Add-on Aliskiren Treatment in Patients With Chronic Congestive Heart Failure

Effects of add-on Aliskiren Treatment on Central and Peripheral Hemodynamics and Biomarkers in Patients With Chronic Congestive Heart Failure (NYHA Class II-IV) (First Year Project)

Aliskiren is a potent direct renin inhibitor and has been recently shown to have favorable neurohumoral effects in patients with heart failure (HF) Objective：To study the effects of add-on aliskiren treatment in patients with HF on components of arterial load, from central aorta to peripheral arterioles and biomarkers Methods：Patients with NYHA Class II to IV HF, who have been treated with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) and beta-blocker are randomized to 6 months of treatment with placebo or aliskiren (150mg per day) treatment. Components of arterial load, from central aorta to peripheral arterioles as well as a wide-range of biomarkers, including inflammatory biomarkers, N-terminal pro-B type natriuretic peptide, arterial remodeling markers (procollagen, matrix metalloproteinase) will be measured before, 2 months and 6 months after treatment.

What is New or Innovative in this study? The importance of central hemodynamics and biomarker changes in patients with HF has been shown in observation studies. This is the first randomized control trial that examines comprehensively the effects of a direct rennin inhibitor on central hemodynamics and biomarkers in HF patients who are receiving standard heart failure therapy.

Study Overview

• Status: Unknown
• Conditions: Congestive Heart Failure
• Intervention / Treatment: Drug: Aliskiren; Drug: Placebo

Detailed Description

Introduction: Aliskiren is a potent direct renin inhibitor and has been recently shown to have favorable neurohumoral effects in patients with heart failure (HF) Objective：To study the effects of add-on aliskiren treatment in patients with HF on components of arterial load, from central aorta to peripheral arterioles and biomarkers Methods：Patients with NYHA Class II to IV HF, who have been treated with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) and beta-blocker are randomized to 6 months of treatment with placebo or aliskiren (150mg per day) treatment. Components of arterial load, from central aorta to peripheral arterioles as well as a wide-range of biomarkers, including inflammatory biomarkers, N-terminal pro-B type natriuretic peptide, arterial remodeling markers (procollagen, matrix metalloproteinase) will be measured before, 2 months and 6 months after treatment.

What is New or Innovative in this study? The importance of central hemodynamics and biomarker changes in patients with HF has been shown in observation studies. This is the first randomized control trial that examines comprehensively the effects of a direct rennin inhibitor on central hemodynamics and biomarkers in HF patients who are receiving standard heart failure therapy.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 4

Contacts and Locations

Study Locations

• Taiwan
  • Taipei, Taiwan, 886
    • National Taiwan University Hospital
  • Taipei, Taiwan, 886
    • Taipei Veteral General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Outpatients ≥ 18 years of age, male or female. Female patients must be either post-menopausal for one year, surgically sterile, or using effective contraceptive methods such as oral contraceptives, barrier method with spermicide or an intrauterine device.
2. Patients with a diagnosis of chronic heart failure (NYHA Class II-IV) and reduced systolic function: LVEF ≤ 45% at Visit 1 (local measurement, measured within the past 6 months assessed by echocardiogram, MUGA, CT scan, MRI or ventricular angiography).
3. Patients must be on a stable dose of either an ACE inhibitor or an ARB for at least 4 weeks prior to Visit 1.
4. Patients must be treated with a beta blocker, unless contraindicated or not tolerated, at a stable dose for at least 4 weeks prior to Visit 1.
5. Patients with documented sinus rhythm at Visit 1.

Exclusion Criteria:

1. History of hypersensitivity to any of the study drugs.
2. Patients who require treatment with both ACEI and ARB.
3. Current acute decompensated HF (exacerbation of chronic HF manifested by signs & symptoms that may require IV therapy).
4. Symptomatic hypotension and/or less than 100 mmHg at the time of screening or less than 90 mmHg at the time of randomization.
5. eGFR < 30 ml/min/1.73m2 as measured by the MDRD formula at Visit 1 (screening) , or a > 25% decrease after 14 days of active run-in period.
6. Serum potassium > 5.0 mmol/L at screening (Visit 1).
7. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or major vascular surgery, percutaneous coronary intervention (PCI) or carotid angioplasty, within the past 3 months prior to visit 1.
8. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within the 6 months after Visit 1.
9. Patients with active or unstable bronchospasm or asthma (patients must be on stable regimen of respiratory medications for 1 month prior to Visit 1).
10. Right heart failure due to severe pulmonary disease.
11. Diagnosis of peripartum or chemotherapy induced cardiomyopathy within the 12 months prior to visit 1.
12. Patients with a history of heart transplant or who are on a transplant list or with left ventricular assistance device (LVAD device).
13. Documented ventricular arrhythmia with syncopal episodes within past 3 months, prior to visit 1, that is untreated.
14. Symptomatic bradycardia or second or third degree heart block without a pacemaker.
15. Implantation of a CRT (cardiac resynchronization therapy) device within the prior 3 months from visit 1 or intent to implant a CRT device.
16. Presence of hemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to left ventricular dilatation.
17. Presence of other hemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic and sub-aortic stenosis.
18. Severe primary pulmonary, renal or hepatic disease.
19. Presence of any other disease with a life expectancy of < 1 year.
20. Chronic long-term requirement for NSAIDs (high dose) or COX2 inhibitors, with the exception of aspirin at doses used for CV prophylaxis (≤325 mg o.d.).
21. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs
22. Subjects are now breast feeding, get pregnant or will be pregnant within 6 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Aliskiren, add-on; HF patients will be randomized to receive add-on aliskiren 150 mg for 6 months	Drug: Aliskiren; all eligible patients will be randomized to receive aliskiren 150 mg on top of optimal HF therapy, including ACEI, ARB, beta blockers as considered appropriate by the investigator and in accordance with standard therapy guidelines for 6 months; Other Names: rasilez
PLACEBO_COMPARATOR: placebo, add-on; patients will be randomized to receive add-on placebo for 6 months	Drug: Placebo; all eligible patients will be randomized to receive placebo on top of optimal HF therapy, including ACEI, ARB, beta blockers as considered appropriate by the investigator and in accordance with standard therapy guidelines for 6 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Central hemodynamics including aortic impedance, central blood pressure, pulse wave velocity	baseline, 2 months, 6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Biomarkers including NT-pro-BNP, CRP, MMP	baseline, 2 months, 6 months

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital
• Collaborators: Taipei Veterans General Hospital, Taiwan
• Investigators: Principal Investigator: Lian-Yu Lin, MD, PhD, National Taiwan University Hospital

Study record dates

Study Major Dates

• Study Start: January 1, 2010
• Primary Completion (ANTICIPATED): July 1, 2010
• Study Completion (ANTICIPATED): January 1, 2011

Study Registration Dates

• First Submitted: December 25, 2009
• First Submitted That Met QC Criteria: December 28, 2009
• First Posted (ESTIMATE): December 29, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): January 20, 2010
• Last Update Submitted That Met QC Criteria: January 18, 2010
• Last Verified: December 1, 2009

More Information

Terms related to this study

• Keywords: Aliskiren; Congestive heart failure; Central hemodynamics
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: 200911004M