risk reduction of in hospital refractory ischemia. The addition of clopidogrel reduced the risk of severe ischemia during the initial hospital visit by 26% (2.8% vs 3.8%, P = 0.003), and the risk of heart failure based on radiologic evidence during the initial hospital stay by 18% (3.7% vs 4.4%, P = 0.03).
* In combination with standard therapy ** Not significant † Heart failure was a secondary end point
The CURE Trial Investigators. N Engl J Med. 2001;345:

17. Beneficial Outcomes with Clopidogrel in Various Subgroups
Percentage of Patients with Event
No. of Patients
Clopidogrel + ASA*
Placebo + ASA*
Characteristic
Overall
Associated MI No associated MI
Male sex Female sex
£65 yr old > 65 yr old
ST-segment deviation No ST-segment deviation
Enzymes elevated at entry Enzymes not elevated at entry
Diabetes No diabetes
Low risk Intermediate risk High risk
History of revascularization No history of revascularization
Revascularization after randomization No revascularization after randomization
There were over 30 subgroup analyses conducted which were remarkably consistent in showing the benefit of clopidogrel plus aspirin. This next slide summarizes some of those results. Note five of the key subgroup analyses:
1. Patients with or without an associated MI,
2. Patients with or without elevation of enzymes,
3. Patients with or without type 2 diabetes,
4. Patients at low, intermediate or high risk,
5. Patients with or without a history of a revascularization.
Although the study was not powered to look at individual subgroups, there was a beneficial trend seen across all subgroups analyzed.
A total of 2838 patients with diabetes were enrolled into the CURE trial. In this subgroup of patients, there was nearly a twofold increase in event rates. The addition of clopidogrel to standard therapy, including aspirin, resulted in a 17% relative risk reduction, a benefit consistent with the primary end point.
0.4
0.6
0.8
1.0
1.2
Clopidogrel Better
Placebo Better
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:
Relative Risk (95% CI)

18. Thrombolytic and IV GP IIb/IIIa Inhibitor Use After Randomization
Placebo + ASA* N = 6303
Clopidogrel + ASA* N = 6259
Relative Risk Reduction CI
P value
Thrombolytics 2.0% 1.1% 43% < 0.001
IV GP IIb/IIIa Inhib 7.2% 5.9% 18%
NEJM
The clopidogrel group reported a 43% relative risk reduction of thrombolytic use (1.1% vs 2.0%, P < 0.001) and a 18% relative risk reduction in the use of IV GP IIb/IIIa inhibitors (5.9% vs 7.2%, P = 0.003)
* As part of standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:

19. Definition of Bleeding
Bleeding was defined as “Major” and “Minor”
Major bleeding was defined as follows:
life threatening: fatal, symptomatic intracranial hemorrhage, leading to a drop in hemoglobin of at least 5 g/dL, significant hypotention requiring IV inotropes, requiring surgical intervention, or requiring transfusion of 4 or more units of blood
non-life-threatening: substantially disabling, intraocular bleeding leading to vision loss, or requiring at least 2 units of blood
Minor
any other bleeds that led to interruption of study medication
Bleeding was divided into Major and Minor Bleeding.
Major bleeding was further subdivided into life-threatening bleeds and non–life threatening bleeds.
Life threatening was defined as fatal or leading to a drop in hemoglobin of at least 5 g/dL, significant hypotension requiring IV inotropes, surgical intervention, symptomatic intracranial hemorrhage or transfusion of 4 or more units of blood.
Non–life-threatening was defined as disabling, intraocular leading to vision loss or requiring at least 2 units of blood.
Minor bleeds were any other bleed that led to interruption of study medication.
The definition of bleeding was conservatively defined in the CURE trial.
The CURE Trial Investigators. N Engl J Med. 2001;345:

