Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy

NCT ID: NCT01917149

Last Updated: 2014-05-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 480 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-03-31
• Study Completion Date: 2013-12-31

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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.

Group Type: EXPERIMENTAL

Metoprolol

Intervention Type: DRUG

Low-dose valsartan

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

Group Type: EXPERIMENTAL

Valsartan

Intervention Type: DRUG

Low dose Benazepril

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

Group Type: EXPERIMENTAL

Benazepril

Intervention Type: DRUG

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.

Group Type: EXPERIMENTAL

Valsartan

Intervention Type: DRUG

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.

Group Type: EXPERIMENTAL

Benazepril

Intervention Type: DRUG

Interventions

Benazepril

Intervention Type: DRUG

Valsartan

Intervention Type: DRUG

Metoprolol

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Xijing Hospital

OTHER

Sponsor Role: lead

Responsible Party

Hezheng

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Zheng He, MD, phD

Role: PRINCIPAL_INVESTIGATOR

Department of Cardiology, Xijing Hospital, Fourth Military Medical University

Qiujun Yu, MD, phD

Role: PRINCIPAL_INVESTIGATOR

Department of Cardiology, Xijing Hospital, Fourth Military Medical University

Locations

Xijing Hospital, Department of Cardiology

Xi'an, , China

Countries

China

References

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.

Reference Type: DERIVED

PMID: 28834619 (View on PubMed)

Other Identifiers

SIRAAS-DC

Identifier Type: -

Identifier Source: org_study_id