Strategies To Prevent Cardiac Allograft Vasculopathy Related Events in Heart Transplant Recipients

Proliferation signal inhibitors (PSIs), sirolimus and everolimus, have been demonstrated to
be effective immunosuppressants and delay the progression of cardiac allograft vasculopathy.
To date, there are no prospective studies designed to evaluate the potential use of PSIs as
a primary immunosuppressant in the prevention of cardiac allograft vasculopathy. The goals
of our study are to compare primary vs. secondary preventive strategies and to evaluate the
role of intravascular ultrasound compared to coronary angiogram in diagnosing CAV and
preventing CAV-related events. The specific aims of the study are:

1. To evaluate the effect of primary vs. secondary initiation of sirolimus on the
development of significant coronary artery (> 70% angiographic stenosis, Mean intimal
thickness (MIT) 0.5mm or greater, IVUS calculated coronary cross sectional area of <
4mm2 / <6mm2 for mid LAD/Left Maim (LM), < 0.75 fractional flow reserve (FFR) lesion
associated with a positive stress test), change in global left ventricle (LV) function,
incidence of rejection episodes, and hospitalizations at 1, 2, 3, and 4 years.

2. To determine the effect of IVUS-guided initiation of sirolimus on short-term and
long-term outcomes vs. angiogram-guided initiation of sirolimus

3. To determine whether prevention of progression of CAV diagnosed by IVUS prevents graft
dysfunction or death related to CAV or heart failure.

4. To assess the correlation between peripheral small artery elasticity, peripheral
biomarkers, and endothelial cells, and development of cardiac allograft vasculopathy in
order to develop a strategy for determining risk of progression and monitoring
treatment.

The study has a prospective and a retrospective arm

Prospective Arm Design: This is a prospective, randomized, partially-blinded pilot study.
Randomization for the study will be done in 2 stages.

The first stage of randomization will randomize subjects to either the early or late
initiation of sirolimus. At this stage of the randomization, subject will have a 30% chance
of being in group 1 (early-initiation of sirolimus), and a 70% chance of being in group 2
(diagnostic-guided sirolimus group).

The second stage randomization will be done only on subjects in group 2 (diagnostic-guided
sirolimus group) at the time of their first annual heart transplant review. At the time of
their annual heart transplant review, subjects in group 2 will have a 50% chance of being in
group 2A (CAV diagnosed by angiogram), and a 50% chance of being in group 2B (CAV diagnosed
by intravascular ultrasound).

Group 1: Initiate sirolimus at 6 months after transplant

Group 2A: Initiate sirolimus after development of angiographic stenosis of >70% in a major
epicardial vessel or >50% in the left main artery

Group 2B: Initiate sirolimus after development of maximal intimal thickness of 0.5 mm on
intravascular ultrasound

Retrospective Arm

The main objective of this retrospective study is to compare a treatment strategy based on
the diagnosis of CAV by intravascular ultrasound to a strategy guided by angiogram.

Design: This is a randomized, partially-blinded pilot study. Subjects will be randomized 1:1
to one of two groups. At the time of the randomization, the subject will have a 50% chance
of being in group 1 (initiation of sirolimus when CAV is diagnosed by angiogram) and a 50%
chance of being in group 2. (Initiation of sirolimus when CAV is diagnosed by IVUS)

Primary Endpoints for Prospective and Retrospective Arms

1. Change in maximal intimal thickness at 1, 2, 3 and 4 years

2. Combination of significant coronary artery disease (as described above), death, major
rejection episodes, and decrease in global ejection function of more than 10% from
baseline at 3 and 4years.

Secondary endpoints for Prospective and Retrospective Arms

1. Mean MIT at 1, 2, 3, and 4 years

2. Percent atheroma volume at 1,2,3 and 4 years

3. Death from CAV, death from any cause, myocardial infarction, need for PCI, number of
hospitalizations, infection rates, evidence of restrictive physiology, arrhythmic event
related to CAV or pulmonary hypertension at 4 years.

4. Change in small artery elasticity at 1, 2, 3, and 4 years

5. Change in endothelial progenitor cell count at 1 and 2 years

6. Change in biomarkers (see table) at 1 and 2 years

Inclusion Criteria

For Prospective Arm:

- 18 years or older

- Successful orthotropic heart transplant within 6 months of enrollment

Inclusion Criteria

For Retrospective Arm:

- 18 years or older

- Successful orthotropic heart transplant within 6 months to 3 years of enrolment

- Less than moderate CAV by angiogram or IVUS

Exclusion Criteria

For Prospective Arm:

- Greater than minimal baseline coronary disease

- Chronic kidney disease with creatinine >2mg/dl

- Baseline (1 month) ejection fraction < 50%

- IV contrast allergy

- Rejection within 3 months of enrollment

- Sensitivity to sirolimus or its derivatives

- Prior sirolimus use

Exclusion Criteria

For Retrospective Arm:

- Significant baseline (one month) coronary artery disease (>50% in one or more vessels
by angiogram or MIT >0.5 by IVUS)

- Chronic kidney disease with creatinine >2mg/dl

- Baseline (1 month) ejection fraction < 50%

- IV contrast allergy

- Rejection within 3 months prior to enrollment

- Sensitivity to sirolimus or its derivatives

- Prior sirolimus use