20. Bleeding Results Placebo + ASA* N = 6303 Clopidogrel + ASA* N = 6259
End Point
Major bleeding 2.7% 3.7%**
Life-threatening bleeding 1.8% 2.2% †
Non-life-threatening bleeding 0.9% 1.5% ‡
Minor bleeding 2.4% 5.1% §
NEJM
There was a significant difference in major and minor bleeding between the clopidogrel and aspirin group compared to the aspirin group alone. However, there was no statistically significant difference in life-threatening bleeding between the two treatment arms, which included fatal bleeding, drop in hemoglobin of at least 5 g/dL, significant hypotension requiring IV inotropes, bleeds requiring surgical interventions, intracranial hemorrhage, or transfusion of 4 or more units of blood.
Major bleeds were increased both early (< 30 days) and late (> 30 days). The principal sites for major bleeding included gastrointestinal and at arterial puncture sites.
There was a statistically significant difference in minor bleeding in the clopidogrel plus aspirin group (2.4% vs 5.1%, P < 0.001).
The number of patients receiving transfusions of 2 or more units of blood was higher in the clopidogrel plus aspirin group (2.8% vs 2.2%, P = 0.02).
Overall, there was no significant excess in major bleeds after coronary bypass graft surgery with clopidogrel plus aspirin vs aspirin. However, in most patients scheduled for CABG, study medication were discontinued prior to procedure (median time of stopping before procedure was 5 days).
* In combination with standard therapy
** P = 0.001; † P = NS; ‡ P = 0.002; § P <
The CURE Trial Investigators. N Engl J Med. 2001;345:

21. Life-Threatening Bleeding
Placebo + ASA* N = 6303
(%)
Clopidogrel + ASA* N = 6259
(%)
Life-Threatening
Fatal
5 g/dL drop hemoglobin
Hypotension-inotropic therapy
Surgery required
Hemorrhagic stroke
 4 Blood units
NEJM
There was no significant difference between the two treatment arms in life-threatening bleeds, which included fatal bleeding, drops in hemoglobin of 5 g/dL or more, bleeds requiring inotropic therapy surgical interventions, intracranial hemorrhage or a transfusion of 4 or more units of blood (P = 0.13).
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:

22. Major Bleeding in IV GP IIb/IIIa Antagonists ACS Trials vs CURE: within 30 Days
Placebo*
Active*
Diff
CURE: % 2.0% +0.5%
IV GP IIb/ IIIa Trials:
PRISM-PLUS % 1.4% +0.6%
PURSUIT % 10.6% +1.5%
excluding CABG 1.3% 3.0% +1.7%
CAPTURE % 3.8% +1.9%
NEJM
The bleeding rate seen in CURE was comparable to that seen with the IV GP IIb/IIIa inhibitor clinical trials. The above data for the IV GP IIb/IIIa inhibitor trials are a summary of the 30-day results based on the TIMI definition, which is less conservative than the CURE definition.
Due to differences in study design, direct comparisons of bleeding rates for the study drugs cannot be made.
TIMI Definition of major bleeding: Severe or life-threatening bleeding was defined as Intracranial hemorrhage or bleeding associated with severe hemodynamic compromise.
Major bleeding was defined as that which was associated with >15% absolute reduction in hematocrit or requiring a blood transfusion
CURE Definition of major bleeding: Life-threatening bleeding which was defined as fatal or leading to one of the following intracranial hemmorhage, drop in hemoglobin of  5 g/dL, substantial hypotension requiring inotropic therapy, surgical intervention, or transfusion of 4 or more units of blood.
Non-life threatening bleeding was defined as substantially disabling bleeding, intraocular bleeding leading to the loss of vision or bleeding necessitating the transfusion of at least 2 units of blood.
The CURE Trial Investigators. N Engl J Med. 2001;345:
* In addition to standard therapy including aspirin and heparin
PRISM-PLUS Investigators. N Engl J Med. 1998;338: PURSUIT Investigators. N Engl J Med. 1998;339: CAPTURE Investigators. Lancet. 1997;349 (9063):

