Efficacy and Safety of Aliskiren and Valsartan Versus Placebo in Patients Stabilized Following an Acute Coronary Syndrome

A Randomized, Double-blind, Parallel-group, Placebo-controlled, Multinational Clinical Trial to Evaluate the Efficacy of Aliskiren and Valsartan Versus Placebo in Lowering Levels on NT-proBNP in Stabilized Patients Post Acute Coronary Syndromes

The purpose of this study is to test the hypothesis that the inhibition of the renin-angiotensin-aldosterone system (RAAS) with the angiotensin receptor blocker valsartan or the renin antagonist aliskiren will improve ventricular hemodynamics, as reflected by a greater reduction in levels of N-terminal proB-type natriuretic peptide (NT-proBNP) compared to placebo in subjects stabilized following acute coronary syndrome (ACS) who are determined to be at high risk due to an elevated concentration of natriuretic peptides.

Study Overview

• Status: Completed
• Conditions: Myocardial Ischemia; Post Acute Coronary Syndrome
• Intervention / Treatment: Drug: Placebo; Drug: Aliskiren 300 mg; Drug: Valsartan 320 mg; Drug: Aliskiren/valsartan 300/320 mg

• Study Type: Interventional
• Enrollment (Actual): 1101
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Investigative Site, Belgium
    • Investigative Site
• Canada
  • Investigative Site, Canada
    • Investigative Site
• Czech Republic
  • Investigative Site, Czech Republic
    • Investigative Site
• Germany
  • Investigative Site, Germany
    • Investigative Site
• Hungary
  • Investigative Site, Hungary
    • Investigative Site
• Netherlands
  • Investigative Site, Netherlands
    • Investigative Site
• Poland
  • Investigative Site, Poland
    • Investigative Site
• Russian Federation
  • Investigative Site, Russian Federation
    • Investigative Site
• Spain
  • Investigative Site, Spain
    • Investigative Site
• Sweden
  • Investigative Site, Sweden
    • Investigative Site
• United States
  • New Jersey
    • Investigative Site, New Jersey, United States
      • Investigative Site

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:

• Male or female outpatients 18 years old or older
• Subjects who are hospitalized for ischemic chest discomfort at rest lasting at least 10 minutes and consistent with cardiac ischemia
• Final diagnosis of acute coronary syndrome
• Elevated concentrations of natriuretic peptide 3-10 days after admission for their qualifying acute coronary syndrome event

Exclusion Criteria:

• Known or suspected contraindications, including history of allergy or hypersensitivity to angiotensin receptor blockers (ARBs), renin antagonists, or to drugs with similar chemical structures.
• Presence of clinically overt heart failure
• Known evidence of left ventricular systolic dysfunction
• Percutaneous coronary intervention (PCI) less than 24 hours before randomization.
• Patients on chronic ACEI or ARB therapy for whom therapy with an ACEI or ARB is clinically required with no reasonable alternative therapy available.

