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Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy

Primary Purpose

Dilated Cardiomyopathy

Status
Completed
Phase
Phase 4
Locations
China
Study Type
Interventional
Intervention
Benazepril
Valsartan
Metoprolol
Sponsored by
Xijing Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Dilated Cardiomyopathy focused on measuring Dilated cardiomyopathy, High dose ACEI/ARB

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Diagnosis of dilated cardiomyopathy
  • Left ventricular ejection fraction < 35%
  • NYHA Functional classes of II-IV
  • Symptomatic but not rapidly deteriorating 1 month before enrollment
  • Signed informed consent

Exclusion Criteria:

  • Contradictions and intolerance of the studied drugs:

    • supine systolic arterial blood pressure < 90 mmHg,
    • renal artery stenosis >50%,
    • pregnancy or lactation,
    • impaired renal function (estimated glomerular filtration rate < 60 ml/min/1.73m2,
    • impaired liver function (total bilirubin >2 times upper limit of normal,
    • serum aspartate AST or alanine ALT >3 times the upper limit of normal),
    • hemoglobin less than 8 mg/dl, hyperkalaemia (serum potassium >5.5mmol/l),
    • obstructive lung disease,
    • advanced atrioventricular block,
    • any co-morbidity with impact on survival, and
    • known intolerance to benazepril, valsartan and metoprolol succinate;

  • HF secondary to a known cause:

    • coronary artery disease based on coronary angiography (≥50% stenosis in ≥1 of the major coronary arteries) and/or a history of myocardial infarction or angina pectoris,
    • acute or subacute stage of myocarditis,
    • primary valve disease,
    • diabetes mellitus,
    • excessive use of alcohol or illicit drugs;
  • Expected or performed cardiac resynchronization therapy and heart transplantation.

Sites / Locations

  • Xijing Hospital, Department of Cardiology

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Metoprolol

Low-dose valsartan

Low dose Benazepril

High dose valsartan

High dose Benazepril

Arm Description

Patients in the metoprolol group were started on 11.875-23.75mg of metoprolol succinct extended-release tablet once daily (11.875mg was recommended for patients with NYHA functional classes III-IV), and then doses were doubled every 2 weeks to achieve asymptomatic bradycardia (50-60 bpm of heart rate) over 4-6 weeks. Investigators were encouraged to up-titrate metoprolol to a maximum dose of 190mg whenever possible.

Patients randomized to low dose valsartan receive valsartan 80 mg until study completion.

Patients randomized to low dose Benazepril receive Benazepril 10 mg until study completion.

Patients randomized to high-dose valsartan were started on valsartan 80mg twice daily, and uptitrated to target doses within 7 days under in-hospital observation. The target high doses of valsartan is determined by left-ventricular end-diastolic diameter (LVEDD) (the maximal value of anteroposterior and lateral diameters) obtained by ECG at the randomization visit. A target dose of valsartan 320mg, 480mg, 640mg daily were assigned to patients with LVEDD of 50-59, 60-69, ≥70 mm respectively.

Patients randomized to high-dose benazepril were started on benazepril 10mg twice daily, and uptitrated to target doses within 7 days under in-hospital observation. The target high doses of benazepril is determined by left-ventricular end-diastolic diameter (LVEDD) (the maximal value of anteroposterior and lateral diameters) obtained by ECG at the randomization visit. A target dose of benazepril 40mg, 60mg, 80mg daily were assigned to patients with LVEDD of 50-59, 60-69, ≥70 mm respectively.

Outcomes

Primary Outcome Measures

All cause death or admission for heart failure
Admission for heart failure was defined as a minimum of 24 h inpatient admission to any health-care facility, with the primary cause being treated for worsening heart failure and during which an additional diuretic drug, intravenous or oral nitrate, or intravenous inotropic agent was given.

Secondary Outcome Measures

Changes in NYHA functional class
Left-ventricular ejection fraction
Left ventricular ejection fraction (LVEF) were calculated from measurements of left ventricular end diastolic and end systolic volumes in apical 4 and 2 chamber views using the modified Simpson's rule according to current guidelines
Left-ventricular end-diastolic diameter

Full Information

First Posted
July 30, 2013
Last Updated
May 16, 2014
Sponsor
Xijing Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT01917149
Brief Title
Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy
Official Title
Efficacy and Safety Study of Supramaximal Titrated Inhibition of RAAS in Idiopathic Dilated Cardiomyopathy
Study Type
Interventional

2. Study Status

Record Verification Date
May 2014
Overall Recruitment Status
Completed
Study Start Date
March 2005 (undefined)
Primary Completion Date
July 2013 (Actual)
Study Completion Date
December 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Xijing Hospital

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Dilated cardiomyopathy (DCM) is a poorly understood cause of systolic heart failure and is the most common indication for heart transplantation worldwide. Despite advances in medical and device therapy, the 5-year mortality of patients with DCM remains high. Patients diagnosed of dilated cardiomyopathy with a NYHA functional class of II to IV and left ventricular ejection fraction(LVEF) <35% were selected for randomized controlled study of the efficacy and safety of high dose Renin-angiotensin system (RAS) inhibitor (benazepril or valsartan), in comparison with low dose RAS inhibitor(benazepril or valsartan) and standard beta-adrenergic blocker therapy (metoprolol). The primary endpoint was all cause death or admission for heart failure. Additional prespecified outcomes included all-cause death, cardiovascular death, all-cause admission, heart failure admission. Secondary cardiovascular outcomes included the changes from baseline to the last available observation after treatment in NYHA functional class, quality-of-life scores, LVEF, LVEDD, mitral regurgitation and wall-motion score index assessed by ECG. Adverse events were reported during in-hospital observation and follow-ups.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Dilated Cardiomyopathy
Keywords
Dilated cardiomyopathy, High dose ACEI/ARB

