Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy

Air Force Military Medical University of People's Liberation Army

Status and phase: Completed; Phase 4

Conditions: Dilated Cardiomyopathy

Treatments: Drug: Metoprolol; Drug: Valsartan; Drug: Benazepril

Study type: Interventional

Funder types: Other

Identifiers

NCT01917149

SIRAAS-DC

Details and patient eligibility

About

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.

Enrollment: 480 patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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480 participants in 5 patient groups

Metoprolol

Experimental group

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.

Treatment:

Drug: Metoprolol

Low-dose valsartan

Experimental group

Description:

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

Treatment:

Drug: Valsartan

Low dose Benazepril

Experimental group

Description:

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

Treatment:

Drug: Benazepril

High dose valsartan

Experimental group

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.

Treatment:

Drug: Valsartan

High dose Benazepril

Experimental group

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.

Treatment:

Drug: Benazepril