Inhaled Selective Pulmonary Vasodilators for Advanced Heart Failure Therapies and Lung Transplantation Outcomes

Study Overview
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Brief Summary
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1. to conduct a clinical investigation to determine if inhaled epoprostenol (Veletri®, iEPO) and inhaled nitric oxide (iNO) will have similar impact on outcomes in adult patients undergoing durable LVAD placement, heart transplantation, or lung transplantation 2. to conduct a cost-capture analysis on the expense each drug incurs per patient.

Detailed Description
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In adult cardiothoracic surgical patients, iNO is used to treat precapillary pulmonary hypertension (PH), right-sided heart failure (RHF), and ventilation-to-perfusion (V:Q) mismatch. Adult patients who undergo durable LVAD implantation (e.g. Heartware®, Heartmate 2®, or Heartmate 3®), cardiac transplantation for HFrEF, or those that have endured lung transplantation as a result of end-stage lung disease, compose the largest subpopulation which receives iPVD therapy at Duke University Hospital. iEPO may display an equivalent efficacy profile to iNO for pulmonary vasodilation and oxygenation and have a similar impact on clinical outcomes. Subjects undergoing LVAD placement or heart transplantation (N=224) or lung transplantation (N=200) will be prospectively enrolled over a three-year period (one-year for follow-up). Patients will be randomly assigned 1:1 according to stratified randomization blocking either iNO or iEPO. Additional study procedures will involve data collection, blood, and tissue sampling.

Official Title
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Inhaled Selective Pulmonary Vasodilators for Advanced Heart Failure Therapies and Lung Transplantation Outcomes

Conditions
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Heart Transplant Surgery, Lung Transplant Surgery

Intervention / Treatment
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* Drug: iNO
* Drug: iEPO


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Heart transplantation LVAD placement Lung Transplantation Exclusion Criteria: Combined Organ Transplantation Age < 18 years old Pregnancy Known allergy to prostaglandin (rare) Refusal of blood products due to personal or religious preference Subject is enrolled in another study protocol, which does not allow randomization of PVD therapy Heart transplant or durable LVAD recipients with adult congenital heart disease (CHD) o Caveat: Does NOT meet exclusion criteria if the scheduled heart transplant or LVAD implantation is due to heart failure from a previous heart transplantation related to CHD, performed more than 90 days previous to the date of trial enrollment Heart transplant recipients diagnosed with Arrythmogenic Right Ventricular Cardiomyopathy Heart transplant recipients diagnosed with Acute Cardiac Allograft Rejection after a previous heart transplantation. Heart transplant or durable LVAD recipients with preoperative RVAD for right heart failure Patient is scheduled to undergo lung transplantation but has undergone heart transplantation in the previous 90 days Patient is scheduled to undergo durable LVAD implantation but has undergone heart transplantation in the previous 90 days Patient is scheduled to undergo heart transplantation but has undergone lung transplantation in the previous 90 days Patients with preoperative Venovenous ECMO as a bridge to lung transplantation Heart transplant or durable LVAD recipients with preoperative RVAD for right heart failure

Ages Eligible for Study
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Minimum Age: 18 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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Lung transplant with iNO<br> | Drug: iNO<br>* Subject will receive inhaled Nitric Oxide in this intervention<br>* Other names: Inhaled Nitric Oxide;|
| Active Comparator: Lung transplant with iEPO<br> | Drug: iEPO<br>* Subject will receive inhaled Epoprostrenol in this intervention<br>* Other names: Inhaled Epoprostrenol;|
| Active Comparator: Heart transplant & LVAD implantation with iNO<br> | Drug: iNO<br>* Subject will receive inhaled Nitric Oxide in this intervention<br>* Other names: Inhaled Nitric Oxide;|
| Active Comparator: Heart transplant & LVAD implantation with iEPO<br> | Drug: iEPO<br>* Subject will receive inhaled Epoprostrenol in this intervention<br>* Other names: Inhaled Epoprostrenol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grade 3 Primary Graft Dysfunction (PGD) for Lung Transplant Subjects | This is defined by the International Society of Heart and Lung Transplantation (ISHLT) as severe hypoxemia with a PaO2-to-FiO2 ratio < 200 or the presence of venovenous extracorporeal membrane oxygenation (VV ECMO) at a time-point within the first 72 hours after lung transplantation. | Up to 72 hours | 
| Number of Participants With Moderate or Severe RV Failure for the LVAD Implantation Subjects and Severe RV Failure for Heart Transplantation Subjects | This is defined by the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) score of moderate or severe right-heart failure for LVADS, and by the incidence of an RVAD placement or ECMO for RHF for heart transplants. | up to approximately 21 days after LVAD placement, up to approximately 30 days after heart transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Postoperative Mechanical Ventilation | Length of time from intubation until patient is extubated | up to approximately 90 days after index surgery | 
| Per Patient Inhaled Pulmonary Vasodilator (iPVD) Cost | Data reflects a per patient cost in dollars that has been scaled to a unit of measure relative to the cost per hour of drug and multiplied by the duration of iPVD administration. In our study, iNO cost 7 times that of iEPO per hour, hence for each patient this outcome value is the duration of iPVD administration multiplied by 7 if a patient is randomized to iNO or multiplied by 1 if randomized to iEPO. | up to approximately 30 days after index surgery | 
| Length of ICU Stay | Length of time from ICU admission from surgery until ICU discharge | up to approximately 90 days after index surgery | 
| Length of Hospital Stay | Length of time from surgery to hospital discharge | up to approximately 1 year after index surgery | 
| Number of Participants With Acute Kidney Injury | defined by Modified KDIGO-AKI definition: Increase in Serum Creatinine (Cr) by ≥0.3mg/dL within 48 hours; or Increase in Cr to ≥1.5 times baseline Urine output is not included as urine could be under-captured after Foley catheter removal | up to approximately 14 days | 
| Number of Participants With In-hospital Mortality | Death that occurs during the hospital stay | up to approximately 1 year after index surgery | 
| Number of Participants With Post-operative Mortality Within 30 Days | From the day of surgery to 30 days postoperatively. | up to approximately 30 days after index surgery | 
| Number of Participants With Post-operative Mortality Within 90 Days | From the day of surgery to 90 days after index surgery | up to approximately 90 days after index surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart and Lung transplantation surgery, Pulmonary vasodilation therapy