Statin InTensity to Prevent Coronary Artery Vasculopathy After Heart Transplantation

Not Applicable

Withdrawn

• Conditions: Vasculopathy
• Interventions: Drug: Atorvastatin 80 Mg Oral Tablet; Drug: Pravastatin 40 Mg Oral Tablet

• Registration Number: NCT05251129
• Lead Sponsor: Montefiore Medical Center

Brief Summary

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 or LS. 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.

Detailed Description

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).

Study Timeline

• Study First Submitted: 2021-12-17
• Study First Submitted QC: 2022-02-17
• Study First Posted: 2022-02-22
• Status Verified: 2025-01
• Study Start: 2025-01
• Last Update Submitted: 2025-01-09
• Last Update Posted: 2025-01-13
• Primary Completion: 2030-06
• Study Completion: 2030-06

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: 70

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Higher Intensity Statin	Atorvastatin 80 Mg Oral Tablet	Atorvastatin 80 milligram (mg) oral tablet
Lower Intensity Statin	Pravastatin 40 Mg Oral Tablet	Pravastatin 40 mg oral tablet

Primary Outcome Measures

Name	Time	Method
Myocardial Flow Reserve	2 year	Myocardial Flow Reserve measured by cardiac positron emission tomography

Secondary Outcome Measures

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