Role of Plavix in Hemorrhagic and Ischemic Complications of Catheterization.

SIGNIFICANCE AND BACKGROUND FOR THE STUDY The benefits of dual anti-platelet therapy with
full dose aspirin and a thienopyridine have been firmly established in patients undergoing
coronary stenting. Leon showed reduction in the combined end-point of death, myocardial
infarction, target vessel revascularization and stent thrombosis from 3.5% with aspirin
alone to 2.3% with aspirin and ticlopidine. This benefit was associated, however, with an
increased rate of bleeding and vascular complications of 5.5% with aspirin+ticlopidine
versus 1.8% with aspirin alone. Multiple other studies have evaluated the safety and
efficacy of the thienopyridine clopidogrel in percutaneous coronary intervention (PCI). In
patients at intermediate risk (without elevation of troponin-T prior to PCI), pretreatment
with clopidogrel several hours before the procedure reduced the event rate and obviated the
need for additional glycoprotein IIb/IIIa receptor inhibition (ISAR-REACT). In the
Clopidogrel for the Reduction of Events During Observation (CREDO) Study, investigators
showed that the benefit of pretreatment with 300 mg of clopidogrel was only seen when the
pretreatment was instituted at least 12 hours pre-procedure (optimally 24 hours before the
PCI). However, survival analysis in this study showed a cumulative event rate at 30 days of
8.3% in the placebo arm, 7.8% in those administered clopidogrel within 15 hours of the
procedure, and 3.5% in those administered clopidogrel more that 15 hours before the index
PCI.

Subsequently, the benefit of higher doses of clopidogrel was studied both ex vivo and in
clinical studies (PRONTO). A 600 mg dose of clopidogrel achieved adequate platelet
inhibition within 2 hours of administration, unlike 300 mg that required at least 3 to 6
hours to achieve full effect Subsequent data from the ISAR-REACT investigators in 2,159
patients showed that the benefit of 600 mg of clopidogrel was not time dependent. The trial
focused on the possible additional benefit of glycoprotein IIb/IIIa inhibition in these
patients who had all been pre-treated with 600 mg of clopidogrel. More recently,
ISAR-REACT-2 showed that clopidogrel pretreatment in moderate to high risk PCI patients
reduced the combined endpoint event rate (relative to placebo) from 11.7% to 5.7% in
patients treated with glycoprotein IIb/IIIa inhibitors and from 15.5% to 7.6% in those not
receiving glycoprotein IIb/IIIa inhibition. The recently published Assessment of the Best
Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis
(ALBION) Trial showed in a low risk group of patients that 600 mg and 900 mg doses of
clopidogrel provide faster and greater platelet inhibition than 300 mg as assessed by
biochemical assays. The study was underpowered to demonstrate clinical benefits, but it
showed a trend towards reduction in troponin-I release as a marker of necrosis from 58% to
42% in the higher dose clopidogrel groups. There was no demonstrable increase in major
bleeding complications (2.9% in both 300 and 900 mg groups), but there was a statistically
insignificant increase in minor bleeding in the 900 mg dose group.

Our investigation will evaluate the safety and efficacy of pre-treatment (≥2 hours) with 600
mg of clopidogrel in 600 outpatients undergoing elective cardiac catheterization with
coronary angiography in our institution who have no evidence of high risk features such as
ischemic ST segment deviations, unstable angina, recent myocardial infarction, or abnormal
troponin-T levels. The benefit of clopidogrel in patients who undergo interventions may be
offset by the bleeding complications encountered, especially in patients who do not undergo
coronary angioplasty. Our trial is designed to assess this potential benefit-risk trade-off.
Unlike the ALBION trial, we will focus on clinical outcomes using a larger sample size. Our
hypothesis is that pretreatment with 600 mg of clopidogrel will significantly reduce the
incidence of ischemic complications in patients undergoing PCI, but with possible increase
in hemorrhagic and vascular complications in the overall population.

