Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy

NCT01917149 | Completed Phase 4 DMC

• 1 other identifier: SIRAAS-DC
• Study Type: interventional
• Target: 480
• Locations: 1 country
• Sites: 1

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.

Conditions

Dilated Cardiomyopathy

Keywords

Dilated cardiomyopathy; High dose ACEI/ARB

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Changes in NYHA functional class

  6,12, 24 and 36 months after enrollment

• Left-ventricular ejection fraction

  6,12, 24 and 36 months after enrollment

• Left-ventricular end-diastolic diameter

  6, 12 , 24 and 36 months after enrollment

Other Outcomes (7)

• All-cause mortality

  48 months after enrollment

• Cardiovascular death

  48 months after enrollment

• All-cause hospital admission

  48 months after enrollment

Study Arms (5)

Metoprolol

EXPERIMENTAL

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

Low-dose valsartan

EXPERIMENTAL

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

Drug: Valsartan

Low dose Benazepril

EXPERIMENTAL

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

Drug: Benazepril

High dose valsartan

EXPERIMENTAL

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

High dose Benazepril

EXPERIMENTAL

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

Interventions

Benazepril DRUG

High dose Benazepril; Low dose Benazepril

Valsartan DRUG

High dose valsartan; Low-dose valsartan

Metoprolol DRUG

Metoprolol

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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,

Sponsors & Collaborators

• Xijing Hospital: lead

Study Sites (1)

Xijing Hospital, Department of Cardiology

Xi'an, 710032, China

Location

Related Publications (1)

• 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.

  PMID: 28834619 DERIVED

MeSH Terms

Conditions

Cardiomyopathy, Dilated

Interventions

benazepril; Valsartan; Metoprolol

Condition Hierarchy (Ancestors)

Cardiomegaly; Heart Diseases; Cardiovascular Diseases; Cardiomyopathies; Laminopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: July 30, 2013
• First Posted: August 6, 2013
• Study Start: March 1, 2005
• Primary Completion: July 1, 2013
• Study Completion: December 1, 2013
• Last Updated: May 19, 2014

Record last verified: 2014-05

Locations

CN (1)