Endothelial Dysfunction
Conditions
Keywords
Endothelial Dysfunction, Endothelial Function, Tekturna, Endothelial Peripheral Arterial Tomography (EndoPAT), Progenitor Cells, renin inhibition, endothelial progenitor cells, early atherosclerosis
Brief summary
We will study the hypothesis that long-term Tekturna treatment will improve endothelial function and the production and function of endothelial progenitor cells (EPCs) in patients with early atherosclerosis. Specifically, long-term Tekturna treatment will increase the Reactive Hyperemia Peripheral Arterial Tonometry indexes and increase the numbers and the function of circulating endothelial progenitor cells, compared to placebo, in association with a reduction in inflammation and oxidative stress.
Detailed description
Aliskiren is a direct renin-inhibitor and may have beneficial effects on the vascular endothelium, similar to other antihypertensive therapies targeting the renin-angiotensin-aldosterone system (RAAS). The current study was designed to test the hypothesis that aliskiren improves endothelial function and increases the number of endothelial progenitor cells (EPCs) in normotensive patients with early atherosclerosis.
Interventions
DRUGAliskiren
150 mg Aliskiren once daily for a period of 4 months
DRUGPlacebo
1 pill per day by mouth for 4 months
Sponsors
National Institute on Aging (NIA)
National Heart, Lung, and Blood Institute (NHLBI)
Novartis
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age \> 18 years old 2. More than two of the following cardiovascular risk factors (determined by prescreen phone call): family history of cardiovascular disease, physical inactivity/sedentary lifestyle, obesity or overweight, family history of diabetes mellitus or hypertension, total cholesterol \> 200 mg/dL, LDL \> 130 mg/dL, HDL \< 50 mg/dL, smoking, stress, or Triglycerides \> 150 mg/dL 3. Demonstrated endothelial dysfunction (reactive hyperemia - EndoPAT score \< 2.0) at time of screening
Exclusion criteria
1. Serum potassium \> 5.0 mmol/L documented at any time prior to the study 2. History of any cardiovascular event (stroke, transient ischemic attack (TIA), myocardial infarction (MI), unstable angina, coronary artery bypass grafting (CABG), percutaneous coronary intervention, hospitalization due to heart failure) during the 3 months prior to the study 3. Hypertension or hypotension (at Randomization): any patient with Mean Seated Systolic Blood Pressure (msSBP) ≥ 170 mmHg, msSBP \< 100 mmHg or Mean Seated Diastolic Blood Pressure (msDBP) ≥ 110 mmHg 4. Congestive heart failure New York Heart Association (NYHA) class III and IV 5. Concomitant treatment with two (2) or more renin-angiotensin-aldosterone system blocking agents, e.g. Angiotensin Converting Enzyme Inhibitor (ACEI), Angiotensin II receptor blockers (ARB) or aldosterone-antagonist 6. Unstable serum creatinine 7. Second (II) or third (III) degree heart block without a pacemaker 8. Concurrent potentially life threatening arrhythmia or other uncontrolled arrhythmia 9. Clinically significant valvular heart disease 10. Known renal artery stenosis 11. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of the study drugs including, but not limited to, any of the following: * History of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection * Any history of pancreatic injury, pancreatitis or evidence of impaired pancreatic function/injury as indicated by abnormal lipase or amylase * Evidence of hepatic disease as determined by a history of hepatic encephalopathy, a history of cirrhosis, esophageal varices, or a history of portocaval shunt 12. History of malignancy other than basal cell skin cancer within the past five years 13. Any concurrent life threatening condition with a life expectancy less than 2 years 14. History or evidence of drug or alcohol abuse within the last 12 months 15. Any surgical or medical condition, which in the opinion of the investigator, may place the patient at higher risk from his/her participation in the study, or is likely to prevent the patient from complying with the requirements of the study or completing the study 16. History of hypersensitivity to any of the study drugs or to medications belonging to the same therapeutic class as the study drugs as well as known or suspected contraindications to the study drugs 17. History of noncompliance to medical regimens or unwillingness to comply with the study protocol 18. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer 19. Any condition that in the opinion of the investigator would jeopardize the evaluation of efficacy or safety 20. Persons directly involved in the execution of this protocol 21. Pregnant or nursing (lactating) women 22. Women of Child-Bearing Potential (WOCBP) unless postmenopausal for at least one year, surgically sterile or using effective methods of contraception as defined by local Health Authorities
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Endothelial Progenitor Cells (EPC) | Baseline, 4 Months | Peripheral blood mononuclear cells were stained for EPC markers (cell-surface antigens CD34/CD133/KDR) and counted by flow-cytometry. |
| Reactive Hyperemia Index (RHI) | Baseline, 4 Months | RHI was measured by the noninvasive endothelial peripheral arterial tomography (EndoPat) test. EndoPAT results are reported as the Endoscore (range 0-3); a score of 1.67 and lower indicates the need for immediate medical attention; a score between 1.68 and 2 indicates a need to reduce risk factors; a score above 2.1 indicates a healthy heart. |
Secondary
| Measure | Time frame |
|---|---|
| Systolic Blood Pressure | Baseline, 4 Months |
| Diastolic Blood Pressure | Baseline, 4 Months |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from the Division of Cardiology at the Mayo Clinic in Rochester, Minnesota. 22 subjects were randomized to the study, 2 subjects were affected by the early study termination and thus have no follow-up data.
