Direct Renin Inhibition Effects on Atherosclerotic Biomarkers
|ClinicalTrials.gov Identifier: NCT00818779|
Recruitment Status : Completed
First Posted : January 8, 2009
Results First Posted : November 19, 2012
Last Update Posted : December 5, 2017
|Condition or disease||Intervention/treatment||Phase|
|Coronary Artery Disease Type 2 Diabetes Mellitus||Drug: Aliskiren Drug: Amlodipine||Phase 4|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||38 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Effects of Direct Renin Inhibition on Atherosclerotic Biomarkers in Patients With Stable Coronary Heart Disease and Type 2 Diabetes Mellitus|
|Study Start Date :||January 2008|
|Actual Primary Completion Date :||August 2011|
|Actual Study Completion Date :||August 2011|
Aliskiren 150-300 mg once daily
150 - 300 mg once daily for 6 weeks
Other Name: Tekturna
Active Comparator: Amlodipine
5-10 mg amlodipine once daily
5-10 mg once daily for 6 weeks
Other Name: Norvasc
- Plasminogen Activator Inhibitor 1 [ Time Frame: 6 weeks (change from baseline) ]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.
- Serum Level of Vascular Cell Adhesion Molecule [ Time Frame: 6 week (change from baseline) ]Surrogate biomarker cardiovascular risk
- Serum Level of Intracellular Cell Adhesion Molecule [ Time Frame: 6 week (change from baseline) ]Surrogate biomarker of cardiovascular risk
- Serum Level of C-reactive Protein [ Time Frame: 6 week (change from baseline) ]Surrogate biomarker of cardiovascular risk
- Serum Level of Nitric Oxide [ Time Frame: 6 week (change from baseline) ]Surrogate biomarker of cardiovascular risk
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00818779
|United States, Texas|
|Texas Tech University Health Sciences Center|
|Lubbock, Texas, United States, 79430|
|Principal Investigator:||Gary E Meyerrrose, MD||Texas Tech Health Sciences Center Department of Internal Medicine|
|Study Director:||Brian K Irons, PharmD||Texas Tech University Health Sciences Center School of Pharmacy|