Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy

Study Overview
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Brief Summary
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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.

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

Conditions
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Dilated Cardiomyopathy

Intervention / Treatment
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* Drug: Benazepril
* Drug: Valsartan
* Drug: Metoprolol


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dilated cardiomyopathy, High dose ACEI/ARB