23. Conclusions
In the CURE study of 12,562 patients with ACS without ST-segment elevation:
clopidogrel demonstrated a 20% relative risk reduction in MI, stroke or cardiovascular death with long-term use† (P <0.001)
the Kaplan-Meier curves began to diverge within hours and continued to diverge over the course of 12 months
clopidogrel also demonstrated a 14% relative risk reduction in MI, stroke, cardiovascular death or refractory ischemia (P <0.001)
Clopidogrel in addition to aspirin and other standard therapy demonstrated an early effect (within hours) and sustained long-term benefit throughout the entire study period of 12 months
Clopidogrel in addition to aspirin and other standard therapy provided a 20% risk reduction in the composite outcome of MI, stroke and cardiovascular death (P < ). This reduction was seen as early as a few hours and continued over the course of 12 months.
The clopidogrel group also provided a 14% relative risk reduction in the second primary endpoint of MI, stroke, CV death or refractory ischemia (P<0.001).
The beneficial outcome was incremental and independent of other acute or long- term therapies (ACE Inhibitors, lipid-lowering agents, IV GP IIb/IIIa inhibitors) or interventions. The beneficial outcome seen with clopidogrel was consistent across different patient subgroups, including patients with diabetes.
Minor bleeding was increased but there was no increase in life-threatening bleeds.
There was a significant decrease in the incidence of heart failure by 18%, P=0.03.
The use of thrombolytics was reduced by 43%,( P < 0.001), and the use of IV GP IIb/IIIa inhibitors decreased by 18% (P < 0.006) in the clopidogrel plus aspirin group.
*cardiovascular death, MI and stroke
†up to 12 months
† Up to 12 months
The CURE Trial Investigators. N Engl J Med. 2001;345:

24. Conclusions
Minor bleeding was increased, but there was no increase in life-threatening bleeds (including intracranial bleeds)
18% Relative Risk Reduction in heart failure (P = 0.03)
Significant reductions in the reported use of:
IV GP IIb/IIIa inhibitor: 18% (P = 0.003)
thrombolytics: 43% (P < 0.001)
Clopidogrel in addition to aspirin and other standard therapy provided a 20% risk reduction in the composite outcome of MI, stroke and cardiovascular death (P < 0.001). This reduction was seen as early as a few hours and continued over the course of 12 months.
The clopidogrel group also provided a 14% relative risk reduction in the second primary endpoint of MI, stroke, CV death or refractory ischemia (P < 0.001).
The beneficial outcome was incremental and independent of other acute or long-term therapies (ACE Inhibitors, lipid-lowering agents, IV GP IIb/IIIa inhibitors) or interventions. The beneficial outcome seen with clopidogrel was consistent across different patient subgroups, including patients with diabetes.
Minor bleeding was increased but there was no increase in life-threatening bleeds.
There was a significant decrease in the incidence of heart failure by 18%, P = 0.03.
The use of thrombolytics was reduced by 43%,( P < 0.001), and the use of IV GP IIb/IIIa inhibitors decreased by 18% (P < 0.006) in the clopidogrel plus aspirin group.
The CURE Trial Investigators. N Engl J Med. 2001;345:

25. PCI-CURE
Design
Prospectively designed study of patients undergoing PCI who were randomized to double-blind therapy with clopidogrel or placebo, both in addition to aspirin and other standard therapy in the CURE trial
Objectives
to test the hypothesis that pre-treatment with clopidogrel in addition to aspirin and other standard therapy would be more effective than aspirin and standard therapy alone in preventing major ischemic events within the first 30 days after PCI
to determine if long-term treatment (up to 1 year) with clopidogrel in addition to aspirin and other standard therapy after PCI would provide additional clinical benefit
Prospectively designed study of patients undergoing PCI who were randomized to double-blind therapy with clopidogrel or placebo, both in addition to aspirin and other standard therapy in the CURE trial.
Objectives:
to test the hypothesis that pre-treatment with clopidogrel in addition to aspirin and other standard therapy would be more effective than aspirin and standard therapy alone in preventing major ischemic events within the first 30 days after PCI
to determine if long-term treatment (up to 1 year) with clopidogrel after PCI would provide additional clinical benefit.
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:

26. PCI-CURE
Study Design
Patients randomized to clopidogrel or placebo at CURE trial entry, both in addition to aspirin and standard therapy
All patients undergoing PCI during the course of the CURE trial were included in PCI-CURE
Timing of PCI was at the physician’s discretion
At time of PCI, study drug was interrupted and open-label therapy was initiated for 2-4 weeks
During open-label therapy, thienopyridines in combination with ASA was permitted
Follow-up ranged from 3-12 months
Patients were randomized to clopidogrel or placebo at CURE trial entry, both in addition to aspirin and other standard therapy.
Medications at time of randomization may include heparin or low–molecular weight heparin, beta-blockers, ACE inhibitors, lipid-lowering agents, calcium channel blockers, and/or other therapies or interventions (PTCA, CABG) at physician’s discretion.
All patients undergoing PCI during the course of the CURE trial were included in PCI- CURE.
Timing of PCI was at the physician’s discretion. Median time overall – 10 days from randomization
the majority occurred during initial hospitalization, median time 6 days
for those occurring after initial discharge, median time was 49 days.
At the time of PCI, study drug was interrupted and open-label therapy was initiated for 2–4 weeks.
During open-label therapy, thienopyridine in addition to ASA was permitted. Overall, >80% of patients in each arm received open-label thienopyridine post-PCI.
Follow-up ranged from 3–12 months.
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:

