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BACKGROUND
CURE ( C lopidogrel in U nstable angina to prevent R ecurrent ischemic E vents): an international study of patients presenting to hospital with an acute coronary syndrome (unstable angina or myocardial infarction without ST segment elevation). Patients were randomized to clopidogrel or matching placebo 300mg loading dose followed by clopidogrel or matching placebo 75mg daily for the duration of follow-up. All patients received ASA in a dose range of 75mg-325mg daily at the discretion of the investigator. 12,562 patients from 28 countries and from 482 clinical centres were enrolled over a period of approximately 20 months. The last patient was randomized to CURE on September 7, 2000 and the study end date was then determined as December 6, 2000. The preliminary results of the study were presented at the American College of Cardiology, Late Breaking Clinical Trials session on March 19, 2001.



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RATIONALE
While aspirin has been a major advance in preventing vascular events in high risk patients, it fails to prevent approximately three-quarters of such events. Combined data from animal studies and randomized trials support the potential increased benefit of thienopyridines when added to aspirin. Clopidogrel has been shown to be an effective and safe agent of this class. There is also a need for easier to use therapies in managing patients with acute coronary syndrome (ACS) both in the acute phase and long term. CURE is a large international study to determine if acute and long-term treatment with the combination of clopidogrel and aspirin is superior to aspirin alone in patients with acute coronary syndrome.


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STUDY OBJECTIVES
The CURE study was designed to test the hypothesis that clopidogrel is superior to placebo in presenting cardiovascular death, MI or stroke in patients presenting to hospital with an acute coronary syndrome. (Unstable Angina or myocardial infarction without ST segment elevation).

The secondary objective was to evaluate the safety of clopidogrel in patients with an acute coronary syndrome who are receiving ASA therapy.



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STUDY POPULATION

Inclusion Criteria

Patients admitted to hospital with symptoms suspected to represent an acute coronary syndrome defined as unstable angina or acute MI without ST segment elevation greater than 1mm, and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischemia were eligible for the study if they gave informed consent and met the following criteria:

  • clinical history with new onset or worsening pattern of characteristic ischemic chest pain occurring at rest or with minimal exercise (lasting longer than 5 minutes or requiring sublingual nitroglycerin for the relief of pain).

and:

  • either ECG changes compatible with new ischemia (eg. ST depression (at least 1 mm in 2 contiguous leads), T wave inversion (at least 2 mm in 2 contiguous leads), or hyperacute peaked T waves).
  • or already elevated cardiac enzymes or Troponin I or T to at least twice the upper limit of normal, provided there is no ST segment elevation.

Patients presented with new LBBB were included if they were not eligible for thrombolysis and met the other inclusion criteria.



Exclusion Criteria

Factors that affect participation in study:

  1. Age < 21 years
  2. Previous disabling stroke (severe cerebral deficit such that the patient is bedridden or demented)
  3. Previous intracranial hemorrhage or hemorrhagic stroke
  4. Severe co-morbid condition such that the patient is not expected to survive 12 months
  5. NYHA Class IV heart failure
  6. Uncontrolled hypertension
  7. Current use of oral anticoagulants, non study antiplatelet agents (including ticlopidine or clopidogrel) or NSAIDs with the intension for long term (>3 months) and regular treatment
  8. Patients concurrently participating in any study with an investigational drug or device
  9. Patients having received a glycoprotein IIB/IIIA receptor antagonist in the previous three days
  10. Patients with previous participation in this study
  11. Patients with recent PTCA/Stent or CABG (within 3 months prior to randomization)
  12. Women of child-bearing potential who are not following an effective method of contraception
  13. Geographic or social factors making study participation impractical
  14. Coronary angiography in the year prior to the eligibility assessment, showing no evidence of significant coronary disease or intraluminal slot

Factors related to ASA and/or clopidogrel treatment:

  1. Clinically severe thrombocytopenia or neutropenia
  2. History of ASA intolerance
  3. Contraindications to clopidogrel or ASA, including patients at high risk of bleeding


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STUDY PROCEDURES

Treatments

A loading dose of study drug (clopidogrel 300 mg or placebo) was to be given as soon as treatment was allocated (Day 1). Patients were then treated with study drug (clopidogrel 75 mg daily or matching placebo) for the duration of follow-up. ASA therapy was to be started simultaneously with the study drug or patients continued with pre-admission ASA therapy, as applicable.



STUDY FLOW CHART


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Epidemiologic Component

Data describing key characteristics, life-style aspects of patients and one blood sample for central analysis was obtained on consenting patients just prior to administration of the study drug. These data will be used to evaluate the consistency of effects of clopidogrel across various strata of patients. For example, patients may be subdivided according to clinical/biochemical markers of inflammation, coagulation factors or other cardiovascular risk factors. These data will also be used to learn more about factors affecting the clinical course of acute coronary syndromes (unstable angina or MI without ST segment elevation).



