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.