Cardiac Allograft Vasculopathy
Conditions
Keywords
Heart Transplantation, Endothelin-1, Cardiac Allograft Vasculopathy
Brief summary
Many patients with end-stage heart failure, a condition in which the heart fails to pump enough blood to support the body's other organs, are fortunate enough to receive a heart transplant. However, despite taking medicines aimed at blunting the immune system's response to the donor heart, some of them will develop transplant-related disease in the coronary arteries supplying their hearts. Fifty years after the first human-to-human heart transplant, this disorder-cardiac allograft vasculopathy (CAV)-remains a leading cause of long-term death and has been coined the 'Achilles' Heel' of heart transplantation. Indeed, a better understanding of how CAV occurs and improved therapies to prevent and/or slow its development are desperately needed to meaningfully impact patient outcomes. Endothelin-1 (ET-1) is a key molecular regulator of arterial health, and our prior data suggests that it is associated with accelerated CAV. In this particular study of recent heart transplant recipients, we are asking: Does ET-1 contribute to the coronary artery's capacity to dilate/constrict? To answer this question, during the cardiac catheterization at 1 year post-transplant (standard of care), we will measure blood levels of ET-1 and perform an invasive evaluation of coronary vasomotor function inn a consecutive subset of patients who will have received a 1-week course of the oral endothelin receptor antagonist (macitentan) prior this catheterization, which will allow us to test how much ET-1 contributes to coronary responsiveness. The findings from this study may provide the necessary foundation to study whether endothelin receptor antagonists are able to effectively reduce the rate of accelerated CAV.
Interventions
DRUGMacitentan
Macitentan is a nonselective endothelin-receptor antagonist (ERA) that is approved for use in pulmonary arterial hypertension (PAH); the use of Macitentan in post-heart transplant patients is considered investigational.
Sponsors
American Heart Association
Janssen, LP
University of California, Los Angeles
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 1\) New heart transplant recipients already enrolled into a prospective cohort (parent) study * 1a) Underwent baseline coronary angiography within the first 4 months of heart transplantation * 1b) Have yet to complete 1-year coronary angiogram * 2\) ≥18 years old * 3\) Have a serum creatinine \< 2.0 mg/dL (to minimize risk of contrast-induced nephropathy) * 4\) Able to provide informed written consent.
Exclusion criteria
* 1\) Multi-organ transplant * 2\) Transplant-related complications and comorbidities that preclude the ability to safely perform an invasive coronary evaluation in the cardiac catheterization laboratory * 3\) Pregnant women due to possible fetal harm; all women of childbearing potential must have a negative pregnancy test within 1 week of starting Macitentan, and 30 days after completing the one-week course of Macitentan. * 4\) Patients who are taking potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir) as these drugs can expose one to higher levels of macitentan * 5\) Cirrhosis or baseline liver function tests (AST/ALT) \> 3x the upper limit of normal
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Macitentan: Nitroglycerin (NTG) Luminal Dilation Ratio as Proportion of Vasomotor Tone Attributable to Endothelin-1 (ET-1) | End of study week 1 (time of 1 year post-transplant coronary angiogram) | Macitentan: NTG luminal volume dilation ratio on Intravascular Ultrasound (IVUS). Vasodilation achieved by Macitentan was compared with that after intracoronary nitroglycerin, a maximal dilator of epicardial arteries, to determine the relative contribution of ET-1 to the overall resting vasomotor tone. The contribution of ET-1 to resting vasomotor tone is expressed as the ratio of dilation to Macitentan over the dilation to nitroglycerin. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intervention Arm A consecutive subset of eligible patients based on inclusion/exclusion criteria will receive a 1-week course of Macitentan (10 mg po daily) prior to their routine 1-year coronary angiogram (7th and final dose of Macitentan will occur on the day of the angiogram).
Macitentan: Macitentan is a nonselective endothelin-receptor antagonist (ERA) that is approved for use in pulmonary arterial hypertension (PAH); the use of Macitentan in post-heart transplant patients is considered investigational. | 19 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Intervention Arm |
|---|---|
| Age, Continuous | 54.2 years |
| Race/Ethnicity, Customized Hispanic | 6 Participants |
| Race/Ethnicity, Customized Non-Hispanic Asian | 1 Participants |
| Race/Ethnicity, Customized Non-Hispanic Black | 1 Participants |
| Race/Ethnicity, Customized Non-Hispanic White | 10 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Region of Enrollment United States | 19 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 19 |
| other Total, other adverse events | 0 / 19 |
| serious Total, serious adverse events | 0 / 19 |
Outcome results
Primary
Macitentan: Nitroglycerin (NTG) Luminal Dilation Ratio as Proportion of Vasomotor Tone Attributable to Endothelin-1 (ET-1)
Macitentan: NTG luminal volume dilation ratio on Intravascular Ultrasound (IVUS). Vasodilation achieved by Macitentan was compared with that after intracoronary nitroglycerin, a maximal dilator of epicardial arteries, to determine the relative contribution of ET-1 to the overall resting vasomotor tone. The contribution of ET-1 to resting vasomotor tone is expressed as the ratio of dilation to Macitentan over the dilation to nitroglycerin.
Time frame: End of study week 1 (time of 1 year post-transplant coronary angiogram)
Population: Sixteen patients had interpretable IVUS data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Participants With Progressive Cardiac Allograft Vasculopathy (CAV) at 1-year Post-transplant | Macitentan: Nitroglycerin (NTG) Luminal Dilation Ratio as Proportion of Vasomotor Tone Attributable to Endothelin-1 (ET-1) | 0.33 ratio |
| Participants Without Progressive Cardiac Allograft Vasculopathy (CAV) at 1-year Post-transplant | Macitentan: Nitroglycerin (NTG) Luminal Dilation Ratio as Proportion of Vasomotor Tone Attributable to Endothelin-1 (ET-1) | 0.30 ratio |