Direct Renin Inhibition Effects on Atherosclerotic Biomarkers
Primary Purpose
Coronary Artery Disease, Type 2 Diabetes Mellitus
Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Aliskiren
Amlodipine
Sponsored by
About this trial
This is an interventional other trial for Coronary Artery Disease focused on measuring diabetes, heart disease, atherosclerosis
Eligibility Criteria
Inclusion Criteria:
- Diagnosis of type 2 diabetes
- Diagnosis of coronary artery disease
- Currently receiving therapy with an ACE-Inhibitor or Angiotensin Receptor Blocker
- Currently receiving antiplatelet therapy and statin therapy
- Baseline blood pressure > 100/75 mm Hg
- BMI 25-35 kg/m2
Exclusion Criteria:
- Concurrent calcium channel blocker therapy
- Documented peripheral edema
- Hyperkalemia
- Serum creatinine > 2.0
- Diagnosed with proteinuria
- Diagnosed with liver dysfunction or serious rheumatological disorder
Sites / Locations
- Texas Tech University Health Sciences Center
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Aliskiren
Amlodipine
Arm Description
Aliskiren 150-300 mg once daily
5-10 mg amlodipine once daily
Outcomes
Primary Outcome Measures
Plasminogen Activator Inhibitor 1
Plasminogen Activator Inhibitor 1 is a biomarker found in serum that indirectly assesses blood clotting activity. Lower PAI-1 levels are thought to be better than higher levels. The primary outcome is mean change from baseline and can include negative numbers as a result.
Secondary Outcome Measures
Serum Level of Vascular Cell Adhesion Molecule
Surrogate biomarker cardiovascular risk
Serum Level of Intracellular Cell Adhesion Molecule
Surrogate biomarker of cardiovascular risk
Serum Level of C-reactive Protein
Surrogate biomarker of cardiovascular risk
Serum Level of Nitric Oxide
Surrogate biomarker of cardiovascular risk
Full Information
NCT ID
NCT00818779
First Posted
January 6, 2009
Last Updated
October 31, 2017
Sponsor
Texas Tech University Health Sciences Center
1. Study Identification
Unique Protocol Identification Number
NCT00818779
Brief Title
Direct Renin Inhibition Effects on Atherosclerotic Biomarkers
Official Title
Effects of Direct Renin Inhibition on Atherosclerotic Biomarkers in Patients With Stable Coronary Heart Disease and Type 2 Diabetes Mellitus
Study Type
Interventional
2. Study Status
Record Verification Date
October 2017
Overall Recruitment Status
Completed
Study Start Date
January 2008 (undefined)
Primary Completion Date
August 2011 (Actual)
Study Completion Date
August 2011 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Texas Tech University Health Sciences Center
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The investigators aim to assess if a new blood pressure medication, aliskiren, reduces various biomarkers of heart disease found in the blood in patients with a history of both heart disease and type 2 diabetes. The primary hypothesis is that aliskiren will reduce these biomarkers compared to a calcium channel blocker.
Detailed Description
Agents that attenuate the renin angiotensin system (RAS), i.e. angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARB), have shown to have therapeutic benefit in a variety of cardiovascular disorders. ACE-Is are considered standard of care for secondary prevention of CAD by the AHA/ACC. Based on the HOPE study, the beneficial effects of ACE-Is in patients at high risk for cardiovascular outcomes may be beyond mere blood pressure control. In addition to their effects on blood pressure, aldosterone, and sodium and water absorption, blockade of the RAS with ACE-Is or ARBs alter key biomarkers of vascular inflammation, vascular endothelial function, and fibrinolytic balance. These surrogate biomarkers are thought to play a role in the progression of atherosclerosis. Biomarkers of vascular inflammation include vascular and intracellular cell adhesion molecule (VCAM and ICAM respectively) and c-reactive protein (CRP). Markers of endothelial function include endothelin-1 (ET-1) and the vasodilator nitric oxide (NO). Plasminogen activator inhibitor-1 (PAI-1) is a prothrombotic marker associated with plaque proliferation and atherosclerosis progression.
ACE-Is block the conversion of angiotensin 1 (Ang 1) to angiotensin 2 (Ang 2). "ACE escape" may attenuate the influence of ACE-Is despite proven benefits in clinical trials.
Aliskiren is the first direct renin inhibitor approved by the FDA for the treatment of hypertension. It is a very specific and potent inhibitor of human renin. As such it may offer an advantage over ACE-I and ARB therapy as it blocks the rate limiting step of the RAS. It does not show a compensatory increase in RAS activity noted with ARBs or non-ACE production of Ang 2 as seen with ACE-Is. Aliskiren appears to have additive blood pressure lowering effects when added to ACE-I or ARB therapy.