In addition, we will also examine whether the use of 5 French arterial sheaths in cases that
do not go onto intervention offsets the increase in bleeding risk, if any, associated with
pretreatment with 600 mg of clopidogrel. Very large diameter arterial sheaths (e.g., 10
French) have been associated with higher vascular complication rates, but whether 5 French
sheaths offer lower vascular complication rates than 6 French sheaths is uncertain. Nearly
all PCIs at our institution are performed using 6 French sheaths (which have larger lumens,
more accommodating of angioplasty equipment and higher injection rates of iodinated
contrast). Patients who undergo PCI following diagnostic angiography using a 5 French sheath
will require exchange for a larger 6 French arterial sheath. On the other hand, patients who
do not need angioplasty after coronary angiography will not require any exchange of their
arterial sheath, and those with smaller sheath sizes may well have less vascular and
bleeding complications.

DESCRIPTION OF RESEARCH PROTOCOL Design: This is a prospective randomized clinical trial
comparing ischemic, hemorrhagic and vascular outcomes in outpatients undergoing elective
cardiac catheterization with coronary angiography following 1:1 randomization to
pretreatment with 600 mg clopidogrel vs. no pretreatment (and clopidogrel dosing
post-procedure if a PCI is performed). Patients will provide written informed consent prior
to enrollment and randomization. Since some operators may feel strongly about using
glycoprotein IIb/IIIa inhibition in patients who did not receive clopidogrel well in advance
of the PCI, blinding of the loading strategy and use of a placebo are not feasible. A
separate 1:1 randomization will assign patients to undergo cardiac catheterization using 5
or 6 French arterial introducing sheaths. Since the arterial sheath sizes are color-coded,
catheter sizes are imprinted on each catheter, and the operator must know the arterial
sheath size in case alternate catheters are required, blinding of sheath size assignment is
also not feasible. The investigator adjudicating and abstracting the outcomes data such as
bleeding and ischemic complications for analysis will be blinded, however, to the
clopidogrel reimen and randomization in order to avoid any bias.

Hypotheses to be tested: The primary hypothesis being examined is that clopidogrel 600 mg
given ≥2 hours prior to cardiac catheterization will reduce the frequency of post-procedural
ischemic events in the subset of patients who undergo ad hoc coronary interventions compared
with those who do not receive clopidogrel pre-procedure. The risk of hemorrhagic and
vascular complications by preloading strategy will be evaluated in all patients randomized
(encompassing those who do and those who do not undergo PCI). Additional analyses will be
performed to see if the size of the initial arterial introducing sheath also has an effect
on the rate of hemorrhagic and vascular complications and if there is any interaction of
sheath size with preloading strategy on these outcomes.

Patient population: All outpatients undergoing elective cardiac catheterization with planned
coronary angiography with possible ad hoc PCI (if lesion anatomy suitable) and who have not
received clopidogrel or ticlopidine during the 14 days prior to the procedure are eligible.
Patients with high-risk clinical features, contraindications to clopidogrel, or planned
upcoming invasive procedures will be excluded (vide infra).

Procedural factors: The decision to perform ad hoc PCI after diagnostic coronary angiography
(vs. medical therapy or bypass surgery) will be made by the interventional cardiologist
performing or overseeing the cardiac catheterization, in consultation with the patient's
clinical cardiologists. The specific angioplasty techniques, devices, equipment,
anti-thrombin and anti-platelet pharmacological regimen to be utilized are NOT specified by
this protocol and are at the discretion of the interventional cardiologist.

Patients randomized to 5 French arterial sheaths and NO clopidogrel preloading will be
allowed to ambulate 2 hours after arterial hemostasis is achieved (with delayed ambulation
if bleeding or orthostatic hypotension occurs). All other participants (i.e., 6 French
arterial sheaths, or 5 French arterial sheaths with clopidogrel preloading) will be allowed
to ambulate no earlier than 4 hours after hemostasis occurs.