27. Study Design R PCI-CURE N = 2,658 patients undergoing PCI PLACEBO
Pretreatment
Open-label thienopyridine
PLACEBO
+ ASA *
N = 1345
End of follow-up
Up to 12 months
after randomization R
PCI
30 days post PCI
This slide summarizes the PCI-CURE design. A total of 2658 patients with non-ST- segment elevation MI undergoing PCI had been randomized to receive clopidogrel or placebo. The majority of patients received an intracoronary stent (81% in the placebo group and 82% in the clopidogrel group).
Patients were treated with the blinded study drug for a median of 6 days prior to the procedure. After the procedure, the majority (> 80%) received open-label thienopyridine (either clopidogrel or ticlopidine) for approximately 4 weeks; then, the blinded study drug was continued until the end of follow-up (average duration of 8 months).
Medications at time of randomization may include heparin or low–molecular weight heparin, beta-blockers, ACE inhibitors, lipid-lowering agents, calcium channel blockers, and/or other therapies or interventions (PTCA, CABG) at physician’s discretion..
The primary end point was the composite of myocardial infarction, cardiovascular death or urgent target vessel revascularization within 30 days of PCI.
Open-label thienopyridine
CLOPIDOGREL
+ ASA *
N = 1313
Pretreatment
* In combination with standard therapy
Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:

28. End Points Composite of the following within 30 days of PCI:
PCI-CURE
End Points
Composite of the following within 30 days of PCI:
myocardial infarction
urgent target-vessel revascularization
cardiovascular death
Composite of the following from PCI to end of follow-up:
The end points were:
within 30 days of PCI: the composite of myocardial infarction (MI), urgent target- vessel revascularization or cardiovascular death
from PCI to end of follow-up: the composite of myocardial infarction or cardiovascular death.
MI was defined as the presence of 2 or more of the following:
ischemic symptoms
cardiac enzyme elevations to at least 3 times the upper limit of normal (ULN) within 48 hours of PCI and 2 times the ULN thereafter
new ECG changes compatible with MI.
Urgent target vessel revascularization was defined as either a second PCI or any CABG procedure performed on a non-elective basis in the target vessel due to recurrent ischemia.
Cardiovascular death included all deaths (including deaths that were sudden, of unknown cause or secondary to complications of a cardiac procedure) unless there was documented evidence of a clear noncardiovascular cause.
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:

29. Baseline Characteristics
PCI-CURE
Baseline Characteristics
Placebo Clopidogrel + ASA* + ASA* (N = 1345) (N = 1313)
Age (mean, years)
Male (%)
Diabetes (%)
Previous MI (%)
Prior PCI (%)
Prior CABG (%)
ST-segment depression (%)
ST-segment elevation (%)
The two study groups were well balanced at the start of the study with respect to age, gender, ECG abnormalities and cardiovascular history.
* In combination with standard therapy
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:

30. Interventional Characteristics
PCI-CURE
Interventional Characteristics
Placebo Clopidogrel + ASA* + ASA* (N = 1345) (N = 1313)
Overall median days after randomization on which PCI was done 10 10
PCI during initial hospitalization 6 6
PCI after initial hospitalization 49 49
Stent use (%)
Use of open-label thienopyridine
Before PCI (%)
Overall (%)
The two groups were well balanced with regard to the timing of intervention, cardiovascular medications used before and after procedure, and stent placement.
Sixty-five percent (1730 procedures) of the interventions were performed during the initial hospitalization and 35% (928 procedures) were performed after the initial discharge.
The two groups were also well balanced in the types of lesions that were treated:
target vessels (clopidogrel vs. placebo): left main (1.8% vs.1.8%); proximal (28.5% vs. 26.1%); mid/distal (23.5% vs 22.3%), left anterior descending, circumflex (29.0% vs. 29.3%); right coronary (31.9% vs. 32.8%); saphenous vein graft (3.3% vs. 2.4%).
Open-label thienopyridine use was >80% in both treatment arms after PCI.
* In combination with standard therapy
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:

31. Efficacy Outcomes PCI-CURE Placebo + ASA* N = 1345
Clopidogrel + ASA* N = 1313
RRR
P value
From PCI to 30 days
MI, urgent revascularization or CV death 6.4% 4.5% 30% 0.03
From PCI to follow-up
CV death or MI 8.0% 6.0% 25% 0.047
NEJM
Clopidogrel provided a 25% relative risk reduction in the composite outcome of MI or CV death at follow-up (8.0% vs 6.0%, P = 0.047), with a 29% reduction in MI (6.4% vs 4.5%, P = 0.03). Cardiovascular death was similar between the two groups at follow-up.
Within 30 days there was also a 30% relative risk reduction in the primary outcome of MI, target vessel revascularization or CV death (6.4% vs 4.5%, P = 0.03), with a significant reduction in MI (3.8% vs 2.1%, RRR 44%) and urgent revascularization (2.8% vs 1.9%, RRR 33%). The rate of CV death was similar between the two groups.
The reduction in the primary end point was seen within 48 hours following PCI, with increasing benefit at 7 and 14 days which continued throughout the 30 days.
The benefits seen with early and long-term clopidogrel in addition to aspirin and other standard therapy, illustrates the need for early and continued antiplatelet protection in these high-risk patients.
* In combination with standard therapy
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:

32. Overall Long-Term Results
PCI-CURE
Overall Long-Term Results
Composite of cardiovascular death or MI from randomization to end of follow-up
0.15
12.6%
Placebo
+ ASA*
0.10
8.8%
Clopidogrel
+ ASA*
Cumulative Hazard Rate
0.05
31% RRR
P = N = 2658
For the end point of MI or cardiovascular death from time of randomization to end of follow-up, treatment with clopidogrel in addition to aspirin and other standard therapy resulted in a 31% RRR (8.8% clopidogrel vs. 12.6% placebo, P = 0.002).
The curves diverged early and continued to separate over the course of 12 months.
This end point included events that were prevented prior to PCI, in addition to those following the procedure.
There were consistent reductions in MI or cardiovascular death in almost every subgroup examined
0.0
100
200
300
400
Days of follow-up
* In combination with standard therapy
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001.

33. PCI-CURE
30 Day Results
Composite of cardiovascular death, MI, or urgent revascularization
0.08
Placebo + ASA*
6.4%
0.06
4.5%
Cumulative Hazard Rate
0.04
Clopidogrel + ASA*
0.02
30% RRR
P = 0.03
N = 2658
Treatment with clopidogrel in addition to aspirin and other standard therapy resulted in a RRR of 30% (P = 0.03) compared with aspirin and standard therapy alone for the endpoint of cardiovascular death, MI, or urgent revascularization at 30 days post-PCI.
The event curves separated early and continued to separate up to 30 days and beyond.
A reduction in this endpoint was observed within 2 days, with continuing benefit throughout the study period (up to 1 year).
The majority of patients (> 80% in both groups) received open-label ADP-receptor antagonist following PCI, suggesting the early benefit was mainly due to clopidogrel pre-treatment.
An “on-treatment” analysis which excluded those patients that received open-label ADP-receptor antagonist prior to PCI (~25% in both groups) demonstrated a 42% RRR (P = 0.005) in this endpoint.
0.0 5 10 15 20 25 30
Days of follow-up
* In combination with standard therapy
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:

34. Subgroup Analysis PCI-CURE Placebo + ASA* Clopidogrel + ASA* RR 95% CI
Overall 12.6% 8.8%
Stent 11.7% 8.7% No stent 16.2% 9.4%
Age £ % 5.9% Age > % 13.4%
Male 11.9% 7.9% Female 14.1% 11.0%
Diabetes 16.5% 12.9% No diabetes 11.7% 7.9%
During initial hosp 12.0% 8.3% After initial hosp 13.8% 9.8%
Several subgroup analysis were performed and select results are summarized above. Although this study was not powered to look at individual subgroups, there was a beneficial trend seen across all subgroups analyzed.
0.1
1.0
10.0
Clopidogrel Better
Placebo Better
* In combination with standard therapy
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:
Relative Risk (95% CI)

