Clopidogrel for the prevention of late cardiac events in patients with asymptomatic perioperative acute coronary syndrome.

Patients undergoing vascular surgery are at increased risk for perioperative
and long-term cardiovascular events. Despite rigorous preoperative risk
assessment and subsequent initiation of appropriate medical therapy and
coronary revascularization, approximately 20% of these patients experience
asymptomatic perioperative myocardial damage as assessed by troponin T
release. Late outcome of these patients is severely compromised: the incidence
of death in the first year after surgery is approximately 25%, mostly
attributable to cardiac causes.

Studies in non-surgical patients with acute coronary syndromes have shown that
clopidogrel on top of aspirin might improve cardiovascular outcome. The
Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial
randomly assigned 12,562 patients who had presented within 24 hours after the
onset of symptoms of an acute coronary syndrome to receive clopidogrel or
placebo in addition to aspirin for 3 to 12 months. In this trial it was shown
that clopidogrel was associated with a 20% relative risk reduction for the
composite of cardiovascular death, nonfatal myocardial infarction or stroke.

Routinely patients undergoing vascular surgery are treated with low molecular
heparins, beta-blockers, statins and aspirin. The addition of clopidogrel might
be beneficial in these patients although safety with respect to bleeding
complications is an important issue. Reassuring are previous study results. The
CASPAR-trial, that was designed to test whether the addition of clopidogrel
would improve patency in 801 patients with peripheral arterial bypass grafts,
showed that the incidence of bleeding episodes increased from 1.2% in patients
with aspirin alone to 2.1% in patients on both aspirin and clopidogrel.
However, the number of episodes of life-threatening bleedings was not
significantly increased in patients on dual antiplatelet therapy. A recent
study performed at Erasmus MC, in which patients with previous coronary stent
placement underwent surgery, showed that the continuation of dual antiplatelet
therapy did not increase the demand for blood transfusion.

Thrombosis caused by a ruptured or eroded atherosclerotic plaque is the usual
underlying mechanism of acute coronary syndromes. Aspirin seems to reduce the
risk of plaque rupture and subsequent death from cardiovascular causes and
nonfatal myocardial infarction but there is still a substantial risk of such
events in both the short term and the long term. The thienopyridine derivative
clopidogrel is an antiplatelet agent that inhibits the platelet aggregation
induced by adenosine diphosphate, thereby reducing ischemic events. Combining
one of this drug with aspirin, which blocks the thromboxane-mediated pathway,
may have an additive effect. Therefore the current study has been set up to
investigate whether the addition of clopidogrel to aspirin in a group of
vascular surgery patients at high cardiac risk is safe and improves long term
cardiac outcome.

The primary objective of this study is to determine whether clopidogrel + best
medical treatment is superior to best medical treatment only in preventing:

A) cardiovascular death, MI, stroke, or severe ischemia of the coronary or
peripheral arterial circulation leading to an intervention in patients with
asymptomatic perioperative troponin release during or shortly after major
vascular surgery.

Secondary objectives include determining the effect of clopidogrel on:

B) Bleeding complications, defined as life-threatening bleeding, moderate and
minor bleeding in patients with asymptomatic perioperative troponin release
after major vascular surgery.


Tertiary objectives also include determining:

C) Identify preoperative risk factors for the occurrence of the primary
endpoint in patients scheduled for major vascular surgery

D) Identify novel biomarkers that predict the occurrence of the primary
endpoint in patients scheduled for major vascular surgery

PATIENT RECRUITMENT:

All patients at the vascular surgery outpatient clinic will be screened for
eligibility in the study. Those that meet one of the inclusion criteria but
none of the exclusion criteria will be asked to participate in the study.
After informed consent is obtained the preoperative case record forms will be
completed and pertinent data will be entered into the study database. Those
patients that do not develop asymptomatic postoperative troponin release will
not be randomized. However these patients will remain in the database and will
be followed according to a prespecified protocol. Data of these patients will
be used for the tertiary objectives of this study. Patients that do develop
asymptomatic troponin release will be randomized to receive, in a double-blind
way, either clopidogrel 75 mg once daily (with an initial dose of 300mg) plus
aspirin or aspirin alone.