Other protocol-defined inclusion/exclusion criteria applied to the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo; Placebo tablets and capsules	Drug: Placebo; Placebo tablets and capsules. In order to adequately blind the study, patients were required to take a total of 1 tablet and 2 capsules during the first 4 weeks of the study. During the remainder of the study, patients were required to take 2 tablets and 2 capsules. Each dose was taken by mouth with water at approximately 8:00 AM with or without food.
EXPERIMENTAL: Aliskiren 300 mg; Following 1 week of treatment with 75 mg of aliskiren (tablets), patients in this arm were titrated up to 150 mg of aliskiren; 1 week later they were titrated up to 300 mg aliskiren for the remainder of the study.	Drug: Aliskiren 300 mg; Following 1 week of treatment with 75 mg of aliskiren (tablets), patients in this arm were titrated up to 150 mg of aliskiren; 1 week later they were titrated up to 300 mg aliskiren for the remainder of the study. If a patient was not up-titrated or required down-titration, the patient continued on that dose for the remainder of the study. If 2 down-titrations were required, they stopped study drug. In order to adequately blind the study, patients were required to take 1 tablet and 2 capsules during the first 4 weeks of the study and 2 tablets and 2 capsules for the remainder of the study. Each dose was taken by mouth with water at approximately 8:00 AM.
EXPERIMENTAL: Valsartan 320 mg; Following 1 week of treatment with 80 mg of valsartan (capsules), patients in this arm were titrated up to 160 mg of valsartan; 1 week later they were titrated up to 320 mg valsartan for the remainder of the study.	Drug: Valsartan 320 mg; Following 1 week of treatment with 80 mg of valsartan (capsules), patients in this arm were titrated up to 160 mg of valsartan; 1 week later they were titrated up to 320 mg valsartan for the remainder of the study. If a patient was not up-titrated or required down-titration, the patient continued on that dose for the remainder of the study. If 2 down-titrations were required, they stopped study drug. In order to adequately blind the study, patients were required to take 1 tablet and 2 capsules during the first 4 weeks of the study and 2 tablets and 2 capsules for the remainder of the study. Each dose was taken by mouth with water at approximately 8:00 AM.
EXPERIMENTAL: Aliskiren/valsartan 300/320 mg; Following 1 week of treatment with 80 mg of valsartan (capsules), patients in this arm were titrated up to 160 mg of valsartan; 1 week later they were titrated up to 320 mg valsartan for the remainder of the study. Beginning with Week 4, in addition to 320 mg valsartan, patients were treated with 75 mg of aliskiren (tablets); 1 week later patients were titrated up to 150 mg of aliskiren and 1 week later they were titrated up to 300 mg aliskiren for the remainder of the study.	Drug: Aliskiren/valsartan 300/320 mg; Following 1 week of treatment with 80 mg of valsartan (capsules), patients in this arm were titrated up to 160 mg of valsartan; 1 week later they were titrated up to 320 mg valsartan for the remainder of the study. Beginning with Week 4, in addition to 320 mg valsartan, patients were treated with 75 mg of aliskiren (tablets); 1 week later patients were titrated up to 150 mg of aliskiren and 1 week later they were titrated up to 300 mg aliskiren for the remainder of the study. If a patient was not up-titrated or required down-titration, the patient continued on that dose for the remainder of the study. If 2 down-titrations were required, they stopped study drug. In order to adequately blind the study, patients were required to take 1 tablet and 2 capsules during the first 4 weeks of the study and 2 tablets and 2 capsules for the remainder of the study. Each dose was taken by mouth with water at approximately 8:00 AM.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in N-terminal proB-type Natriuretic Peptide (NT-proBNP) at Week 8	Blood samples for the measurement of NT-proBNP were collected, processed, and shipped to the TIMI Biomarker Core Laboratory, Boston MA for storage and analysis. The change from baseline to Week 8 was expressed as the geometric mean of the ratio: Week 8/Baseline.	Baseline to Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in B-type Natriuretic Peptide (BNP) at Week 8	Blood samples for the measurement of BNP were collected, processed, and shipped to the TIMI Biomarker Core Laboratory, Boston MA for storage and analysis. The change from baseline to Week 8 was expressed as the geometric mean of the ratio: Week 8/Baseline.	Baseline to Week 8
Percentage of Patients With a Cardiac Event	A cardiac event was defined as at least one of the following events: Cardiovascular death, recurrent myocardial infarction (MI), or hospitalization for congestive heart failure (CHF), all to be confirmed by adjudication.	Baseline to Week 8
Percentage of Patients With a Composite Clinical-biochemical Event	A composite clinical-biochemical event was defined as at least one of the following events: cardiovascular death confirmed by adjudication, recurrent MI confirmed by adjudication, hospitalization for CHF confirmed by adjudication, and/or NT-proBNP => 200 pg/mL.	Baseline to Week 8

Collaborators and Investigators

• Sponsor: Novartis
• Collaborators: The TIMI Study Group
• Investigators: Study Chair: Eugene Braunwald, MD, TIMI Study Group, Boston, MA

Study record dates

Study Major Dates

• Study Start: February 1, 2007
• Primary Completion (ACTUAL): April 1, 2009
• Study Completion (ACTUAL): April 1, 2009

Study Registration Dates

• First Submitted: December 7, 2006
• First Submitted That Met QC Criteria: December 8, 2006
• First Posted (ESTIMATE): December 11, 2006

Study Record Updates

• Last Update Posted (ESTIMATE): April 19, 2011
• Last Update Submitted That Met QC Criteria: April 15, 2011
• Last Verified: April 1, 2011

More Information

Terms related to this study

• Keywords: Acute; B-type natriuretic peptide; coronary syndrome; Post acute coronary syndrome; N-terminal; pro-B-type natriuretic peptide; myocardial infarctions
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Disease; Myocardial Ischemia; Syndrome; Ischemia; Acute Coronary Syndrome; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Valsartan
• Other Study ID Numbers: CSPP100A2347