LION-HEART
Levosimendan Intermittent administration in Outpatients: effects on Natriuretic peptides in advanced chronic HEART failure
Multicentre, randomized, double-blind, parallel group, placebo-controlled trial to test the efficacy and safety of intravenous administration of intermittent doses of levosimendan in outpatients with advanced chronic heat failure
J. Comín-Colet (PI), N. Manito, J. Segovia, J. Delgado, L. Almenar. E. de Teresa, M.G. Crespo-Leiro, A. Sionis, M. Grau and J. Bruguera for the LION-Heart Investigators
EudraCT Number 2009-014242-28 www.ClinicalTrials.gov identifier NCT 01536132
Disclosures
ü The Sponsor of the Trial was the Hospital del Mar Medical Research Institute (IMIM), Barcelona (Spain)
ü The LION-HEART study was funded by an unrestricted grant by Orion Pharma
ü J. Comín-Colet, N. Manito and J. Delgado have received lecture fees from Orion Pharma
LION-HEART – Study Background
ü Patients with advanced chronic heart failure (CHF) suffer from a great functional impairment and have high morbidity and mortality
ü There are limited therapeutic options in these patients
ü Levosimendan has 3 main actions:Calcium sensitization ⇨ positive inotropic effectsOpens sarcolemma KATP channels ⇨ vasodilation Opens mitochondrial KATP channels ⇨ cardio-protection
ü Thus, intermittent, repetitive ambulatory administration of levosimendan may be safe and translate in clinical benefits in patients with advanced CHF
LION-HEART – Study Hypothesis and End-Points
ü Aim: prospective, multicenter, randomized, double-blind, parallel group study was to evaluate the effect of intermittent administration of levosimendan compared to placebo (2:1) in an outpatient basis in terms of safety and efficacy in patients with advanced CHF
ü Primary end-point: Changes from baseline to end-of therapy (12 weeks, 6 cycles of 6 hour-levosimendan infusion without bolus) in the concentration of natriuretic peptides (NT-proBNP)
ü Secondary end-points: clinical events (all-cause death, HF hospitalization and composite clinical endpoints), patient reported outcomes , safety (adverse events)
ü Key inclusion criteria: LVEF <35% and criteria for advanced CHF according to: persistence of NYHA III or IV for al least 4 weeksepisodes of pulmonary and or systemic congestion requiring intravenous therapy
during the preceding 12 months optimal therapy (including implantable devices) or attempts to optimize it
LION-HEART – Study Protocol
1
Informed Consent70 patients
Primary End-PointChanges in NT-proBNP
Comparing AUC of NT-proBNP from pre and post 24h infusion levels of NT-proBNP)
Screening1 week
Randomization69 patients
Outpatient Therapy3 months
Follow-up9 months
End of Study
2 3 4 5 6
PROWeek 13
PROWeek 25
Levosimendan0.2μg/Kg/min for 6 hours every 2 weeks
Placebo0.2μg/Kg/min for 6 hours every 2 weeks
Arrhythmia Evaluation(24 h Holter Monitoring)
LION-HEART – Baseline Characteristics
LION-HEART – Baseline Treatment
LION-HEART – Study Results
Cicles of Intermittent Levosimendan
❶ ❷ ❸ ❹ ❺ ❻
pre post pre post pre post pre post pre post pre post
P=0.004P=0.002
NT-proB
NP pg/m
L
Days (Treatment Period)
LION-HEART – Study Results
LION-HEART – Study Results- Safety
*24-ECG monitoring
LION-HEART – Study Results- Safety and Tolerability
LION-HEART – Study Results- Clinical Events
Placebon=21
Levosimendann=48
p-value HR (95% CI)*
Heart Failure Hospitalization 14 (67%) 11 (23%) 0.002 0.25 (0.11-0.55)All-cause Death 7 (33%) 14 (29%) 0.951 0.85 (0.34-2.12)All-cause Death or Heart Failure Hospitalization 17 (81%) 23 (48%) 0.022 0.39 (0.21-0.74)
*Cox Proportional Hazards Models (time to first event)
HF Hospitalization All-cause death or HF Hospitalization
KM curves
LION-HEART – Study Results- PRO (EQ-5D VAS score)
*MCID (minimal clinically important difference): 5 points in EQ-5D VAS Scale
LION-HEART – Conclusions
ü In the LION-HEART Study, the treatment with 6 cycles of intermittent infusions of levosimendan every 2 weeks at a dose of 0.2 μg/kg/min in outpatients with advanced CHF significantly reduced the levels of natriuretic peptides (primary end-point of the study) compared to patients that received placebo.
ü The positive effects of levosimendan on NT-proBNP levels translated into clinical improvements. Compared to placebo, patients that received levosimendan experienced
A significant reduction in the risk of HF hospitalization and the risk of the combined end-point of all-cause death or HF hospitalization
A lesser decline in their health-related QoL over time
ü The outpatient intermittent administration of levosimendan was safe and well tolerated in these patients with advanced CHF
ü Further studies are required to confirm the beneficial effects in terms of morbidity observed in the present study
Thanks to Patients And
Thanks to InvestigatorsLION-HEART Investigators
Hospital del Mar (Barcelona): Josep Comín-Colet, Jordi Bruguera, Cristina Enjuanes, Sonia Ruiz; Hospital de Bellvitge (Hospitalet): Nicolás Manito, José González-Costello; Hospital Puerta del Hierro (Madrid): Javier Segovia, Manuel Gómez, Luis Alonso-Pulpón; Hospital 12 de Octubre (Madrid): Juan Delgado, Maria José Ruiz;, Hospital la Fe (Valencia): Luis Almenar, Ignacio Sánchez-Lázaro; Hospital Virgen de la Victoria (Malaga): Eduardo de Teresa, Jose Manuel Garcia-Pinilla; Hospital de A Coruña: Marísa Crespo-Leiro, Chus Paniagua; Hospital de Sant Pau (Barcelona): Alessandro Sionis, Eulàlia Roig; Hospital Virgen de la Arrixaca (Murcia): Domingo Pascual, Iris Garrido; Hospital Miguel Servet (Zaragoza): Teresa Blasco, Marisa Sanz; Hospital Marques de Valdecilla (Santander): Francisco Gonzalez-Vilchez; Hospital Central de Asturias (Oviedo): José Luis Rodriguez Lambert, Beatriz Díaz.
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