PREOPERATIVE WORK UP

Preoperative work up will be done according to current ACC/AHA guidelines but
must include at least:

Risk factor assessment:
Of all screened patients the following risk factors will be assessed:
1. Age > 70 years
2. History of angina pectoris or current angina pectoris
3. History of myocardial infarction
4. History of transient ischemic attack (TIA) or cerebrovascular accident (CVA)
5. History of congestive heart failure or current congestive heart failure
6. Diabetes mellitus, insulin dependent (IDDM) or non-insulin dependent (nIDDM)
7. Renal dysfunction (creatinine > 160 mmol/l), and creatinine clearance
8. History of hypertension or current untreated hypertension
9. Chronic obstructive pulmonary disease

Laboratory measurements:
Of all screened patients the following laboratory results will be obtained
preoperatively:
1. NT-proBNP
2. fasting glucose
3. Troponin T
4. Total cholesterol, LDL, HDL, triglycerides
5. High-sensitive CRP
6. Interleukin-6, sTNF-alfa
7. An additional 10 ml blood sample of all patients for storage

Echocardiography:
All screened patients will undergo preoperative echocardiography to assess
1. Left ventricular function
2. Wall motion abnormalities
3. Valve abnormalities

Stress testing:
Patients referred for stress testing are patients with 3 or more cardiac risk
factors (MI, stroke, AP, CHF, renal failure, age > 70 years). Preoperative
stress test results will guide perioperative management. Patients with
evidence of left main disease will undergo coronary revascularization.

Electrocardiography:
All screened patients will undergo preoperative electrocardiography.

Ankle-arm index:
During admission the ankle-arm index will be measured in all patients

Medical therapy:
All patients without contraindication will receive at least the following
medication:
1. Beta-blocker therapy, preferably bisoprolol, with dose titration to a target
heart rate of 60 -65 beats/minute
2. Statin therapy, preferably fluvastatin XL 80mg
3. Aspirin therapy
4. Proton pump inhibitor therapy, preferably pantoprazol 40mg


PERIOPERATIVE MANAGEMENT:

Perioperative management will be done according to current ACC/AHA guidelines
but must include:
1. Troponin T measurement preoperatively and on day 1, 2, 3, and 7
postoperatively.
2. ECG recording on day 1, 3, and 7 postoperatively or whenever clinically
indicated.
3. Randomization of patients to clopidogrel or placebo in case of asymptomatic
troponin
release, using a computer generated randomization list with stratification
according to participating centre.
4. Ensurement of adequate medical therapy if medication cannot be given orally;
i.v. administration of beta-blockers and restart of statins and aspirin as
soon as
possible.

Management after discharge
Patients will be treated according to current ACC/AHA guidelines but must
include at least a follow-up visit 30 days, 3 months, 6 months and 12 months
after surgery. During these visits case record forms will be completed to
assess the occurrence of the predefined (safety) endpoints. Completed case
record forms will be faxed to the Project Office.

Patients who develop asymptomatic troponin release during the perioperative
phase, will be randomised to either clopidogrel or not on top of standard
medical treatment.

NATURE AND EXTENT OF THE BURDEN ASSOCIATED WITH PARTICIPATION
Laboratory measurements: no extra tests associated with participation
Doctor / follow up visits: No extra visits associated with participation
Physical examination: No extra burden associated with participation

RISKS ASSOCIATED WITH PARTICIPATION
Patients treated with clopidogrel simultaniously with aspirin have an slighty
increased risk for non-fatal bleedings complications, sometimes requiring
transusions. However, studies show (see background) no increase in the risk for
life-threatening bleeding complications.