Variables of interest include baseline demographic and clinical characteristics (including
age, gender, left ventricular ejection fraction, diabetes mellitus, hypertension,
dyslipidemia, chronic renal insufficiency, serum creatinine level, tobacco use, extent of
coronary disease, symptom severity, prior myocardial infarction, prior PCI, prior CABG),
angiographic lesion characteristics (e.g., bifurcation location, lesion class), procedural
factors (e.g., pharmacological antithrombin regimen, glycoprotein IIb/IIIa inhibitor use),
and post-procedural tests (including serum creatinine, serum creatine kinase and its MB
isoform, troponin-T, and radiological imaging studies). Information will be gleaned from the
Cardiac Catheterization Laboratory Quality Assurance Database, from electronic medical
records, from review of the procedural angiograms, and conversations with the patient (or if
the patient cannot be located, their family or health care providers).

Endpoints: All endpoints will be assessed at 14 days post-procedure (and divided for
analytical purposes into in-hospital and post-discharge events). See Endpoint section of
this document for details.

Follow-up: Written and electronic medical records will be reviewed to identify clinical
events occurring during the hospitalization (through the 1st 14 days post-procedure if the
length of stay is prolonged). Participants will have provided written informed consent for
clinical follow-up at 14 days post-procedure prior to entry into this study, and contact
information for the patient, his/her primary care provider, his/her cardiologist, and
his/her next of kin will be collected before discharge. The patient, his/her physicians, or
his/her next of kin will be contacted by telephone at 14 or more days post-procedure and
asked if the patient was treated after discharge for any heart-related, bleeding, or
vascular access site problems (i.e., any of the clinical events detailed above). If yes,
attempts will be made, with the patient's authorization, to obtain more information about
the event, including requests for documentation from other health care facilities and
providers.

Data Monitoring and Safety Plan: A independent data safety monitoring committee (DSMC)
comprised of Murray Mittleman, MD, DrPH (BIDMC cardiovascular epidemiologist, serving as
Chair), David J. Cohen, MD, MSc (interventional cardiologist at the Mid America Heart
Institute), and Shiva Gautam, PhD (BIDMC biostatistician) will review the rates of the 4
composite endpoints enumerated above after 14 day follow-up has been completed on the 1st
300 subjects enrolled. The DSMC will advise the principal investigator whether the study
should terminated because of concerning and striking differences in the ischemic or
vascular/bleeding complication rates between treatment strategies or if the study should be
allowed to continue to the planned enrollment of 600 participants. Study recruitment will be
suspended during the DSMC's review and deliberations.

Data Management: Much of the data required for this study is routinely collected as part of
current clinical care, quality assurance and regulatory processes and stored in the Cardiac
Catheterization Laboratory Quality Assurance Database (residing a commercial application
named Apollo and manufactured by Lumedx). The fields of interest for patients randomized in
this study will be queried form the Apollo database and transferred directly to the Access
database that serves as the primary electronic data repository for this study. This database
will be housed on a network server within the BIDMC firewall with restricted access
(password and valid user identification required). Additional information (from medical
records or patient contacts) will be collected on paper case report forms prior to entry
into the Access database. All case report forms and paper clinical information with patient
identifiers will be stored in a locked file drawer within a locked office. Angiograms will
be reviewed using clinical workstations in physically secured areas, and electronic copies
of angiograms will be made with all patient identifiers electronically removed. Medical
record numbers and names will be removed prior to creation of final analytical dataset. All
paper and electronic information will be destroyed in a HIPAA-compliant fashion after
completion and publication of this study.

Statistical Considerations Randomization: A randomization scheme will be prepared using
1:1:1:1 ratios (for the 2 clopidogrel dosing strategies combined independently with 5 vs. 6
French arterial sheaths) with permuted blocks of random sizes of 4 or 8. The treatment
assignment will be designated in opaque, tamper-resistant randomization envelopes provided
by the Statistical Department of the Harvard Clinical Research Institute.

