Direct Renin Inhibition Effects on Atherosclerotic Biomarkers

October 31, 2017 updated by: Texas Tech University Health Sciences Center

Effects of Direct Renin Inhibition on Atherosclerotic Biomarkers in Patients With Stable Coronary Heart Disease and Type 2 Diabetes Mellitus

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

38

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Texas
      • Lubbock, Texas, United States, 79430
        • Texas Tech University Health Sciences Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Aliskiren
Aliskiren 150-300 mg once daily
Drug: Aliskiren
150 - 300 mg once daily for 6 weeks
Other Names:
  • Tekturna
Active Comparator: Amlodipine
5-10 mg amlodipine once daily
Drug: Amlodipine
5-10 mg once daily for 6 weeks
Other Names:
  • Norvasc

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
6 weeks (change from baseline)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Serum Level of Vascular Cell Adhesion Molecule
Time Frame: 6 week (change from baseline)
Surrogate biomarker cardiovascular risk
6 week (change from baseline)
Serum Level of Intracellular Cell Adhesion Molecule
Time Frame: 6 week (change from baseline)
Surrogate biomarker of cardiovascular risk
6 week (change from baseline)
Serum Level of C-reactive Protein
Time Frame: 6 week (change from baseline)
Surrogate biomarker of cardiovascular risk
6 week (change from baseline)
Serum Level of Nitric Oxide
Time Frame: 6 week (change from baseline)
Surrogate biomarker of cardiovascular risk
6 week (change from baseline)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

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

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2008

Primary Completion (Actual)

August 1, 2011

Study Completion (Actual)

August 1, 2011

Study Registration Dates

First Submitted

January 6, 2009

First Submitted That Met QC Criteria

January 7, 2009

First Posted (Estimate)

January 8, 2009

Study Record Updates

Last Update Posted (Actual)

December 5, 2017

Last Update Submitted That Met QC Criteria

October 31, 2017

Last Verified

October 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Tekturna 1

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Coronary Artery Disease

Clinical Trials on Aliskiren

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Bosnia & Herzegovina

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe