Advanced Chronic Heart Failure Clinical Trial
Official title:
Early Use of Levosimendan Compared to Usual Care in Advanced Chronic Heart Failure (ACHF)
The purpose of this study is to compare in patients with Advanced Chronic Heart Failure the
effects of Levosimendan versus diuretic (single 24-hour infusion) applied at the early
detection of impending destabilization on hospitalization-free survival during 12 months.
Patients with advanced chronic heart failure (ACHF) have a short term reduced life
expectancy with recurrent hospital admissions for clinical exacerbations. Levosimendan
improves contractility by calcium-dependent binding to troponin C, determines vasodilation
of the coronary arteries and systemic resistance vessels, thus decreasing preload and
afterload, while exerting a protective effect on the myocardium against ischemia-reperfusion
damage. In randomized clinical trials of acute heart failure patients, levosimendan improved
hemodynamics and patients' quality of life and decreased natriuretic peptide plasma levels,
with no excess mortality The study will assess whether the administration of levosimendan
(single 24-hour infusion) at the early detection of deterioration may reduce frequency and
duration of hospital admissions, improve functional status and quality of life in ACHF
patients, with respect to diuretic infusion.
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.
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