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
480 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Metoprolol
Arm Type
Experimental
Arm Description
Patients in the metoprolol group were started on 11.875-23.75mg of metoprolol succinct extended-release tablet once daily (11.875mg was recommended for patients with NYHA functional classes III-IV), and then doses were doubled every 2 weeks to achieve asymptomatic bradycardia (50-60 bpm of heart rate) over 4-6 weeks. Investigators were encouraged to up-titrate metoprolol to a maximum dose of 190mg whenever possible.
Arm Title
Low-dose valsartan
Arm Type
Experimental
Arm Description
Patients randomized to low dose valsartan receive valsartan 80 mg until study completion.
Arm Title
Low dose Benazepril
Arm Type
Experimental
Arm Description
Patients randomized to low dose Benazepril receive Benazepril 10 mg until study completion.
Arm Title
High dose valsartan
Arm Type
Experimental
Arm Description
Patients randomized to high-dose valsartan were started on valsartan 80mg twice daily, and uptitrated to target doses within 7 days under in-hospital observation. The target high doses of valsartan is determined by left-ventricular end-diastolic diameter (LVEDD) (the maximal value of anteroposterior and lateral diameters) obtained by ECG at the randomization visit. A target dose of valsartan 320mg, 480mg, 640mg daily were assigned to patients with LVEDD of 50-59, 60-69, ≥70 mm respectively.
Arm Title
High dose Benazepril
Arm Type
Experimental
Arm Description
Patients randomized to high-dose benazepril were started on benazepril 10mg twice daily, and uptitrated to target doses within 7 days under in-hospital observation. The target high doses of benazepril is determined by left-ventricular end-diastolic diameter (LVEDD) (the maximal value of anteroposterior and lateral diameters) obtained by ECG at the randomization visit. A target dose of benazepril 40mg, 60mg, 80mg daily were assigned to patients with LVEDD of 50-59, 60-69, ≥70 mm respectively.
Intervention Type
Drug
Intervention Name(s)
Benazepril
Intervention Type
Drug
Intervention Name(s)
Valsartan
Intervention Type
Drug
Intervention Name(s)
Metoprolol
Primary Outcome Measure Information:
Title
All cause death or admission for heart failure
Description
Admission for heart failure was defined as a minimum of 24 h inpatient admission to any health-care facility, with the primary cause being treated for worsening heart failure and during which an additional diuretic drug, intravenous or oral nitrate, or intravenous inotropic agent was given.
Time Frame
48 months after enrollment
Secondary Outcome Measure Information:
Title
Changes in NYHA functional class
Time Frame
6,12, 24 and 36 months after enrollment
Title
Left-ventricular ejection fraction
Description
Left ventricular ejection fraction (LVEF) were calculated from measurements of left ventricular end diastolic and end systolic volumes in apical 4 and 2 chamber views using the modified Simpson's rule according to current guidelines
Time Frame
6,12, 24 and 36 months after enrollment
Title
Left-ventricular end-diastolic diameter
Time Frame
6, 12 , 24 and 36 months after enrollment
Other Pre-specified Outcome Measures:
Title
All-cause mortality
Time Frame
48 months after enrollment
Title
Cardiovascular death
Time Frame
48 months after enrollment
Title
All-cause hospital admission
Time Frame
48 months after enrollment
Title
Heart failure admission
Time Frame
48 months after enrollment
Title
changes in mitral regurgitation
Time Frame
12, 24 and 36 months after enrollment
Title
wall-motion score index
Description
Wall motion score index (WMSI) was analyzed using an 11 segments model (3) (basal lateral, middle lateral, basal inferior, middle inferior, basal posterior interventricular septum, middle posterior interventricular septum, basal anterior free wall, middle anterior free wall, basal anterior interventricular septum, middle anterior interventricular septum and apex) with six segments each assigned to anterior and inferior regions, the apex being common. The motion of individual segments was graded as follows: normal 0, hypokinesia 1, akinesia 2, and dyskinesia 3. Global systolic wall motion score was calculated by dividing the total score by the number of segments analyzable. Results were only included when at least four segments from each of the anterior and inferior regions were analyzable. The lowest value of segment motion was chosen from the recorded motion amplitude of all 11 segments
Time Frame
12, 24 and 36 months after enrollment
Title
Adverse events
Description
Hypotension Hyperkalaemia Renal impairment Liver dysfunction Nonfatal stroke Angioedema
Time Frame
48 months after enrollment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of dilated cardiomyopathy Left ventricular ejection fraction < 35% NYHA Functional classes of II-IV Symptomatic but not rapidly deteriorating 1 month before enrollment Signed informed consent Exclusion Criteria: Contradictions and intolerance of the studied drugs: supine systolic arterial blood pressure < 90 mmHg, renal artery stenosis >50%, pregnancy or lactation, impaired renal function (estimated glomerular filtration rate < 60 ml/min/1.73m2, impaired liver function (total bilirubin >2 times upper limit of normal, serum aspartate AST or alanine ALT >3 times the upper limit of normal), hemoglobin less than 8 mg/dl, hyperkalaemia (serum potassium >5.5mmol/l), obstructive lung disease, advanced atrioventricular block, any co-morbidity with impact on survival, and known intolerance to benazepril, valsartan and metoprolol succinate; HF secondary to a known cause: coronary artery disease based on coronary angiography (≥50% stenosis in ≥1 of the major coronary arteries) and/or a history of myocardial infarction or angina pectoris, acute or subacute stage of myocarditis, primary valve disease, diabetes mellitus, excessive use of alcohol or illicit drugs; Expected or performed cardiac resynchronization therapy and heart transplantation.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Zheng He, MD, phD
Organizational Affiliation
Department of Cardiology, Xijing Hospital, Fourth Military Medical University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Qiujun Yu, MD, phD
Organizational Affiliation
Department of Cardiology, Xijing Hospital, Fourth Military Medical University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Xijing Hospital, Department of Cardiology
City
Xi'an
ZIP/Postal Code
710032
Country
China

12. IPD Sharing Statement

Citations:
PubMed Identifier
28834619
Citation
He Z, Sun Y, Gao H, Zhang J, Lu Y, Feng J, Su H, Zeng C, Lv A, Cheng K, Li Y, Li H, Luan R, Wang L, Yu Q. Efficacy and safety of supramaximal titrated inhibition of renin-angiotensin-aldosterone system in idiopathic dilated cardiomyopathy. ESC Heart Fail. 2015 Dec;2(4):129-138. doi: 10.1002/ehf2.12042. Epub 2015 Jul 14.
Results Reference
derived

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Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy

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