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Direct Renin Inhibition Effects on Atherosclerotic Biomarkers

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00818779
Recruitment Status : Completed
First Posted : January 8, 2009
Results First Posted : November 19, 2012
Last Update Posted : December 5, 2017
Information provided by (Responsible Party):
Texas Tech University Health Sciences Center

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.

Condition or disease Intervention/treatment Phase
Coronary Artery Disease Type 2 Diabetes Mellitus Drug: Aliskiren Drug: Amlodipine Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 38 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
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

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Diseases

Arm Intervention/treatment
Experimental: Aliskiren
Aliskiren 150-300 mg once daily
Drug: Aliskiren
150 - 300 mg once daily for 6 weeks
Other Name: Tekturna

Active Comparator: Amlodipine
5-10 mg amlodipine once daily
Drug: Amlodipine
5-10 mg once daily for 6 weeks
Other Name: Norvasc

Primary Outcome Measures :
  1. 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.

Secondary Outcome Measures :
  1. Serum Level of Vascular Cell Adhesion Molecule [ Time Frame: 6 week (change from baseline) ]
    Surrogate biomarker cardiovascular risk

  2. Serum Level of Intracellular Cell Adhesion Molecule [ Time Frame: 6 week (change from baseline) ]
    Surrogate biomarker of cardiovascular risk

  3. Serum Level of C-reactive Protein [ Time Frame: 6 week (change from baseline) ]
    Surrogate biomarker of cardiovascular risk

  4. Serum Level of Nitric Oxide [ Time Frame: 6 week (change from baseline) ]
    Surrogate biomarker of cardiovascular risk

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00818779

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United States, Texas
Texas Tech University Health Sciences Center
Lubbock, Texas, United States, 79430
Sponsors and Collaborators
Texas Tech University Health Sciences Center
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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
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Responsible Party: Texas Tech University Health Sciences Center Identifier: NCT00818779    
Other Study ID Numbers: Tekturna 1
First Posted: January 8, 2009    Key Record Dates
Results First Posted: November 19, 2012
Last Update Posted: December 5, 2017
Last Verified: October 2017
Keywords provided by Texas Tech University Health Sciences Center:
heart disease
Additional relevant MeSH terms:
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Coronary Artery Disease
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Coronary Disease
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Arterial Occlusive Diseases
Vascular Diseases
Antihypertensive Agents
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Vasodilator Agents