LION-HEART. Levosimendan Intermittent administration in Outpatients: effects on Natriuretic peptides in advanced chronic HEART failure

Transcription

1 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 identifier NCT

2 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

3 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 effects Opens sarcolemma K ATP channels vasodilation Opens mitochondrial K ATP channels cardio-protection ü Thus, intermittent, repetitive ambulatory administration of levosimendan may be safe and translate in clinical benefits in patients with advanced CHF

4 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 weeks episodes of pulmonary and or systemic congestion requiring intravenous therapy during the preceding 12 months optimal therapy (including implantable devices) or attempts to optimize it

5 LION-HEART Study Protocol Screening 1 week 1 Outpatient Therapy 3 months Follow-up 9 months Levosimendan 0.2μg/Kg/min for 6 hours every 2 weeks Placebo 0.2μg/Kg/min for 6 hours every 2 weeks End of Study Informed Consent 70 patients Randomization 69 patients Arrhythmia Evaluation (24 h Holter Monitoring) Primary End-Point Changes in NT-proBNP Comparing AUC of NT-proBNP from pre and post 24h infusion levels of NT-proBNP) PRO Week 13 PRO Week 25

6 LION-HEART Baseline Characteristics

7 LION-HEART Baseline Treatment

8 LION-HEART Study Results NT-proBNP pg/ml P=0.002 P=0.004 pre post pre post pre post pre post pre post pre post Days (Treatment Period) ❶ ❷ ❸ ❹ ❺ ❻ Cicles of Intermittent Levosimendan

9 LION-HEART Study Results

10 LION-HEART Study Results- Safety *24-ECG monitoring

11 LION-HEART Study Results- Safety and Tolerability

12 LION-HEART Study Results- Clinical Events KM curves HF Hospitalization All-cause death or HF Hospitalization *Cox Proportional Hazards Models (time to first event) Placebo n=21 Levosimendan n=48 p-value HR (95% CI)* Heart Failure Hospitalization 14 (67%) 11 (23%) ( ) All-cause Death 7 (33%) 14 (29%) ( ) All-cause Death or Heart Failure Hospitalization 17 (81%) 23 (48%) ( )

13 LION-HEART Study Results- PRO (EQ-5D VAS score) *MCID (minimal clinically important

14 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

15 Thanks to Patients And Thanks to Investigators LION-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.