E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
myocardial injury in patients undergoing major vascular surgery, leading to (spontaneous) acute coronary syndrome and death through intracoronary plaque damage and subsequent thrombosis after major vascular surgery. |
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E.1.1.1 | Medical condition in easily understood language |
Patients undergoing major vascular surgery are at risk for long term complications such as myocardial damage, infarction or even death because of the extensive risk of thrombosis. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
In patients with asymptomatic hsTnT release before and after major vascular surgery the following objectives will be investigated:
Primary objective:
To asses the efficacy of clopidogrel, as compared to placebo, on top of standard treatment with aspirin on
A: the composite endpoint of MACE, defined as;
-cardiovascular death,
-nonfatal myocardial infarction,
-stroke,
-severe ischemia of the peripheral arterial circulation leading to intervention
In patients with myocardial injury (defined as asymptomatic troponin release) after major vascular surgery |
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E.2.2 | Secondary objectives of the trial |
B: individual components of MACE
C: To assess the safety of clopidogrel, in terms of bleeding complications, defined as life-threatening bleeding, moderate and minor bleeding, postoperatively and during long-term follow-up.
In patients with asymptomatic preoperative hsTnT release scheduled for major vascular surgery the following objective will be investigated
D: Presence of significant coronary artery disease and the impact of presence of vulnerable plaques according to PROSPECT criteria
In the specific subgroup of patients undergoing major vascular surgery.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Preoperative myocardial injury (baseline value), defined as hsTnT release > 14 ng/L.
2.Absence of significant occlusive coronary artery disease as diagnosed through angiography (and confirmed by FFR).
3.Postoperative myocardial injury, defined as hsTnT release > 14 ng/L, which exceed the baseline value.
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E.4 | Principal exclusion criteria |
1. if troponin elevation is diagnosed as myocardial infarction by cardiologist.
2. Presence of significant occlusive coronary artery disease, as diagnosed through preoperative angiography, requiring treatment.
3. No postoperative hsTnT values above the clinical reference of 14 ng/L and no rise with respect to baseline value.
4. Active bleeding.
5. Active cardiac conditions at the time of randomisation such as unstable angina pectoris, active congestive heart failure (CHF), serious cardiac arrhythmias, symptomatic valvular disease.
6. Clear indication for long-term P2Y12 inhibitor use.
7. Preoperative use of P2Y12 inhibitors.
8. Previous allergy or intolerance to clopidogrel.
9. Use of oral anticoagulants after surgery.
10. Use of intravenous glycoprotein IIB/IIA receptor inhibitors in the previous three days.
11. Coronary revascularization therapy in the previous six months.
12. Renal failure requiring dialysis.
13. Significant liver disease (i.e. ALAT, ASAT > 3x ULN).
14. Cancer with an expected life expectancy less than 6 months.
15. Excessive alcohol use.
16. No informed consent.
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Efficacy outcomes:
MACE:
Defined as a composite of cardiovascular death, non-fatal myocardial infarction, stroke and arterial thrombotic events.
Death:
Subdivided as cardiovascular and non-cardiovascular. All deaths with a clear cardiovascular cause including haemorrhagic or unknown cause will be classified as cardiovascular. Only deaths due to a documented non-cardiovascular cause will be classified as non-cardiovascular.
Myocardial infarction (2 of 3 criteria):
1. Typical ischemic chest pain,
2. Elevation of troponin (TnT) values,
3. New ECG changes which include new persistent ST/T changes, new BBB or new Q-waves in at least 2 consecutive leads
Severe coronary ischemia leading to an intervention:
Unstable angina with ECG changes requiring hospitalization, which leads to coronary revascularization (PTCA, CABG) (or transfer for revascularization) during hospitalization.
Revascularization of coronary arteries:
PTCA
CABG
Arterial thrombotic events complicating vascular surgery, leading to severe limb ischemia and consequently to intervention:
Severe limb ischemia of the lower extremity which is deemed to threaten the viability of the limb, and is associated with continuing ischemic pain, and neurological deficit, or inadequate skin capillary circulation, or inaudible arterial flow signals by Doppler of the pedal arteries AND which leads to hospitalization for an intervention such as thrombolytic therapy, angioplasty, bypass surgery or amputation.
Reperfusion of peripheral arteries:
1. Catheter directed thrombolytic therapy of a peripheral artery
2. Percutaneous transluminal angioplasty of the iliac or femoral arteries
3. Surgical revascularization of the aortic or infrainguinal arteries
Stroke:
New focal neurological deficit thought to be vascular in origin lasting greater than 24 hours. Confirmation with CT scan/MRI is recommended but not mandatory. Strokes will be further classified as ischemic, haemorrhagic, or uncertain.
TIA :
Transient ischemic attack; new onset focal neurological deficit that resolves within 24 hours.
Unstable angina with ECG changes:
An episode of angina lasting greater than 15 minutes which is refractory to the patient’s usual medications, which leads to hospital admission and is associated with ECG changes consistent with coronary ischemia.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Patients will be seen on outpatient clinic visit monthly for a total follow-up time of 1 year. |
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E.5.2 | Secondary end point(s) |
Safety outcomes
Life-threatening bleeding
Fatal or intra-cranial bleeding or bleeding requiring surgical intervention or transfusion of at least 4 units of blood or plasma expanders, or a drop in hemoglobin of ≥ 5 g/dL hemoglobin or a ≥ 15% absolute decrease in hematocrit.
Moderate and minor bleeding
Bleeding which requires ≤3 units of blood or blood products. Minor bleedings will be classified as all other bleedings not requiring transfusion, however will lead to temporary or permanent cessation of study medication and/or aspirin.
(Bleeding definitions are in concordance with TIMI bleeding criteria)
Other endpoints:
Presence of significant obstructive coronary artery disease:
Significant obstructive coronary artery disease will be assed by consulting cardiologist and measurements and cut-off values are according to current guidelines used in the Erasmus Medical Center.
Quality of life during follow-up period
Novel biomarker identification:
Identification of biomarkers that predict the recurrence of an acute vascular event during 1-year follow-up. Blood sample collection will be done as described elsewhere. Blood samples will be analysed after all study participants have completed one-year follow-up.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Patients will be seen on outpatient clinic visits postoperatively on 30-days and every 3 months for a total follow-up time of 1 year.
Quality of life will be assessed twice, at 6 months and at end of study. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |