Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy

Phase 4

Completed

• Conditions: Dilated Cardiomyopathy
• Interventions: Drug: Valsartan; Drug: Benazepril; Drug: Metoprolol

• Registration Number: NCT01917149
• Lead Sponsor: Xijing Hospital

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2005-03
• Primary Completion: 2013-07
• Study First Submitted: 2013-07-30
• Study First Submitted QC: 2013-08-03
• Study First Posted: 2013-08-06
• Study Completion: 2013-12
• Status Verified: 2014-05
• Last Update Submitted: 2014-05-16
• Last Update Posted: 2014-05-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 480

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Low-dose valsartan	Valsartan	Patients randomized to low dose valsartan receive valsartan 80 mg until study completion.
Low dose Benazepril	Benazepril	Patients randomized to low dose Benazepril receive Benazepril 10 mg until study completion.
Metoprolol	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.
High dose valsartan	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.
High dose Benazepril	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.

Primary Outcome Measures

Name	Time	Method
All cause death or admission for heart failure	48 months after enrollment	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

Name	Time	Method
Left-ventricular end-diastolic diameter	6, 12 , 24 and 36 months after enrollment
Left-ventricular ejection fraction	6,12, 24 and 36 months after enrollment	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
Changes in NYHA functional class	6,12, 24 and 36 months after enrollment

Trial Locations

Locations (1)

Xijing Hospital, Department of Cardiology; 🇨🇳 Xi'an, China