Angiotensin Converting Enzyme (ACE) Inhibition and Cardiac Allograft Vasculopathy

• Sponsor: Stanford University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01078363
• Collaborator: VA Palo Alto Health Care System (U.S. Fed), Cedars-Sinai Medical Center (Other)
• Enrollment: 96
• Locations: 2
• Arms: 2
• Duration (Months): 70
• Patients Per Site: 48
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

Cardiac transplantation is the ultimate treatment option for patients with end stage heart failure.

Cardiac allograft vasculopathy remains a leading cause of morbidity and mortality after transplantation.

Angiotensin converting enzyme inhibitors are used in less than one half of transplant recipients. Preliminary data suggest that angiotensin converting enzyme inhibitors retard the atherosclerotic plaque development that is the hallmark of cardiac allograft vasculopathy. Moreover, this class of drug appears to increase circulating endothelial progenitor cell number and has anti-inflammatory properties, both of which improve endothelial dysfunction, the key precursor to the development of cardiac allograft vasculopathy.

The objective of this project is to investigate the role of an angiotensin converting enzyme inhibitor, ramipril, in preventing the development of cardiac allograft vasculopathy. During the first month after cardiac transplantation subjects will undergo coronary angiography with intravascular ultrasound measurements of plaque volume in the left anterior descending coronary artery. Using a coronary pressure wire, epicardial artery and microvascular physiology will be assessed. Finally, endothelial function and mediators of endothelial function, including circulating endothelial progenitor cells, will be measured. Subjects will then be randomized in a double blind fashion to either ramipril or placebo. After 1 year, the above assessment will be repeated. The primary endpoint will be the development of cardiac allograft vasculopathy based on intravascular ultrasound-derived parameters. The second aim will be to assess the effect of ramipril on endothelial dysfunction early after transplantation. The final aim is to determine the impact of ramipril on coronary physiology early after transplantation.

Condition or Disease	Intervention/Treatment	Phase
Cardiac Allograft Vasculopathy	Drug: ramipril; Drug: Placebo	N/A

Detailed Description

During the first 4 years of this study, we plan to recruit patients within the first month after OHT. As has become routine at Stanford, study subjects will undergo baseline coronary angiography and IVUS assessment of their left anterior descending coronary artery. Coronary endothelial function will be assessed as well transmyocardial levels of ADMA and other mediators of endothelial function. Blood samples will be obtained for analyzing circulating EPC number and function. Epicardial and microvascular coronary physiology in the left anterior descending coronary artery will be determined by measuring FFR and IMR with a coronary pressure wire(in the adults only). Subjects will then be randomized to either the ACE I(Ramipril), or to placebo, in addition to their usual medications. During years 2 through 5 of this project, study subjects will undergo the above routine invasive assessments at 1 year after OHT. During the 5th year of this project, data analysis and manuscript preparation will occur.

Table 2. Patient Flowchart Time post OHT Event 0-4 Weeks Recruitment and enrollment 4-6 Weeks Baseline angiogram, endothelial function, coronary physiology and IVUS studies 4-6 (at time of baseline)Weeks Baseline blood sampling for circulating EPC studies 4-6 Weeks Randomization to ramipril or placebo to begin one week after baseline studies 5-7 Weeks Titration up of ramipril or placebo Month 3 and month 6: blood sampling for EPC studies. 11-13 Months 1 year angiogram, endothelial function, coronary physiology and IVUS studies 11-13 Months 1 year blood sampling for circulating EPC studies The primary endpoint of the study will be change in plaque volume as determined by IVUS analysis at baseline and 1 year later, between those treated with ramipril compared to those treated with placebo.

Secondary endpoints will include change in circulating EPC number and function, change in ADMA levels,change in coronary endothelium-dependent vasodilation, and change in coronary physiology (FFR and IMR)from baseline to 1 year. Although there are multiple potential mechanisms by which ACE I might reduce CAV, evaluating each of these is beyond the scope of this project. For this reason, we will focus on the likely common final pathway of endothelial dysfunction mediated by dysregulation of ADMA and NOS, as well as changes in EPCs. If this study shows a benefit to ACE I therapy in this population, the goal of future studies will be to determine the exact mechanism by which this occurs and to perform a large, multicenter study comparing ACE I to placebo with hard clinical endpoints. Study visits include two major time points 1) baseline angiogram and IVUS which include recording of angiographic data, lab data, clinical data. 2)assessment at the usual follow up periods post transplant, and these data points will also be collected for research purposes. after base line which usually occurs one month post transplant plus or minus 2 weeks. F/u = q 2 weeks until two months out from tx, then once per month until six months out from TX, then every two months until the patient is 12 months out from TX. Each routine f/u visit includes a physical exam,vital signs, echocardiogram, chest x-ray, a complete metabolic panel ( contains a Creatinine), Complete blood count, immunosuppressant drug blood levels, and a heart biopsy (at the same intervals described above).

