The Rotterdam Antiplatelet Therapy in Vascular Patients Study

In the past few years there efficacy and safety of double antiplatelet therapy,
as compared to aspirin, has been investigated increasingly for prevention of
cardiovascular complications after non-cardiac surgery.
The CURE study showed that in patients with myocardial damage, but not having a
myocardial infarction, improvement in first year survival can be achieved by
adding Clopidogrel to standard therapy with aspirin. A significant reduction
in incidence of the primary endpoint, defined as death from cardiovascular
cause, myocardial infarction and stroke, from 11.4% to 9.3% was found in
patients undergoing non-cardiac surgery, when treated with double antiplatelet
therapy. The CHARISMA trial was next in line to investigate the same study
population but having multiple atherosclerotic risk factors. Results also
showed a reduction of primary endpoint of 7.3% to 6.8%, although not
significant. A desirable effect of treatment with double antiplatelet therapy
was seen among patients with proven coronary artery disease. A meta-analysis by
Bowry et al of 2008 displayed favourable effects of double antiplatelet therapy
on the compound endpoint death, new myocardial infarction and stroke, having an
odds ratio reduction of 15 % in patients having an acute coronary syndrome and
34% in patients undergoing percutaneous coronary intervention. A significant
reduction in fatal and non-fatal myocardial infarction was also shown. On the
contrary, double antiplatelet therapy is associated with a significant
increased risk on major bleeding when used > 30 days, OR 1.80, if compared to
aspirin monotherapy resulting in an absolute risk increase of 1.5% on major
bleeding. Aspirin has a baseline risk of 1.9% on major bleeding when used for a
period of 13 months. Subsequently, an meta-analysis by Zhou et al (2012) showed
comparable results when using double antiplatelet therapy on the same primary
endpoints and risk on major bleeding. Gualandro et al showed that amongst 480
patients having an acute coronary syndrome (ACS) perioperatively, 50 % had
coronary plaque rupture, displaying evidence for type 1 myocardial infarction.
This is in contradiction with the for many years generally accepted hypothesis
that patients having an ACS perioperatively, suffered from type 2 myocardial
infarction. This new insight, combined with increased knowledge on stress
induced plaque inflammation leading to plaque instability and subsequent
thrombus formation, creates the basis to reexamine the potential beneficial
effect of double antiplatelet therapy in a (not previously examined) high risk
patient category such as vascular patients, in preventing cardiovascular
(atherothrombotic) complications. This specific subgroup has not been
investigated previously.

The objective of the proposed study is to evaluate if results as are written
above, are to be extrapolated on high risk patients who underwent vascular
surgery. In this group of patients, there is a substantial risk of 15-20% to
die in the first year postoperatively. In contrast, patients who underwent
myocardial infarction have a chance of 'only' 10%. Differences could be
explained simply by failure to provide adequate treatment of atherosclerotic
cardiovascular diseases and adding extra antiplatelet therapy would be a
logical next step given the presumed pathofysiological process in this specific
subgroup of patients.

Patients are eligible for inclusion in case of outpatient clinic elevated
troponin value above the 99th percentile of that specific assay. During this
visit, patients will be informed about participation into the study. Second,
patients will be evaluated for significant coronary obstructive disease by a
cardiologist through angiography. Next, vascular surgery will be performed
without interference. Postoperatively, troponin values will be measured on day
1 through 3. Randomisation will be accorded definitely if at least one of these
measurements is above the 99th percentile and elevated with respect to baseline
value. A cardiologist will be consulted to exclude myocardial infarction if
necessary. If patients meet all of the inclusion criteria, but non of the
exclusion criteria, randomization to study medication can be accorded
(treatment with either clopidogrel or placebo), on top of standard treatment
with aspirin for 12 months. At 30-days after surgery and after that every 3
months, patients are seen on outpatient clinic visits for blood samples and
quality of life questionnaires. Study ends after completion of 12 month
follow-up.

This will be a randomized controlled double blind clinical trial with an
intention-to-treat analysis.

Patients will be randomized to receive either clopidogrel or placebo on top of
standard treatment with aspirin for 12 months postoperatively, in case of
postoperative troponin elevation, above the 99th percentile and elevation with
respect to the baseline value, within the first 3 days after surgery.
Randomization will only be accorded if patients meet all of the inclusion- but
non of the exclusion criteria.

During the 12 month follow-up period, patients will be seen 5 times at out
outpatient clinical visit at 30days after surgery and thereafter every 3
months. In total, 6 blood samples ( a 10mL) will be collected important for
analysis of the primary endpoint: one during index hospitalization (=standard
of care) and 5 during outpatient clinic visits (additional measurements in this
study).

Patients with preoperative troponin elevation will be refferend to a
cardiologist for analysis of the presence of significant occlusive coronary
artery disease through angiography. Significant and intermediate lesions will
be assessed using Fractional Flow Reserve (conform international guidelines).

Burden
Patients will be asked for outpatient clinic visits on 30 days and therafter
every 3 months, for 12 months follow-up (5 visits). In total, 6 blood samples
and 2 questionnaires on quality of life will be taken (1 bloodsample is
considered standard of care directly after surgery, other 5 are additional
measurements). Patients are asked for a total of 5 extra outpatient clinic
visits.

Risks
Patients will be exposed to a higher risk of major bleeding when compared to
aspirin monotherapy. According to a meta-analysis performed by Bowry et al,
there is an absolute risk increase of 1.5% when using clopidogrel combined with
aspirin for 1 year (the baseline risk on bleeding on Aspirin monotherapy is
1.9% over a 13 month period of treatment).
Other adverse events reported with clopidogrel: bruising, epistaxis, diarrhea
and abdominal pains.

We do not suspect unexpected adverse events hence there is extensive clinical
experience using clopidogrel.

Patients will be asked for changes in health status during routine outpatient
clinical visits through the entire study and actions will be taken according to
good clinical practice if required.