Statistical Analysis: All statistical analyses will be performed using SAS for Windows v9.
The primary analysis will compare the cumulative incidence at 14 days of the primary
composite endpoint (any death, myocardial infarction, or myocardial necrosis) in patients
with PCI attempted between those randomized to clopidogrel loading vs. those randomized to
standard clopidogrel administration using the Fisher's exact test. A p value of 0.05 or less
will be required for statistical significance. The secondary endpoint of stent thrombosis
among those who undergo stent deployment will also be evaluated using Fisher's exact test.
The other endpoints (including vascular and bleeding) will be examined in all patients
randomized (and not just subsets who had PCI attempted or stents deployed). Two group
comparisons (clopidogrel loading vs. standard dosing; 5 French vs. 6 French arterial
sheaths) and 4 group comparisons (the 4 combinations of clopidogrel dosing strategy and
arterial sheath size; or subgroups with PCI or no PCI by clopidogrel dosing strategy) will
be performed using Fisher's exact test, t-tests, ANOVA, or analogous non-parametric tests as
appropriate. Since multiple exploratory analyses will be performed, p-values for everything
other than the primary analysis delineated above must be interpreted with caution.
Logistical regression models will also be constructed to identify pre-procedural predictors
of ischemic and of bleeding or vascular complications.

Inclusion Criteria:

1. Patient less than 18 years of age

2. Patient referred as an outpatient for elective cardiac catheterization with coronary
angiography and ad hoc percutaneous coronary intervention (if coronary anatomy
suitable)

3. Patient has stable angina or a stress test suggestive of ischemia and/or prior
myocardial infarction

4. Anticipated femoral arterial approach for the cardiac catheterization procedure

5. Patient provides written informed consent

Exclusion Criteria:

Patients will be excluded if any of the following are present:

1. Use of clopidogrel or ticlopidine during the 14 days prior to the scheduled procedure

2. Known hypersensitivity to clopidogrel (regardless of desensitization) or to any other
components of Plavix

3. Contraindication to clopidogrel, including

1. Pre-existing bleeding disorder or hematological dyscrasia

2. INR >1.4 immediately prior to the scheduled procedure

3. Platelet count <50 K/uL

4. Significant bleeding during the 14 days prior to the scheduled procedure

5. Surgery or invasive procedure at a non-compressible location during the 30 days
prior to the scheduled procedure

6. Anticipated need for surgery or other invasive procedure within 30 days
following the scheduled procedure

7. Patient states unwillingness to undergo transfusion of red blood cells even in
the event of life threatening bleeding

4. Unstable cardiac status

1. Patient was admitted for a cardiac condition and referred as an inpatient for
cardiac catheterization

2. Myocardial infarction diagnosed as occurring during the 30 days prior to the
scheduled procedure

3. Pre-procedure troponin-T >0.01 ng/mL

4. Unstable angina

i. Ischemic symptoms at rest ii. Ischemic symptoms with mild exertion (e.g., walking
one to two level blocks or climbing one flight of stairs) e. Pre-procedure
electrocardiogram with ST segment changes indicative of ongoing myocardial injury or
ischemia

5. Chronic renal failure (which may raise troponin-T levels)

1. Patient currently undergoing dialysis

2. Serum creatinine >2 mg/dL

3. Estimated glomerular filtratation rate (eGFR using the MDRD formula) <45
mL/min/1.73 m2

6. Procedural factors

1. Patient does not require coronary angiography as part of the scheduled cardiac
catheterization

2. Patient is not a candidate for percutaneous coronary intervention during the
same procedure as the diagnostic coronary angiography

3. Anticipated need for arterial access using brachial, radial or other non-femoral
approach

4. Anticipated need to access the femoral artery via a femoral bypass graft

5. Anticipated need for an arterial sheath 6 French in size or larger (e.g.,
planned evaluation of aortic stenosis or hypertrophic cardiomyopathy)

6. Anticipated need for heparin anticoagulation during the diagnostic cardiac
catheterization procedure (e.g., crossing a stenosed aortic valve with a 0.035"
wire, planned intra-vascular ultrasound or pressure wire study)

7. Woman of child-bearing potential who does not have a negative pregnancy test
immediately prior to the scheduled procedure

8. Participation in another non-observational clinical study that has not yet completed
all mandatory follow-up (i.e., patients who are participating in a "natural history"
observational registry where no active therapy is being investigated may participate)

9. Prior participation in this study

10. Inability to provide written informed consent or demonstrate understanding of the
risks and benefits associated with participation in this study