35. Other Outcomes PCI-CURE Placebo + ASA* N = 1345
Clopidogrel + ASA* N = 1313
RRR
P value
IV GP IIb/ IIIa use 26.6% 20.9% 21% 0.001
Second revascularization 17.1% 14.2% 18% 0.049
NEJM
Unless the patients developed refractory ischemia, the use of GP IIb/IIIa inhibitors was discouraged. The clopidogrel group reported a 21% relative risk reduction in GP IIb/IIIa inhibitor use (26.6% vs 20.9%, P = 0.001). There was also an 18% relative risk reduction in the need for a second revascularization (17.1% vs 14.2%, P = 0.049) in the clopidogrel plus aspirin group.
* In combination with standard therapy
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:

36. Bleeding Outcomes PCI-CURE Placebo + ASA* Clopidogrel + ASA*
From PCI to 30 days
Major 1.4% 1.6% †
Life threatening 0.7% 0.7% †
Minor 0.7% 1.0% †
From PCI to end of follow-up
Major 2.5% 2.7% †
Life threatening 1.3% 1.2% †
Minor 2.1% 3.5% ‡
NEJM
There was no significant difference in major bleeding at 30 days or at end of follow-up (2.5% vs 2.7%, RR 1.12, P = 0.64). Similarly, there was no significant difference in life- threatening bleeding at 30 days (0.7% vs 0.7%) or at follow-up (1.3% vs. 1.2%). Minor bleeding was slightly increased in the clopidogrel group at 30 days (0.7% vs. 1.0%) and significantly increased at follow-up (2.1% vs. 3.5%, RR 1.68, P = 0.03).
* In combination with standard therapy
† P = NS, ‡ P = 0.03
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:

37. PCI-CURE
Conclusions
For the composite of MI or cardiovascular death in the 2658 patients who underwent PCI in the CURE trial:
clopidogrel plus aspirin* demonstrated a 31% relative risk reduction from randomization to the end of follow-up (P = 0.002)
clopidogrel plus aspirin* demonstrated a 25% relative risk reduction in the composite of MI or cardiovascular death with long-term use† from PCI to end of follow-up (P = 0.04)
clopidogrel in addition to aspirin and other standard therapy provides early beneficial effects and sustained long-term† benefit in ACS patients requiring PCI
In the 2658 patients who underwent percutaneous coronary intervention (PCI) in the CURE trial:
clopidogrel demonstrated a 25% relative risk reduction in the composite of MI or cardiovascular death with long-term (up to 12 months) use from PCI to end of follow- up (P = 0.04)
in the 30 days after PCI, clopidogrel reduced the incidence of MI, urgent revascularization or cardiovascular death by 30% (P = 0.03)
clopidogrel in addition to aspirin and other standard therapy provides early beneficial effect and sustained long-term† benefit.
There was no significant difference in major (2.5% vs 2.7%, P = 0.64) or life-threatening bleeding (1.3% vs 1.2%, P = 0.78) from PCI to end of follow-up between the placebo plus aspirin and clopidogrel plus aspirin group, respectively. However, there was a significant increase in minor bleeding in the clopidogrel plus aspirin group (2.1% vs 3.5%, P = 0.03) from PCI to end of follow-up.
* In combination with standard therapy
† Up to 12 months
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:

38. PCI-CURE
Conclusions
Long-term† administration of clopidogrel plus aspirin* resulted in an overall 25% relative risk reduction in MI and CV death from PCI to end of follow-up
Pretreatment with clopidogrel plus aspirin* resulted in a 30% relative risk reduction in CV death, MI and target vessel revascularization in 30 days post PCI
There was an increase in minor bleeding, but was no significant difference in major or life-threatening bleeding between the two treatment groups
Long-term administration (mean duration 8 months) resulted in an overall 26% relative risk reduction in CV death or MI.
Pretreatment with clopidogrel, prior to PCI, resulted in a 30% relative risk reduction in CV death, MI and target vessel revascularization for 30 days post PCI. This benefit was seen as early as 2 days after the procedure.
† Up to 12 months
* In combination with standard therapy
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21: