Heart Transplant Surgery, Lung Transplant Surgery
Conditions
Keywords
Heart and Lung transplantation surgery, Pulmonary vasodilation therapy
Brief summary
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
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.
Interventions
DRUGiNO
Subject will receive inhaled Nitric Oxide in this intervention
DRUGiEPO
Subject will receive inhaled Epoprostrenol in this intervention
Sponsors
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Grade 3 Primary Graft Dysfunction (PGD) for Lung Transplant Subjects | Up to 72 hours | 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. |
| Number of Participants With Moderate or Severe RV Failure for the LVAD Implantation Subjects and Severe RV Failure for Heart Transplantation Subjects | up to approximately 21 days after LVAD placement, up to approximately 30 days after heart transplantation | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Length of ICU Stay | up to approximately 90 days after index surgery | Length of time from ICU admission from surgery until ICU discharge |
| Length of Hospital Stay | up to approximately 1 year after index surgery | Length of time from surgery to hospital discharge |
| Number of Participants With Acute Kidney Injury | up to approximately 14 days | 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 |
| Duration of Postoperative Mechanical Ventilation | up to approximately 90 days after index surgery | Length of time from intubation until patient is extubated |
| Number of Participants With Post-operative Mortality Within 30 Days | up to approximately 30 days after index surgery | From the day of surgery to 30 days postoperatively. |
| Number of Participants With Post-operative Mortality Within 90 Days | up to approximately 90 days after index surgery | From the day of surgery to 90 days after index surgery |
| Number of Participants With In-hospital Mortality | up to approximately 1 year after index surgery | Death that occurs during the hospital stay |
| Per Patient Inhaled Pulmonary Vasodilator (iPVD) Cost | up to approximately 30 days after index surgery | 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. |
Countries
United States
Participant flow
Pre-assignment details
519 participants were randomized, but 87 of those were unable to undergo surgery on protocol. 432 participants started the study (i.e., underwent surgery on protocol).
Participants by arm
| Arm | Count |
|---|---|
| Lung Transplant With iNO iNO: Subject will receive inhaled Nitric Oxide in this intervention | 98 |
| Lung Transplant With iEPO iEPO: Subject will receive inhaled Epoprostrenol in this intervention | 103 |
| Heart Transplant & LVAD Implantation With iNO iNO: Subject will receive inhaled Nitric Oxide in this intervention | 111 |
| Heart Transplant & LVAD Implantation With iEPO iEPO: Subject will receive inhaled Epoprostrenol in this intervention | 120 |
| Total | 432 |
Baseline characteristics
| Characteristic | Lung Transplant With iNO | Lung Transplant With iEPO | Heart Transplant & LVAD Implantation With iNO | Heart Transplant & LVAD Implantation With iEPO | Total |
|---|---|---|---|---|---|
| Age, Continuous | 64 years | 64 years | 59 years | 58 years | 60 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 3 Participants | 1 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 92 Participants | 96 Participants | 107 Participants | 116 Participants | 411 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 4 Participants | 1 Participants | 3 Participants | 12 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 9 Participants | 44 Participants | 47 Participants | 112 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) White | 83 Participants | 91 Participants | 66 Participants | 72 Participants | 312 Participants |
| Sex: Female, Male Female | 39 Participants | 33 Participants | 25 Participants | 35 Participants | 132 Participants |
| Sex: Female, Male Male | 59 Participants | 70 Participants | 86 Participants | 85 Participants | 300 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 98 | 10 / 103 | 10 / 111 | 21 / 120 |
| other Total, other adverse events | 42 / 98 | 41 / 103 | 40 / 111 | 48 / 120 |
| serious Total, serious adverse events | 9 / 98 | 10 / 103 | 10 / 111 | 21 / 120 |
Outcome results
Primary
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.
Time frame: Up to 72 hours
Population: Only applicable to lung transplant patients on protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lung Transplant With iNO | Number of Participants With Grade 3 Primary Graft Dysfunction (PGD) for Lung Transplant Subjects | 39 Participants |
| Lung Transplant With iEPO | Number of Participants With Grade 3 Primary Graft Dysfunction (PGD) for Lung Transplant Subjects | 46 Participants |
p-value: 0.01990% CI: [-0.064, 0.162]two one sided test p-value
Primary
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.
Time frame: up to approximately 21 days after LVAD placement, up to approximately 30 days after heart transplantation
Population: Only applicable to heart transplant and LVAD implantation cohort that were treated on protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lung Transplant With iNO | Number of Participants With Moderate or Severe RV Failure for the LVAD Implantation Subjects and Severe RV Failure for Heart Transplantation Subjects | 25 Participants |
| Lung Transplant With iEPO | Number of Participants With Moderate or Severe RV Failure for the LVAD Implantation Subjects and Severe RV Failure for Heart Transplantation Subjects | 30 Participants |
p-value: 0.01290% CI: [-0.066, 0.116]two one-sided test p-value
Secondary
Duration of Postoperative Mechanical Ventilation
Length of time from intubation until patient is extubated
Time frame: up to approximately 90 days after index surgery
Population: Among patients extubated, if patients transitioned directly from intubation to tracheostomy the duration of mechanical ventilation was censored at the time of tracheostomy placement
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lung Transplant With iNO | Duration of Postoperative Mechanical Ventilation | 17 hours |
| Lung Transplant With iEPO | Duration of Postoperative Mechanical Ventilation | 18 hours |
| Heart Transplant & LVAD Implantation With iNO | Duration of Postoperative Mechanical Ventilation | 26 hours |
| Heart Transplant & LVAD Implantation With iEPO | Duration of Postoperative Mechanical Ventilation | 24 hours |
p-value: 0.74795% CI: [-3, 3]Log Rank
p-value: 0.63895% CI: [-1, 1]Log Rank
Secondary
Length of Hospital Stay
Length of time from surgery to hospital discharge
Time frame: up to approximately 1 year after index surgery
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lung Transplant With iNO | Length of Hospital Stay | 23 days |
| Lung Transplant With iEPO | Length of Hospital Stay | 23 days |
| Heart Transplant & LVAD Implantation With iNO | Length of Hospital Stay | 16 days |
| Heart Transplant & LVAD Implantation With iEPO | Length of Hospital Stay | 17 days |
p-value: 0.86495% CI: [0.75, 1.41]log-linear regression
p-value: 0.82595% CI: [0.73, 1.28]log-linear regression
Secondary
Length of ICU Stay
Length of time from ICU admission from surgery until ICU discharge
Time frame: up to approximately 90 days after index surgery
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lung Transplant With iNO | Length of ICU Stay | 4 days |
| Lung Transplant With iEPO | Length of ICU Stay | 4 days |
| Heart Transplant & LVAD Implantation With iNO | Length of ICU Stay | 6 days |
| Heart Transplant & LVAD Implantation With iEPO | Length of ICU Stay | 6 days |
p-value: 0.45395% CI: [0.76, 1.87]log-linear regression
p-value: 0.81695% CI: [0.57, 1.56]log-linear regression
Secondary
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
Time frame: up to approximately 14 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lung Transplant With iNO | Number of Participants With Acute Kidney Injury | 72 Participants |
| Lung Transplant With iEPO | Number of Participants With Acute Kidney Injury | 68 Participants |
| Heart Transplant & LVAD Implantation With iNO | Number of Participants With Acute Kidney Injury | 96 Participants |
| Heart Transplant & LVAD Implantation With iEPO | Number of Participants With Acute Kidney Injury | 101 Participants |
p-value: 0.25195% CI: [0.78, 2.61]Chi-squared
p-value: 0.61995% CI: [0.58, 2.5]Chi-squared
Secondary
Number of Participants With In-hospital Mortality
Death that occurs during the hospital stay
Time frame: up to approximately 1 year after index surgery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lung Transplant With iNO | Number of Participants With In-hospital Mortality | 5 Participants |
| Lung Transplant With iEPO | Number of Participants With In-hospital Mortality | 7 Participants |
| Heart Transplant & LVAD Implantation With iNO | Number of Participants With In-hospital Mortality | 6 Participants |
| Heart Transplant & LVAD Implantation With iEPO | Number of Participants With In-hospital Mortality | 11 Participants |
Secondary
Number of Participants With Post-operative Mortality Within 30 Days
From the day of surgery to 30 days postoperatively.
Time frame: up to approximately 30 days after index surgery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lung Transplant With iNO | Number of Participants With Post-operative Mortality Within 30 Days | 2 Participants |
| Lung Transplant With iEPO | Number of Participants With Post-operative Mortality Within 30 Days | 1 Participants |
| Heart Transplant & LVAD Implantation With iNO | Number of Participants With Post-operative Mortality Within 30 Days | 4 Participants |
| Heart Transplant & LVAD Implantation With iEPO | Number of Participants With Post-operative Mortality Within 30 Days | 7 Participants |
p-value: 0.61495% CI: [0.19, 23.82]Fisher Exact
p-value: 0.542495% CI: [0.17, 2.12]Fisher Exact
Secondary
Number of Participants With Post-operative Mortality Within 90 Days
From the day of surgery to 90 days after index surgery
Time frame: up to approximately 90 days after index surgery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lung Transplant With iNO | Number of Participants With Post-operative Mortality Within 90 Days | 4 Participants |
| Lung Transplant With iEPO | Number of Participants With Post-operative Mortality Within 90 Days | 4 Participants |
| Heart Transplant & LVAD Implantation With iNO | Number of Participants With Post-operative Mortality Within 90 Days | 5 Participants |
| Heart Transplant & LVAD Implantation With iEPO | Number of Participants With Post-operative Mortality Within 90 Days | 12 Participants |
Secondary
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.
Time frame: up to approximately 30 days after index surgery
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lung Transplant With iNO | Per Patient Inhaled Pulmonary Vasodilator (iPVD) Cost | 544 relative cost units | Standard Deviation 513 |
| Lung Transplant With iEPO | Per Patient Inhaled Pulmonary Vasodilator (iPVD) Cost | 70 relative cost units | Standard Deviation 70 |
| Heart Transplant & LVAD Implantation With iNO | Per Patient Inhaled Pulmonary Vasodilator (iPVD) Cost | 772 relative cost units | Standard Deviation 554 |
| Heart Transplant & LVAD Implantation With iEPO | Per Patient Inhaled Pulmonary Vasodilator (iPVD) Cost | 114 relative cost units | Standard Deviation 121 |