Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy

Efficacy and Safety Study of Supramaximal Titrated Inhibition of RAAS in Idiopathic Dilated Cardiomyopathy

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.

Study Overview

• Status: Completed
• Conditions: Dilated Cardiomyopathy
• Intervention / Treatment: Drug: Valsartan; Drug: Benazepril; Drug: Metoprolol

• Study Type: Interventional
• Enrollment (Actual): 480
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Xi'an, China, 710032
    • Xijing Hospital, Department of Cardiology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metoprolol; 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.	Drug: Metoprolol
Experimental: Low-dose valsartan; Patients randomized to low dose valsartan receive valsartan 80 mg until study completion.	Drug: Valsartan
Experimental: Low dose Benazepril; Patients randomized to low dose Benazepril receive Benazepril 10 mg until study completion.	Drug: Benazepril
Experimental: High dose valsartan; 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.	Drug: Valsartan
Experimental: High dose Benazepril; 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.	Drug: Benazepril

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	48 months after enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in NYHA functional class		6,12, 24 and 36 months after enrollment
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	6,12, 24 and 36 months after enrollment
Left-ventricular end-diastolic diameter		6, 12 , 24 and 36 months after enrollment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality		48 months after enrollment
Cardiovascular death		48 months after enrollment
All-cause hospital admission		48 months after enrollment
Heart failure admission		48 months after enrollment
changes in mitral regurgitation		12, 24 and 36 months after enrollment
wall-motion score index	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	12, 24 and 36 months after enrollment
Adverse events	Hypotension Hyperkalaemia Renal impairment Liver dysfunction Nonfatal stroke Angioedema	48 months after enrollment

Collaborators and Investigators

• Sponsor: Xijing Hospital
• Investigators: Principal Investigator: Zheng He, MD, phD, Department of Cardiology, Xijing Hospital, Fourth Military Medical University; Principal Investigator: Qiujun Yu, MD, phD, Department of Cardiology, Xijing Hospital, Fourth Military Medical University

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: March 1, 2005
• Primary Completion (Actual): July 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: July 30, 2013
• First Submitted That Met QC Criteria: August 3, 2013
• First Posted (Estimate): August 6, 2013

Study Record Updates

• Last Update Posted (Estimate): May 19, 2014
• Last Update Submitted That Met QC Criteria: May 16, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Keywords: Dilated cardiomyopathy; High dose ACEI/ARB
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Cardiomegaly; Laminopathies; Cardiomyopathies; Cardiomyopathy, Dilated; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Protease Inhibitors; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Valsartan; Metoprolol; Benazepril
• Other Study ID Numbers: SIRAAS-DC