A very commonly prescribed antihypertensive, the dihydropyridine calcium channel blocker amlodipine, has a synergistic effect on lowering BP when used with an ACE-I. It has been shown to have mixed effects on atherosclerotic biomarkers in a variety of subjects. Type 2 diabetes affects many of the atherosclerotic markers described above and as such can be a confounding variable in research involving these biomarkers.
With the addition of a new therapeutic agent that affects the RAS, its different pharmacodynamic effects on the RAS compared to ACE-I and ARB therapy, and that Ang 2 levels are not fully blocked by ACE-I therapy, it is critical to better understand how the new class of direct renin inhibitors may influence atherosclerotic biomarkers in patients with a variety of cardiovascular disorders. The objectives of this application are to determine whether the direct renin inhibitor, aliskiren, affects atherosclerotic biomarkers in patients with stable coronary artery disease and diabetes currently receiving standard ACE-I therapy and if aliskiren has a more favorable effect on these markers compared to the calcium antagonist amlodipine.
Large clinical trials have proven the benefit of RAS blockade in reducing cardiovascular morbidity and mortality. The significance of this research is that more information is needed to better understand how antihypertensive agents, particularly those that block the RAS, reduce cardiovascular disease beyond blood pressure reduction alone. Research that elucidates how agents may reduce atherosclerosis is very important to help better target drug therapy to a condition that is the leading cause of death in this country.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Coronary Artery Disease, Type 2 Diabetes Mellitus
Keywords
diabetes, heart disease, atherosclerosis
7. Study Design
Primary Purpose
Other
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
38 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Aliskiren
Arm Type
Experimental
Arm Description
Aliskiren 150-300 mg once daily
Arm Title
Amlodipine
Arm Type
Active Comparator
Arm Description
5-10 mg amlodipine once daily
Intervention Type
Drug
Intervention Name(s)
Aliskiren
Other Intervention Name(s)
Tekturna
Intervention Description
150 - 300 mg once daily for 6 weeks
Intervention Type
Drug
Intervention Name(s)
Amlodipine
Other Intervention Name(s)
Norvasc
Intervention Description
5-10 mg once daily for 6 weeks
Primary Outcome Measure Information:
Title
Plasminogen Activator Inhibitor 1
Description
Plasminogen Activator Inhibitor 1 is a biomarker found in serum that indirectly assesses blood clotting activity. Lower PAI-1 levels are thought to be better than higher levels. The primary outcome is mean change from baseline and can include negative numbers as a result.
Time Frame
6 weeks (change from baseline)
Secondary Outcome Measure Information:
Title
Serum Level of Vascular Cell Adhesion Molecule
Description
Surrogate biomarker cardiovascular risk
Time Frame
6 week (change from baseline)
Title
Serum Level of Intracellular Cell Adhesion Molecule
Description
Surrogate biomarker of cardiovascular risk
Time Frame
6 week (change from baseline)
Title
Serum Level of C-reactive Protein
Description
Surrogate biomarker of cardiovascular risk
Time Frame
6 week (change from baseline)
Title
Serum Level of Nitric Oxide
Description
Surrogate biomarker of cardiovascular risk
Time Frame
6 week (change from baseline)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Diagnosis of type 2 diabetes
Diagnosis of coronary artery disease
Currently receiving therapy with an ACE-Inhibitor or Angiotensin Receptor Blocker
Currently receiving antiplatelet therapy and statin therapy
Baseline blood pressure > 100/75 mm Hg
BMI 25-35 kg/m2
Exclusion Criteria:
Concurrent calcium channel blocker therapy
Documented peripheral edema
Hyperkalemia
Serum creatinine > 2.0
Diagnosed with proteinuria
Diagnosed with liver dysfunction or serious rheumatological disorder
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gary E Meyerrrose, MD
Organizational Affiliation
Texas Tech Health Sciences Center Department of Internal Medicine
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Brian K Irons, PharmD
Organizational Affiliation
Texas Tech University Health Sciences Center School of Pharmacy
Official's Role
Study Director
Facility Information:
Facility Name
Texas Tech University Health Sciences Center
City
Lubbock
State/Province
Texas
ZIP/Postal Code
79430
Country
United States
12. IPD Sharing Statement
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Direct Renin Inhibition Effects on Atherosclerotic Biomarkers
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