Six Months Efficacy and Safety of Aliskiren Therapy on Top of Standard Therapy, on Morbidity and Mortality in Patients With Acute Decompensated Heart Failure

Study Overview
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Brief Summary
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This study evaluated the effect of early initiation of aliskiren therapy, compared to standard therapy, in the reduction of cardiovascular death and heart failure re-hospitalization events within 6 months, in congestive heart failure (CHF) patients hospitalized for an episode of acute decompensated heart failure.

Official Title
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A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Study to Evaluate the 6 Months Efficacy and Safety of Aliskiren Therapy on Top of Standard Therapy, on Morbidity and Mortality When Initiated Early After Hospitalization for Acute Decompensated Heart Failure

Conditions
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Acute Decompensated Heart Failure, Congestive Heart Failure

Intervention / Treatment
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* Drug: Aliskiren
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patient hospitalized with a primary diagnosis of worsening heart failure ≥ 18 years of age, male or female. Patients with a diagnosis of acute heart failure expressed by symptoms (dyspnea or fatigability - NYHA Class III-IV) and signs of fluid overload (i.e., jugular venous distension, edema or positive rales auscultation or pulmonary congestion on chest x-ray) at the time of hospitalization. LVEF < 40% (measured within the last 6 months). Hospitalization for ADHF and remain stabilized for at least 6 hours (defined as SBP ≥ 110 mm Hg after acute decompensated episode) and did not receive IV vasodilators (other than nitrates) and/or IV inotropic drugs at anytime from ADHF presentation to time of randomization. Elevated BNP at Visit 1 or at randomization (BNP ≥ 400 pg/ml). Patients with a history of chronic heart failure on standard therapy defined as requiring HF treatment for at least 30 days before the current hospitalization (NYHA Class II - IV). Exclusion Criteria: Patients that required any use of IV vasodilators (except nitrates), and/or any IV inotropic therapy from the time of presentation for worsening HF to randomization. Concomitant use of ACEI and ARB at randomization. Right heart failure due to pulmonary disease. Diagnosis of postpartum cardiomyopathy. Myocardial infarction or cardiac surgery, including percutaneous transluminal coronary angioplasty (PTCA), within past 3 months. Patients with a history of heart transplant or who are on a transplant list. Unstable angina or coronary artery disease likely to require coronary artery bypass graft (CABG) or PTCA before randomization. Other protocol-defined inclusion/exclusion criteria applied.

Ages Eligible for Study
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Minimum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aliskiren<br>Randomized patients in this arm received, Aliskiren 150 mg once daily for 2 weeks. From week 2 upto 6 months , patients who could tolerate study medication were up-titrated to aliskiren 300 mg once daliy. | Drug: Aliskiren<br>* Aliskiren 150 mg and Aliskiren 300 mg<br>* Other names: SPP100;|
| Placebo Comparator: Placebo<br>Randomized patients in this arm received matching placebo of Aliskiren. At week 2, Patients who could tolerate study medication were up-titrated to matching placebo of 300 mg aliskiren. | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Event Analysis: Number of Patients Experienced the First Confirmed Occurrence of Either Cardiovascular Death or Heart Failure (HF) Re-hospitalization Within 6 Months | Time to first confirmed occurrence of either cardiovascular death or heart failure re-hospitalization within 6 months of randomization was the primary efficacy variable. For the primary efficacy analysis, an event will be considered for the analysis if it occurs on or before Day 190 (189 days from randomization). The primary composite endpoint is the the composite of cardiovascular death or heart faliure re-hospitalization within 6 months. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Event Analysis: Number of Patients Experienced the First Confirmed Occurrence of Either Cardiovascular Death or Heart Failure (HF) Re-hospitalization Within 12 Months | Time to first confirmed occurrence of either cardiovascular death or heart failure re-hospitalization within 12 months of randomization was the key secondary efficacy variable. For the primary efficacy analysis, an event will be considered for the analysis if it occurs on or before Day 395 (394 days from randomization). The secondary composite endpoint is the the composite of cardiovascular death or heart faliure re-hospitalization within 12 months. | 12 months | 
| Change From Baseline in the Clinical Summary Score to 1 Month, 6 Months and 12 Months | Symptom reduction and reduction in physical limitations was assessed using the clinical summary score of the Kansas City Cardiomyopathy Questionnaire (KCCQ). The KCCQ is a self-administered questionnaire and contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Health-Related Quality of Life (QoL), including limitations, frequency, bother, change in condition, understanding, levels of enjoyment and satisfaction. Each scale score was calculated as the mean of its item scores and transformed to a 0-100 scale, with higher score indicating higher level of functioning. A score of 100 represents perfect health whereas a score of 0 represents death. A positive change in score from baseline indicates an improvement. | Baseline, 1 months, 6 months and 12 months | 
| Time to Event Analysis: Number of Patients With First Cardiovascular (CV) Event Hospitalized for an Acute Heart Faliure (AHF) Event Within 6 Months | A cardiovascular event defined as CV death, heart faliure re-hospitalization, non-fatal myocardial infarction (MI), nonfatal stroke, sudden death with resuscitation. | 6 months | 
| Time to Event Analysis: Number of Patients With All-cause Mortality Hospitalized for an AHF Event Within 12 Months |  | 12 months | 
| Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Level at 1 Month, 6 Months, and 12 Months | The reported Least square means, and Confidential Interval were from a repeated measures model on log transformed NT-proBNP data containing treatment, visit, and region as factors, log baseline NT-proBNP as a continuous covariate and treatment by visit and visit by log baseline NT-proBNP as interaction terms. | Baseline, 1 month, 6 months and 12 months | 
| Time to Event Analysis: Number of Patients With First Cardiovascular (CV) Event Hospitalized for an Acute Heart Faliure (AHF) Event Within 12 Months | A cardiovascular event defined as CV death, heart faliure re-hospitalization, non-fatal myocardial infarction (MI), nonfatal stroke, sudden death with resuscitation. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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reduced LVEF, elevated BNP, Acute Heart Failure, Cardiovascular death, CHF, hospitalization, morbi-mortality trial, outcome study, endpoint driven, plasma renin activity, renin angiotensin, aldosterone system, direct renin inhibitors, BNP, KCCQ, eGFR