Participants by arm
| Arm | Count |
|---|---|
| Aliskiren 150 mg Aliskiren once daily for a period of 4 months. Not all baseline data were available from started subjects, therefore only baseline data for completed subjects is presented. | 12 |
| Placebo 1 pill per day by mouth for 4 months. Not all baseline data were available from started subjects, therefore only baseline data for completed subjects is presented. | 5 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Early Study Termination | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Aliskiren | Placebo | Total |
|---|---|---|---|
| Age Continuous | 43.1 years STANDARD_DEVIATION 17.5 | 51.0 years STANDARD_DEVIATION 20.7 | 45.4 years STANDARD_DEVIATION 18.2 |
| Region of Enrollment United States | 12 participants | 5 participants | 17 participants |
| Sex: Female, Male Female | 7 Participants | 1 Participants | 8 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 12 | 2 / 5 |
| serious Total, serious adverse events | 0 / 12 | 0 / 5 |
Outcome results
Primary
Endothelial Progenitor Cells (EPC)
Peripheral blood mononuclear cells were stained for EPC markers (cell-surface antigens CD34/CD133/KDR) and counted by flow-cytometry.
Time frame: Baseline, 4 Months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Aliskiren | Endothelial Progenitor Cells (EPC) | Baseline | 24 counts per 100,000 gated events |
| Aliskiren | Endothelial Progenitor Cells (EPC) | 4 Months | 3 counts per 100,000 gated events |
| Placebo | Endothelial Progenitor Cells (EPC) | Baseline | 9 counts per 100,000 gated events |
| Placebo | Endothelial Progenitor Cells (EPC) | 4 Months | 8 counts per 100,000 gated events |
Comparison: Change in EPCs from baseline to 4 monthsp-value: 0.02t-test, 2 sided
Primary
Reactive Hyperemia Index (RHI)
RHI was measured by the noninvasive endothelial peripheral arterial tomography (EndoPat) test. EndoPAT results are reported as the Endoscore (range 0-3); a score of 1.67 and lower indicates the need for immediate medical attention; a score between 1.68 and 2 indicates a need to reduce risk factors; a score above 2.1 indicates a healthy heart.
Time frame: Baseline, 4 Months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Aliskiren | Reactive Hyperemia Index (RHI) | Baseline | 1.93 units on a scale |
| Aliskiren | Reactive Hyperemia Index (RHI) | 4 Months | 1.73 units on a scale |
| Placebo | Reactive Hyperemia Index (RHI) | Baseline | 1.81 units on a scale |
| Placebo | Reactive Hyperemia Index (RHI) | 4 Months | 1.68 units on a scale |
Comparison: P-value for intergroup comparison of change from baseline to month 4p-value: 0.94t-test, 2 sided
Secondary
Diastolic Blood Pressure
Time frame: Baseline, 4 Months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aliskiren | Diastolic Blood Pressure | 4 Months | 70.0 mm Hg | Standard Deviation 11.6 |
| Aliskiren | Diastolic Blood Pressure | Baseline | 77.8 mm Hg | Standard Deviation 9.9 |
| Placebo | Diastolic Blood Pressure | Baseline | 68.6 mm Hg | Standard Deviation 10.2 |
| Placebo | Diastolic Blood Pressure | 4 Months | 67.6 mm Hg | Standard Deviation 9.8 |
Comparison: Difference in diastolic blood pressure from baseline to 4 months.p-value: 0.04t-test, 2 sided
Secondary
Systolic Blood Pressure
Time frame: Baseline, 4 Months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aliskiren | Systolic Blood Pressure | Baseline | 124.6 mm Hg | Standard Deviation 12.2 |
| Aliskiren | Systolic Blood Pressure | 4 Months | 112.3 mm Hg | Standard Deviation 12.4 |
| Placebo | Systolic Blood Pressure | Baseline | 118.8 mm Hg | Standard Deviation 18.1 |
| Placebo | Systolic Blood Pressure | 4 Months | 116.2 mm Hg | Standard Deviation 11.9 |
Comparison: Difference in systolic blood pressure from baseline to 4 months.p-value: 0.006t-test, 2 sided