Direct Renin Inhibition Effects on Atherosclerotic Biomarkers

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Texas Tech University Health Sciences Center
ClinicalTrials.gov Identifier:
NCT00818779
First received: January 6, 2009
Last updated: October 18, 2012
Last verified: October 2012
  Purpose

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 Intervention Phase
Coronary Artery Disease
Type 2 Diabetes Mellitus
Drug: Aliskiren
Drug: Amlodipine
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Official Title: Effects of Direct Renin Inhibition on Atherosclerotic Biomarkers in Patients With Stable Coronary Heart Disease and Type 2 Diabetes Mellitus

Resource links provided by NLM:


Further study details as provided by Texas Tech University Health Sciences Center:

Primary Outcome Measures:
  • Plasminogen Activator Inhibitor 1 [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: 6 week ] [ Designated as safety issue: No ]
  • Serum Level of Intracellular Cell Adhesion Molecule [ Time Frame: 6 week ] [ Designated as safety issue: No ]
  • Serum Level of C-reactive Protein [ Time Frame: 6 week ] [ Designated as safety issue: No ]
  • Serum Level of Nitric Oxide [ Time Frame: 6 week ] [ Designated as safety issue: No ]

Enrollment: 38
Study Start Date: January 2008
Study Completion Date: August 2011
Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00818779

Locations
United States, Texas
Texas Tech University Health Sciences Center
Lubbock, Texas, United States, 79430
Sponsors and Collaborators
Texas Tech University Health Sciences Center
Investigators
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
  More Information

No publications provided

Responsible Party: Texas Tech University Health Sciences Center
ClinicalTrials.gov Identifier: NCT00818779     History of Changes
Other Study ID Numbers: Tekturna 1
Study First Received: January 6, 2009
Results First Received: June 18, 2012
Last Updated: October 18, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by Texas Tech University Health Sciences Center:
diabetes
heart disease
atherosclerosis

Additional relevant MeSH terms:
Coronary Artery Disease
Coronary Disease
Diabetes Mellitus
Diabetes Mellitus, Type 2
Myocardial Ischemia
Arterial Occlusive Diseases
Arteriosclerosis
Cardiovascular Diseases
Endocrine System Diseases
Glucose Metabolism Disorders
Heart Diseases
Metabolic Diseases
Vascular Diseases
Amlodipine
Antihypertensive Agents
Calcium Channel Blockers
Cardiovascular Agents
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses
Vasodilator Agents

ClinicalTrials.gov processed this record on October 21, 2014