Study Design

• Study Type: Interventional
• Actual Enrollment: 96 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• Official Title: ACE Inhibition and Cardiac Allograft Vasculopathy
• Study Start Date: Jun 1, 2009
• Actual Primary Completion Date: Apr 1, 2015
• Actual Study Completion Date: Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: ramipril ramipril, 5mg starting dose to maximum dose of 20mg daily dose for one year.	Drug: ramipril; Use of a ACE ( angiotension converting enzyme) inhibitors post heart Transplant for Blood pressure control.; Other Names: Altace
Placebo Comparator: Placebo Sugar pill manufactured to mimic ramipril 5mg starting dose , increasing to 20mg daily for one year.	Drug: Placebo; Use of a placebo post heart Transplant for Blood pressure control.

Outcome Measures

Primary Outcome Measures

1. Cardiac Allograft Vasculopathy(CAV) Defined as Change in IVUS-assessed Plaque Volume From Baseline to One Year [Baseline and 1 Year]

   also called transplant coronary artery disease or cardiac transplant vasculopathy defined as coronary artery stenosis(narrowing) ranging from 30 to 70 percent by coronary angiography. Measured in this study as change in IVUS-assessed Plaque Volume from baseline to one year.

Secondary Outcome Measures

1. Percentage of Participants With ≥20% Coronary Artery Diameter Reduction After Acetylcholine [At Baseline and 1 Year]

   The percent change in diameter of the left anterior descending artery was measured by quantitative angiography after acetylcholine and compared to baseline angiography. The percentage of participants who had ≥20% coronary artery diameter reduction after acetylcholine at one year is presented.

2. ADMA Level at One Year Post Transplant [1 year post Transplant]

   asymmetric dimethylarginine (ADMA), is an inhibitor of endothelial nitric oxide synthase which is a primary regulator of endothelial function.

3. The Percentage of Endothelial Progenitor Cells ( EPC) in Peripheral Blood in Patients One Year After Transplant [at one year]

   The determination of the percentage of EPC in peripheral blood involved surface staining peripheral blood mononuclear cells (PBMCs) with appropriate fluorescently-labeled antibodies to delineate EPCs from other blood cells, followed by analysis by conventional flow cytometry.

4. Fractional Flow Reserve (FFR) at One Year Post Transplant [at one year post Transplant]

   FFR is a technique used in coronary catheterization to measure pressure differences across a coronary artery stenosis (narrowing, usually due to atherosclerosis) to determine the likelihood that the stenosis impedes oxygen delivery to the heart muscle (myocardial ischemia). It is defined as the ratio of the distal coronary pressure to the proximal coronary pressure.

5. Index of Microcirculatory Resistance at One Year Post Heart Transplant [one year]

   The index of microcirculatory resistance (IMR) is a pressure-temperature sensor guidewire-based measurement, performed during cardiac catheterization, of the minimum microcirculatory resistance in a specific coronary artery. The IMR provides a quantitative measure of coronary microvasculature status.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Heart transplant recipient within the first month of transplant;

• 12 years of age or older;

• Must have a serum creatinine less than 2.0 mg/dl;

• Will provide written informed consent;

• Female patients of childbearing potential must have negative pregnancy test;

• For pediatric patient, parent(s) will provide consent and the child will sign assent.

Exclusion Criteria:

• Less than 12 years of age;

• Have more than one solid organ transplant at time of heart transplant;

• Has serum creatinine greater than 2.0 mg/dl;

• Pregnancy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Palo Alto Health Care System	Palo Alto	California	United States	94304
2	Stanford University School of Medicine	Stanford	California	United States	94305

Sponsors and Collaborators

• Stanford University
• VA Palo Alto Health Care System
• Cedars-Sinai Medical Center

Investigators

• Principal Investigator: William F Fearon, Stanford University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: William Fearon, Associate Professor of Medicine, Stanford University
• ClinicalTrials.gov Identifier: NCT01078363
• Other Study ID Numbers: SU-12162009-4562; 16155 (William Fuller Fearon)
• First Posted: Mar 2, 2010
• Last Update Posted: Jan 26, 2017
• Last Verified: Dec 1, 2016

• Keywords provided by William Fearon, Associate Professor of Medicine, Stanford University: Heart Transplantation
• Additional relevant MeSH terms: Vascular Diseases; Ramipril

