ELEVATE Early LEvosimendan Vs Usual Care in Advanced Chronic hearT failurE

• Number of days alive free of Transplant and out-of-hospital (DAOH) [ Time Frame: Measured at 12 months ] [ Designated as safety issue: Yes ]
  

• Incidence of acute renal dysfunction [ Time Frame: Measured at at 24 hours since inception of randomized treatment for acute worsening HF ] [ Designated as safety issue: Yes ]
  proportion of subjects who develop AKIN stage 1 (increase > 0.3 mg/dl or > 25% in serum creatinine from previous visit)
  
  
• All cause mortality, hospital readmission and unscheduled office and emergency department visits for ADCHF [ Time Frame: Measured at 12 months ] [ Designated as safety issue: Yes ]
  A combination of all cause hospital admissions/death/urgent heart transplantation/LV assist device implantation
  
  
• BNP changes [ Time Frame: Measured at at end-of- study and at each eventual destabilization ] [ Designated as safety issue: No ]
  Percent changes in BNP vs baseline
  
  
• Number of hospital admissions for acute worsening HF [ Time Frame: Measured at 12 months ] [ Designated as safety issue: Yes ]
  Number of hospital admissions for acute worsening HF
  
  
• Costs [ Time Frame: Measured at 12 months ] [ Designated as safety issue: No ]
  Direct health care costs for days in hospital, supplementary visits, drug treatment
  
  
• Treatment-related adverse events [ Time Frame: Measured at 12 months ] [ Designated as safety issue: Yes ]
  death, hospital a dimission, emergency room or clinic unscheduled visits
  
  
• Adverse changes in blood pressure or heart rate [ Time Frame: Measured at 24 hours after iv treatment ] [ Designated as safety issue: Yes ]
  Hypotension (< 90 mmHg), tachycardia (> 110 bpm)
  
  
• ECG changes [ Time Frame: Measured at 24 hours after iv treatment ] [ Designated as safety issue: Yes ]
  Rhythm, rate, conduction disturbances, ventricular arrhythmias, repolarization changes
  
  

BACKGROUND Patients with advanced chronic heart failure (ACHF) have a short term reduced life expectancy with recurrent hospital admissions for clinical exacerbations. ACHF poses a heavy burden to cardiology departments, where these patients are referred for the severity of their clinical condition, which require a specialist approach, and results in high health care costs due to frequent rehospitalizations.

Patients with ACHF ≥ 2 hospital admissions in 6 months are at high risk of recurrent exacerbations. The benefits of strict outpatient follow-up at specialised HF vs standard community care in ACHF patients have been consistently demonstrated. The standard approach at HF clinics is based on flexible diuretic dose and outpatient iv diuretics as bolus or infusion at early signs of decompensation. Although this strategy results in symptomatic benefit and prevents approximately one third of hospital admission for acute exacerbations, a relevant proportion of patients will still need hospitalization. Predictors of lack of benefit are low systolic blood pressure, prior increase in oral diuretics and beta-blocker use, which taken together represent markers of severe disease susceptible to evolve in a low output state.

In the HF clinic setting, a novel strategy for these patients, to include early support to myocardial contractility, i.e. before compelling criteria for hospital admission become manifest, might prevent further prolonged hospitalizations, myocardial damage and impairment in renal function TRIAL RATIONALE Levosimendan improved hemodynamics and patients' quality of life and decreased natriuretic peptide plasma levels, with no excess mortality, in randomized clinical trials of acute heart failure. In SURVIVE an early larger treatment effect of levosimendan was apparent in patients with acute worsening of chronic HF treatment than in those with de novo disease, possibly because a greater proportion of these patients may be on beta-blockers, that are known to interfere with dobutamine or may potentiate the circulatory actions of levosimendan. Thus levosimendan may be unattractive first-line agent in destabilized ACHF patients on beta-blockers.

Based on the drug cardioprotective properties, hemodynamic and neurohormonal effects, we propose a novel therapeutic approach for the clinically-driven use of levosimendan in recurrent acute exacerbations of ACHF.

Dosing of the drug will omit the bolus to increase tolerability in this severely ill patient population.