Direct Renin Inhibition Effects on Atherosclerotic Biomarkers

• Sponsor: Texas Tech University Health Sciences Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00818779
• Collaborator: (none)
• Enrollment: 38
• Location: 1
• Arms: 2
• Duration (Months): 43
• Patients Per Site Per Month: 0.9

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• 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: Jan 1, 2008
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Aug 1, 2011

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Plasminogen Activator Inhibitor 1 [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 [6 week (change from baseline)]

   Surrogate biomarker cardiovascular risk

2. Serum Level of Intracellular Cell Adhesion Molecule [6 week (change from baseline)]

   Surrogate biomarker of cardiovascular risk

3. Serum Level of C-reactive Protein [6 week (change from baseline)]

   Surrogate biomarker of cardiovascular risk

4. Serum Level of Nitric Oxide [6 week (change from baseline)]

   Surrogate biomarker of cardiovascular risk

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Texas Tech University Health Sciences Center
• ClinicalTrials.gov Identifier: NCT00818779
• Other Study ID Numbers: Tekturna 1
• First Posted: Jan 8, 2009
• Last Update Posted: Dec 5, 2017
• Last Verified: Oct 1, 2017

• Keywords provided by Texas Tech University Health Sciences Center: diabetes; heart disease; atherosclerosis
• Additional relevant MeSH terms: Coronary Artery Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2; Amlodipine

Study Results

Participant Flow

Arm/Group Title	Aliskiren	Amlodipine
Arm/Group Description	Aliskiren 150-300 mg once daily	5-10 mg amlodipine once daily
Period Title: Overall Study
STARTED	22	16
COMPLETED	16	15
NOT COMPLETED	6	1

Baseline Characteristics

Arm/Group Title	Aliskiren	Amlodipine	Total
Arm/Group Description	Aliskiren 150-300 mg once daily	5-10 mg amlodipine once daily	Total of all reporting groups
Overall Participants	22	16	38
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	7 31.8%	6 37.5%	13 34.2%
>=65 years	15 68.2%	10 62.5%	25 65.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	68 (10)	63 (16)	65 (13)
Sex: Female, Male (Count of Participants)
Female	8 36.4%	6 37.5%	14 36.8%
Male	14 63.6%	10 62.5%	24 63.2%
Region of Enrollment (participants) [Number]
United States	22 100%	16 100%	38 100%

Outcome Measures

1. Primary Outcome

Title	Plasminogen Activator Inhibitor 1
Description	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.
Time Frame	6 weeks (change from baseline)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aliskiren	Amlodipine
Arm/Group Description	Aliskiren 150-300 mg once daily	5-10 mg amlodipine once daily
Measure Participants	16	15
Mean (95% Confidence Interval) [ng/ml]	0.65	3.82

2. Secondary Outcome

Title	Serum Level of Vascular Cell Adhesion Molecule
Description	Surrogate biomarker cardiovascular risk
Time Frame	6 week (change from baseline)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aliskiren	Amlodipine
Arm/Group Description	Aliskiren 150-300 mg once daily	5-10 mg amlodipine once daily
Measure Participants	16	15
Mean (95% Confidence Interval) [ng/ml]	-2.4	-45.9

3. Secondary Outcome

Title	Serum Level of Intracellular Cell Adhesion Molecule
Description	Surrogate biomarker of cardiovascular risk
Time Frame	6 week (change from baseline)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aliskiren	Amlodipine
Arm/Group Description	Aliskiren 150-300 mg once daily	5-10 mg amlodipine once daily
Measure Participants	16	15
Mean (95% Confidence Interval) [ng/ml]	-4.9	-10.3

4. Secondary Outcome

Title	Serum Level of C-reactive Protein
Description	Surrogate biomarker of cardiovascular risk
Time Frame	6 week (change from baseline)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aliskiren	Amlodipine
Arm/Group Description	Aliskiren 150-300 mg once daily	5-10 mg amlodipine once daily
Measure Participants	16	15
Mean (95% Confidence Interval) [mg/l]	0.0397	0.1032

5. Secondary Outcome

Title	Serum Level of Nitric Oxide
Description	Surrogate biomarker of cardiovascular risk
Time Frame	6 week (change from baseline)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aliskiren	Amlodipine
Arm/Group Description	Aliskiren 150-300 mg once daily	5-10 mg amlodipine once daily
Measure Participants	16	15
Mean (95% Confidence Interval) [mmmol/l]	2.66	7.49

Adverse Events

Arm/Group Title	Aliskiren		Amlodipine
Arm/Group Description	Aliskiren 150-300 mg once daily		5-10 mg amlodipine once daily
All Cause Mortality
	Aliskiren		Amlodipine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Aliskiren		Amlodipine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Aliskiren		Amlodipine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/16 (0%)

Limitations/Caveats

Small sample size led to large standard deviation in biomarkers assessed and limited power to detect a diffference

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.