Direct Renin Inhibition Effects on Atherosclerotic Biomarkers

NCT ID: NCT00818779

Last Updated: 2017-12-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 38 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-01-31
• Study Completion Date: 2011-08-31

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.

Conditions

Coronary Artery Disease; Type 2 Diabetes Mellitus

Keywords

diabetes; heart disease; atherosclerosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

Aliskiren

Aliskiren 150-300 mg once daily

Group Type: EXPERIMENTAL

Aliskiren

Intervention Type: DRUG

150 - 300 mg once daily for 6 weeks

Amlodipine

5-10 mg amlodipine once daily

Group Type: ACTIVE_COMPARATOR

Amlodipine

Intervention Type: DRUG

5-10 mg once daily for 6 weeks

Interventions

Aliskiren

150 - 300 mg once daily for 6 weeks

Intervention Type: DRUG

Amlodipine

5-10 mg once daily for 6 weeks

Intervention Type: DRUG

Other Intervention Names

Tekturna; Norvasc

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Texas Tech University Health Sciences Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Gary E Meyerrrose, MD

Role: PRINCIPAL_INVESTIGATOR

Texas Tech Health Sciences Center Department of Internal Medicine

Brian K Irons, PharmD

Role: STUDY_DIRECTOR

Texas Tech University Health Sciences Center School of Pharmacy

Locations

Texas Tech University Health Sciences Center

Lubbock, Texas, United States

Countries

United States

Other Identifiers

Tekturna 1

Identifier Type: -

Identifier Source: org_study_id