Study Results

Participant Flow

Arm/Group Title	Ramipril	Placebo
Arm/Group Description	ramipril, 5mg starting dose to maximum dose of 20mg daily dose for one year. ramipril or placebo: Use of a ACE ( angiotension converting enzyme) inhibitors versus placebo post heart Transplant for Blood pressure control.	Sugar pill manufactured to mimic ramipril 5mg starting dose , increasing to 20mg daily for one year. ramipril or placebo: Use of a ACE ( angiotension converting enzyme) inhibitors versus placebo post heart Transplant for Blood pressure control.
Period Title: Overall Study
STARTED	47	49
COMPLETED	47	49
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Ramipril	Placebo	Total
Arm/Group Description	ramipril, 5mg starting dose to maximum dose of 20mg daily dose for one year. ramipril or placebo: Use of a ACE ( angiotension converting enzyme) inhibitors versus placebo post heart Transplant for Blood pressure control.	Sugar pill manufactured to mimic ramipril 5mg starting dose , increasing to 20mg daily for one year. ramipril or placebo: Use of a ACE ( angiotension converting enzyme) inhibitors versus placebo post heart Transplant for Blood pressure control.	Total of all reporting groups
Overall Participants	47	49	96
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55 (15)	52 (17)	53 (16)
Gender (Count of Participants)
Female	11 23.4%	17 34.7%	28 29.2%
Male	36 76.6%	32 65.3%	68 70.8%

Outcome Measures

1. Primary Outcome

Title	Cardiac Allograft Vasculopathy(CAV) Defined as Change in IVUS-assessed Plaque Volume From Baseline to One Year
Description	also called transplant coronary artery disease or cardiac transplant vasculopathy defined as coronary artery stenosis(narrowing) ranging from 30 to 70 percent by coronary angiography. Measured in this study as change in IVUS-assessed Plaque Volume from baseline to one year.
Time Frame	Baseline and 1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ramipril	Placebo
Arm/Group Description	ramipril, 5mg starting dose to maximum dose of 20mg daily dose for one year. ramipril or placebo: Use of a ACE ( angiotension converting enzyme) inhibitors versus placebo post heart Transplant for Blood pressure control.	Sugar pill manufactured to mimic ramipril 5mg starting dose , increasing to 20mg daily for one year. ramipril or placebo: Use of a ACE ( angiotension converting enzyme) inhibitors versus placebo post heart Transplant for Blood pressure control.
Measure Participants	47	49
Mean (Standard Deviation) [mm3/mm]	3.39 (1.65)	3.65 (1.89)

2. Secondary Outcome

Title	Percentage of Participants With ≥20% Coronary Artery Diameter Reduction After Acetylcholine
Description	The percent change in diameter of the left anterior descending artery was measured by quantitative angiography after acetylcholine and compared to baseline angiography. The percentage of participants who had ≥20% coronary artery diameter reduction after acetylcholine at one year is presented.
Time Frame	At Baseline and 1 Year

Outcome Measure Data

Analysis Population Description

Only a subset of participants (those adult patients enrolled at Stanford University) underwent the acetylcholine measurements.

Arm/Group Title	Ramipril	Placebo
Arm/Group Description	ramipril, 5mg starting dose to maximum dose of 20mg daily dose for one year. ramipril or placebo: Use of a ACE ( angiotension converting enzyme) inhibitors versus placebo post heart Transplant for Blood pressure control.	Sugar pill manufactured to mimic ramipril 5mg starting dose , increasing to 20mg daily for one year. ramipril or placebo: Use of a ACE ( angiotension converting enzyme) inhibitors versus placebo post heart Transplant for Blood pressure control.
Measure Participants	25	22
Number [percentage of participants]	9.4 20%	4.8 9.8%

3. Secondary Outcome

Title	ADMA Level at One Year Post Transplant
Description	asymmetric dimethylarginine (ADMA), is an inhibitor of endothelial nitric oxide synthase which is a primary regulator of endothelial function.
Time Frame	1 year post Transplant

Outcome Measure Data

Analysis Population Description

Blood samples were not acquired in all participants which accounts for the discrepancy in number of participants analyzed.

Arm/Group Title	Ramipril	Placebo
Arm/Group Description	ramipril, 5mg starting dose to maximum dose of 20mg daily dose for one year. ramipril: Use of a ACE ( angiotension converting enzyme) inhibitors post heart Transplant for Blood pressure control.	Sugar pill manufactured to mimic ramipril 5mg starting dose , increasing to 20mg daily for one year. Placebo: Use of a placebo post heart Transplant for Blood pressure control.
Measure Participants	41	40
Mean (Standard Deviation) [micromole]	.54 (.14)	.55 (.16)

4. Secondary Outcome

Title	The Percentage of Endothelial Progenitor Cells ( EPC) in Peripheral Blood in Patients One Year After Transplant
Description	The determination of the percentage of EPC in peripheral blood involved surface staining peripheral blood mononuclear cells (PBMCs) with appropriate fluorescently-labeled antibodies to delineate EPCs from other blood cells, followed by analysis by conventional flow cytometry.
Time Frame	at one year

Outcome Measure Data

Analysis Population Description

Not all blood samples obtained were adequate for EPC determination which explains the discrepancy in number of participants analyzed.

Arm/Group Title	Ramipril	Placebo
Arm/Group Description	ramipril, 5mg starting dose to maximum dose of 20mg daily dose for one year. ramipril or placebo: Use of a ACE ( angiotension converting enzyme) inhibitors versus placebo post heart Transplant for Blood pressure control.	Sugar pill manufactured to mimic ramipril 5mg starting dose , increasing to 20mg daily for one year. ramipril or placebo: Use of a ACE ( angiotension converting enzyme) inhibitors versus placebo post heart Transplant for Blood pressure control.
Measure Participants	40	40
Mean (Standard Deviation) [percentage of EPC]	.104 (.068)	.098 (.133)

5. Secondary Outcome

Title	Fractional Flow Reserve (FFR) at One Year Post Transplant
Description	FFR is a technique used in coronary catheterization to measure pressure differences across a coronary artery stenosis (narrowing, usually due to atherosclerosis) to determine the likelihood that the stenosis impedes oxygen delivery to the heart muscle (myocardial ischemia). It is defined as the ratio of the distal coronary pressure to the proximal coronary pressure.
Time Frame	at one year post Transplant

Outcome Measure Data

Analysis Population Description

Only a subset of participants (adult patients enrolled at Stanford University) underwent fractional flow reserve assessment.

Arm/Group Title	Ramipril	Placebo
Arm/Group Description	ramipril, 5mg starting dose to maximum dose of 20mg daily dose for one year. ramipril or placebo: Use of a ACE ( angiotension converting enzyme) inhibitors versus placebo post heart Transplant for Blood pressure control.	Sugar pill manufactured to mimic ramipril 5mg starting dose , increasing to 20mg daily for one year. ramipril or placebo: Use of a ACE ( angiotension converting enzyme) inhibitors versus placebo post heart Transplant for Blood pressure control.
Measure Participants	26	23
Mean (Standard Deviation) [Ratio]	.88 (.04)	.90 (.04)

6. Secondary Outcome

Title	Index of Microcirculatory Resistance at One Year Post Heart Transplant
Description	The index of microcirculatory resistance (IMR) is a pressure-temperature sensor guidewire-based measurement, performed during cardiac catheterization, of the minimum microcirculatory resistance in a specific coronary artery. The IMR provides a quantitative measure of coronary microvasculature status.
Time Frame	one year

Outcome Measure Data

Analysis Population Description

Only a subset of participants (adult patients enrolled at Stanford University) underwent index of microcirculatory resistance assessment.

Arm/Group Title	Ramipril	Placebo
Arm/Group Description	ramipril, 5mg starting dose to maximum dose of 20mg daily dose for one year. ramipril or placebo: Use of a ACE ( angiotension converting enzyme) inhibitors versus placebo post heart Transplant for Blood pressure control.	Sugar pill manufactured to mimic ramipril 5mg starting dose , increasing to 20mg daily for one year. ramipril or placebo: Use of a ACE ( angiotension converting enzyme) inhibitors versus placebo post heart Transplant for Blood pressure control.
Measure Participants	26	22
Mean (Standard Deviation) [mmHg x seconds]	14.4 (6.3)	21.5 (20)

Adverse Events

Arm/Group Title	Ramipril		Placebo
Arm/Group Description	ramipril, 5mg starting dose to maximum dose of 20mg daily dose for one year. ramipril or placebo: Use of a ACE ( angiotension converting enzyme) inhibitors versus placebo post heart Transplant for Blood pressure control.		Sugar pill manufactured to mimic ramipril 5mg starting dose , increasing to 20mg daily for one year. ramipril or placebo: Use of a ACE ( angiotension converting enzyme) inhibitors versus placebo post heart Transplant for Blood pressure control.
All Cause Mortality
	Ramipril		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ramipril		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/47 (4.3%)		2/49 (4.1%)
Cardiac disorders
Death	2/47 (4.3%)		2/49 (4.1%)
Other (Not Including Serious) Adverse Events
	Ramipril		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/47 (0%)		0/49 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.