Statin InTensity to Prevent Coronary Artery Vasculopathy After Heart Transplantation

Study Overview
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Brief Summary
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The investigator's propose to conduct an open-label randomized controlled trial to determine if higher intensity statin (HS) can reduce CAV in comparison to lower intensity statin (LS) after HT. All consecutive patients that meet eligibility criteria will be approached for participation. After heart transplantation, participants (n=70) will be randomized in a 1:1 manner to either HS (Atorvastatin 80 mg daily) or LS (Pravastatin 40 mg daily). Study participation will be for 2 years from the time of randomization.

Detailed Description
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Outcomes after heart transplantation (HT) are limited by development of coronary allograft vasculopathy (CAV). CAV comprises of macro- and microvascular coronary disease and is the third leading cause of graft dysfunction and late mortality following HT. The pathophysiology of CAV is multifactorial and major pathways that are implicated include inflammation and dyslipidemia. These pathways are inhibited by statins which serve as the mainstay of CAV prevention. The International Society of Heart and Lung Transplantation (ISHLT) guidelines recommend administration of low intensity statins (LS) due to a potential drug-drug interaction (DDI) with calcineurin inhibition (CNI) therapy. This DDI is related to concurrent use of an older generation CNI, cyclosporin A (CsA). CsA inhibits intestinal P-glycoprotein to reduce the efflux of statin into the gastrointestinal tract, thereby increasing statin levels in the blood and risk of myopathy. However, the current generation of CNI being utilized in most patients, Tacrolimus, does not inhibit P glycoprotein and may not impact statin levels after HT. Despite use of LS, the residual risk of CAV development is elevated with nearly half of the patients having angiographic detection 5 years after HT. However, angiography is limited by its inability to detect microvascular disease and invasiveness. Early CAV is also detectable by non-invasive imaging with cardiac positron emission tomography (cPET) through measurement of myocardial flow reserve (MFR). MFR assesses total burden of macro- and microvascular disease and is well correlated with invasive measures of CAV and prognosis. The protective and inhibitory effects of statins are proportional to their intensity with higher intensity statins (HS) leading to a greater reduction in low density lipoprotein (LDL) and inflammatory markers such as C-reactive protein (CRP) in comparison to LS. Despite these potentially beneficial effects of HS, LS remains the agent of choice for primary prevention of CAV after HT in the absence of a randomized controlled trial (RCT). The investigator's propose to conduct an open-label RCT to determine if HS can reduce CAV in comparison to LS after HT. All consecutive HT candidates that meet eligibility criteria will be approached for participation. After HT, participants (n=70) will be randomized in a 1:1 manner to either HS (Atorvastatin 80 mg daily) or LS (Pravastatin 40 mg daily). Study participation will be for 2 years from the time of randomization. Study outcomes will be compared by research staff blinded to statin group assignment.

Official Title
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Statin InTensity to Prevent Coronary Artery Vasculopathy After Heart Transplantation - SToP-CAV

Conditions
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Vasculopathy

Intervention / Treatment
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* Drug: Atorvastatin 80 Mg Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Waitlisted for Heart Transplantation Capacity to provide informed consent Exclusion Criteria: History of statin allergy or intolerance Hepatic dysfunction Redo Heart Transplant Awaiting combined heart and liver transplantation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open-label, randomized controlled trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Higher Intensity Statin<br>Atorvastatin 80 mg daily | Drug: Atorvastatin 80 Mg Oral Tablet<br>* Higher intensity statin<br>* Other names: Lipitor;|
| Active Comparator: Lower Intensity Statin<br>Pravastatin 40 mg daily | Drug: Atorvastatin 80 Mg Oral Tablet<br>* Higher intensity statin<br>* Other names: Lipitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myocardial Flow Reserve | Myocardial Flow Reserve measured by cardiac positron emission tomography | 2 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Coronary Vascular Resistance | Coronary Vascular Resistance measured by cardiac positron emission tomography | 2 year | 
| Change in Global Longitudinal Strain | Change in Global Longitudinal Strain measured by echocardiography | baseline, 1 year and 2 year | 
| Blood level of Low Density Lipoprotein | Blood level of Low Density Lipoprotein | baseline, 6, 12, 18, 24 months | 
| Blood level of High Sensitivity C-Reactive Protein | Blood level of High Sensitivity C-Reactive Protein | baseline, 6, 12, 18, 24 months |