Heart Failure with Mid-range Ejection Fraction, Heart Failure with Preserved Ejection Fraction
Conditions
Keywords
heart failure, mid-range ejection fraction, preserved ejection fraction, diastolic dysfunction, Spironolactone, Mineralcorticoid Receptor Antagonist
Brief summary
The purpose of this study is to determine whether the treatment of patients with HFmrEF and HFpEF at high risk of cardiovascular events with the mineralocorticoid receptor antagonist (MRA) spironolactone reduces a composite of recurrent heart failure hospitalizations and cardiovascular mortality.
Detailed description
The primary objective of the SPIRIT-HF study is to compare Spironolactone to Placebo in reducing the rate of the composite endpoint of recurrent heart failure hospitalizations and cardiovascular (CV) death in symptomatic HF patients (NYHA II-IV) with mid-range (LVEF 40- 49 %) or preserved (LVEF ≥ 50 %) ejection fraction. The efficacy and safety of mineralocorticoid receptor antagonist (MRA) in reducing the risk of death and hospitalizations has been proven with two separate substances (Spironolactone; RALES 1999 and Eplerenone; EMPHASIS 2011) in symptomatic heart failure patients with reduced left- ventricular ejection fraction (HFrEF). In 2013 the TOPCAT investigators tried to proof similar efficacy in patients with heart failure and preserved ejection fraction (≥ 45%). Because of regional variations in the enrollment process and difficulties regarding drug adherence the trial revealed neutral findings but the substance spironolactone was still able to show its potential benefit in the American cohort. Hence, the investigators see a strong rationale for testing a mineralocorticoid receptor blocker in patients suffering from heart failure with mid-range or preserved left ventricular ejection fraction. Intervention: Mineralocorticoid receptor blocker Spironolactone in tablet form taken daily. Starting dosage will be 25 mg OD with dosage escalation to 50 mg OD within 4 weeks if kidney function at VR was \> 30 mL/min/m2 and potassium \< 4.5 mmol/L. Spironolactone is not approved for the treatment of HFmrEF and HFpEF. Matching placebo in tablet form taken daily with dosage escalation rules in accordance with dosage of the study drug Spironolactone. Visits: Screening (VScr), Visit of Randomization (VR), V1 Safety Visit (1 week), V2 (4 weeks), V2S Safety Visit (5 week), V3 (4 months), V4 (8 months), V5 (12 months), V6 (18 months), V7 (24 months), V8 (30 months), V9 (36 months), V10 (42 months), V11/EOT (48 months); VXS (1 week after Visit X). Individual intervention duration with spironolactone or placebo will be continued until the overall expected event rate is reached or until withdrawal of informed consent. Based on previous HF trials the investigators calculate a mean follow-up duration of 3 years (range 2-4 years) depending on the individual inclusion date. Duration of follow-up will be event-rate based, with an expected overall study duration of 60 months. With an anticipated recruitment phase of 24 months; this will result in a maximum follow-up of 48 months and an average follow-up per patient of 36 months assuming a constant recruitment rate.
Interventions
DRUGExperimental: Spironolactone
Spironolactone (an aldosterone antagonist) in tablet form taken daily. The initial study drug dose is 25 mg/day (one tablet) and may be titrated up to 50 mg/day (two tablets) within 4 weeks if kidney function at VR was \> 30 mL/min/m2 and potassium \< 4.5 mmol/L.
DRUGPlacebo Comparator
Placebo of Spironolactone in tablet form taken daily with dosage escalation rules in accordance with dosage of the study drug Spironolactone.
Sponsors
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
Echo Core Lab Berlin
University of Göttingen
University Medicine Greifswald
Ludwig-Maximilians - University of Munich
Institute for Cardiovascular Computer-assisted Medicine, Charité
Coordinating Centre for Clinical Trials, Charité
Charite University, Berlin, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 1. Written informed consent. 2. Male or female, age ≥ 50 years 3. Current symptoms of Heart Failure (NYHA ≥ II) during VR 4. Symptom(s) of HF ≥ 30 days prior to VR 5. HF Hospitalization or treatment with intravenous (IV) diuretics for worsening HF within 12 months prior to VR 6. Left ventricular ejection fraction ≥ 40 % at screening measured by echocardiography and evidence of structural/ functional abnormalities (at least one of the following criteria): LAVI \> 34 ml/m2// E/émean ≥ 13// Mean e' (septal and lateral) \< 9 cm/s 7. NT-proBNP \> 300 pg/ml (SR) or \> 900 pg/ml (AF) on the Visit 1 ECG; only if NT-proBNP is NOT available: BNP \> 80/ 250 pg/ml (SR/AF) 8. Controlled systolic BP: defined as a target systolic BP \< 140 mm Hg. Subjects with BP up to and including 160 mm Hg are eligible for enrollment if on 3 or more medications to control BP (Patients with uncontrolled BP should be considered for Re-Screening after optimization of antihypertensive therapy has been established) 9. Serum potassium \< 5.0 mmol/L prior to randomization
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. The investigator may apply no additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Objective: Cumulative number of primary composite events of cardiovascular (CV) death and total HF hospitalizations | Time Frame: Total follow up time (up to 48 months) | Cumulative number of primary composite events of cardiovascular (CV) death and total (first and recurrent) HF hospitalizations in symptomatic HF patients (NYHA II-IV) with mid-range (LVEF 40- 49 %) or preserved (LVEF ≥ 50 %) ejection fraction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Secondary Objective: Comparison of spironolactone to placebo in reducing the rate of hospitalisations and deaths | Time Frame: Total follow up time (up to 48 months) | * To compare Spironolactone to placebo in reducing the recurrent rate of heart failure Hospitalizations \[Time Frame: Follow-up time up to 48month.\] * To compare Spironolactone to placebo in reducing the rate of recurrent non-fatal hospitalizations from cardiovascular (CV) cause (i.e. hospitalization for non-fatal MI, non-fatal stroke, or the management of heart failure, whichever occurred first) \[Time Frame: Total follow up time (up to 48 months)\]. * To compare Spironolactone to placebo in reducing the recurrent rate of hospitalizations from any cause \[Time Frame: Total follow up time (up to 48 months)\]. * To compare Spironolactone to placebo in reducing the rate of death from cardiovascular (CV) cause \[Time Frame: Total follow up time (up to 48 months)\]. * To compare Spironolactone to placebo in reducing the rate of death from any cause \[Time Frame: Total follow up time (up to 48 months)\]. |
Countries
Austria, France, Germany, Netherlands, Serbia
Outcome results
None listed