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CURE PATIENT SCHEDULE


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STUDY DESIGN

CURE is a international, multi-centre, randomized, parallel group, double blind, clinical trial of clopidogrel versus placebo in patients with unstable angina or myocardial infarction without ST segment elevation (acute coronary syndrome [ACS]) who are receiving ASA therapy.

The original sample size of 9,000 patients was increased to 12,500 in June, 1999 due to a lower than expected event rate.

Patients were randomized through an automated central randomization service from the Canadian Cardiovascular Collaboration (CCC) Project Office.

Patients were treated in the acute phase with a 300mg loading dose of study drug followed by 75mg daily for the duration of follow-up which varied between a minimum of 3 months to a maximum of 12 months.



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STUDY OUTCOMES

1 st Co-Primary Outcome
First occurrence of any one of the following:
  • CV Death
  • Myocardial Infarction
  • Stroke (ischemic, hemorrhagic or of uncertain type)
over duration of follow-up



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2 nd Co-Primary Outcome
First occurrence of any component of the following cluster:
  • CV Death
  • Myocardial Infarction
  • Stroke (ischemic, hemorrhagic or of uncertain type)
  • Refractory Ischemia
over duration of follow-up



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Other Outcomes
  • Total Death
  • Severe Ischemia (during hospitalization)
  • Recurrent Angina
  • Coronary Revascularization
    • Mechanical (PTCA/Stent or CABG)
    • Pharmacological (thrombolytic therapy)




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STUDY DEFINITIONS

CV Death: defined as

  • Any death with a clear cardiovascular (including hemorrhagic) or unknown cause

Note: only deaths due to a documented non-vascular cause will be classified as non-CV.

MI: defined as at least 2 of 3 criteria

  1. Ischemic Chest Pain (x20 min, + sl nitro or narcotic)
  2. Elevated cardiac enzymes to at least 2 x upper limit of normal
  3. ECG changes
    • ST elevation of at least 1 mm in 2 cont. leads, or
    • persistent ST segment depression, or
    • persistent T wave inversion, or
    • Q waves

MI Post-PTCA defined as: at least 2 of the 3 criteria listed above (enzymes must be evaluated to at least 3 x the upper limit of normal)

MI Post CABG defined as:

  1. elevation of cardio-specific enzymes to at least 5 x the upper limit of normal, or
  2. development of new pathological Q waves

Stroke: defined as

  • New focal neurological deficit
  • Vascular in origin
  • Signs and symptoms > 24 hours
  • CT scan / MRI strongly recommended

    To be further classified as:
    • Ischemic
    • Hemorrhagic
    • Uncertain type

Refractory Ischemia: defined as

Either: During Initial Hospitalization

  • recurrent chest pain >5 min
  • ischemic ECG changes
  • on optimal medical therapy
  • must lead to additional intervention/procedure by midnight of the next day

Or: Rehospitalization for Unstable Angina

  • > 24 hr hospital stay
  • prolonged chest pain unresponsive to usual Rx
  • and ischemic ECG changes

    (may or may not lead to intervention/procedure)

Severe Ischemia: defined as

During Initial Hospitalization

  • At least 1 episode of chest pain > 5 min
  • On optimal medical therapy
  • Documented ischemic ECG changes

Note:

  • Differs from Refractory Ischemia - no intervention by midnight of next day

Recurrent Angina: defined as

During Initial Hospitalization

  • At least 1 episode of chest pain > 5 min
  • Increase in or addition of new anti-anginal med (narcotic if on optimal medical therapy)

Documented ECG changes - not required

Coronary Revascularization: defined as

  • PTCA
  • PTCA/Stent
  • CABG
  • Thrombolytic Therapy

Note:

  • Urgent if performed within 1 week of (re) hosp for acute MI or UA

Bleeding Definitions:

Life-threatening: defined as fatal or leading to a drop in hemoglobin of at least 5 g/dl, or significant hypotension with the need for inotropes, or requiring surgery (other than vascular site repair), or symptomatic intracranial hemorrhage, or requiring transfusion of four or more units of red blood cells or equivalent whole blood

Major: defined as significantly disabling, intraocular bleeding leading to significant loss of vision or bleeding requiring transfusion of two or three units of red blood cells or equivalent whole blood

Minor: Any other bleeding requiring modification of the study drug regimen.



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PATIENT RECRUITMENT


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CURE STUDY ORGANIZATIONAL CHART
"Click the group to view committee members"
Study Organization Link to Data Safety and Monitoring Link to Event Adjudication Link to Sponsors Link to CCC Project Office Staff Link to Operations Committee Link to International Steering Committee Link to National Coordinators


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