Douglas L. Mann, Randall J. Lee, Andrew J.S. Coats, Gheorghe Neagoe, Dinu Dragomir, on behalf of the AUGMENT- HF Inves=gators

Transcription

1 One Year Follow- Up Results from AUGMENT- HF: A Mul=center Randomized Controlled Clinical Trial of the Efficacy of LeG Ventricular Augmenta=on with Algisyl- LVR in the Treatment of Heart Failure* Douglas L. Mann, Randall J. Lee, Andrew J.S. Coats, Gheorghe Neagoe, Dinu Dragomir, Enrico Pusineri, Massimo Piredda, Luca BeAari, Bridget- Anne Kirwan, Robert Dowling, Maurizio Volterrani, ScoA D. Solomon, Hani N. Sabbah, Andy Hinson, Stefan D. Anker on behalf of the AUGMENT- HF Inves=gators Disclosures: Scien&fic Advisory Board - Lone Star Heart, miragen therapeu&cs, Lilly Corpora&on Consultant Bio Control Medical, Cardioxyl, Medtronic Grant Support NIH 1

2 Background Therapeutic options are limited for patients with advanced heart failure who become refractory to conventional pharmacological therapies The injection of biomaterials into diseased myocardium has been shown to reduce myofiber stress, LV wall stress, restore LV geometry and improve LV function 1,2 Algisyl is a medical device that consists of an alginate hydrogel that is injected into the midwall of the LV, where it remains as a permanent implant that is intended to reduce LV wall stress and prevent or reverse the progression of HF Results of the AUGMENT-HF 6-month primary endpoint analysis were presented at this meeting in 2014 and published earlier this summer 3 1 Sabbah HN, et. al., JACC Heart Fail. 2013;1(3): Lee RJ, et. al, Int J Cardiol Jul 2;199: Anker, SD, et. al. Eur Heart J Sep 7;36(34):

3 LV Restoration & Laplace s Law Mechanism of Ac=on of Algisyl R h R h Dilated Modified (LVR) σ = P x R 2h σ = P x R 2h 3

4 LV Restoration with Algisyl Placement of Alginate Hydrogel via a Limited Thoracotomy Mean procedure duration 80.5 (±24.9) minutes Mean number of implants 15.5 (±2.0) Mean total volume of Alginate-hydrogel 4.6 (±0.6) ml 4

5 AUGMENT-HF Study Design & Objectives Multicenter prospective randomized clinical trial 78 Patients with moderate to severe HF that had been treated with optimal medical and/or device therapy, randomized 1:1 40 patients randomized to Algisyl implant procedure + optimal standard medical therapy (SMT) 38 patients randomized to optimal standard medical therapy alone 15 centers in Australia, Italy, Romania, Netherlands & Germany Primary Efficacy Endpoint: peak VO 2 assessed by a blinded core lab Secondary Endpoints: peak VO 2, 6MWT, Symptoms, QOL and measures of LV remodeling (echo) at 12, 18 and 24 months Safety: clinical outcomes (MACE) adjudicated by blinded CEC 5

6 AUGMENT-HF Key Inclusion & Exclusion Criteria Inclusion criteria Written informed consent ischemic or non-ischemic HF patients who are symptomatic despite optimal evidence-based therapies for HF LVEF 35% Peak VO 2 of ml/min/kg LVEDDi 30 to 40mm/m 2 (LVEDD/BSA) Stable, evidence-based therapy for heart failure! Previously reported high compliance: diuretics (99%) Beta Blockers (95%), ARBs/ACE-enzyme inhibitors (89%) and MRAs (69%) Exclusion criteria Acceptable renal, hepatic, stroke and MI status LV wall thickness > 8 mm required for implant 6

7 AUGMENT-HF Baseline Demographics All Patients (n=73)* Patients Completing 1-year follow-up All (n=59)** Control (n=33) Algisyl (n=26) Age (years) 62.6 ± ± ± ± 9.0 Ischemic HF 42 (58%) 35 (59%) 20 (61%) 15 (58%) Non-ischemic HF 31 (42%) 24 (41%) 13 (39%) 11 (42%) NYHA Class III/IV 81% 79% 76% 81% LVEF (%) 25.5 ± ± ± ± 5.0 Peak VO 2 (ml/min/kg) 12.2 ± ± ± ± 1.8 6MWT distance (m) 293 ± ± ± ± 95 Mitral regurgitation (51%) 27 (46%) 18 (55%) 9 (35%) Hypertension 43 (59%) 37 (63%) 20 (61%) 17 (65%) Diabetes 29 (40%) 25 (42%) 15 (46%) 10 (39%) Previous PCI or CABG 20 (27%) 17 (29%) 9 (27%) 8 (31%) * Modified Intention-to-Treat (mitt) population; ** 1 patient assessed by telephone only 7

8 Peak VO 2 - Mean Change from Baseline (a) 2.5 P=0.014 P<0.001 Peak VO2 (ml/min/kg) Mean change from baseline (SE) Time since randomisation (months) # of available values Control Algisyl Control Algisyl Algisyl was superior to SMT at 12 months with a mean treatment effect of 2.10 ml/ kg/min (CI ). Algisyl patients completed the 1 year follow-up with a mean peak VO2 of 14.0 (±3.1) ml/min/kg 8

9 Anaerobic Threshold Mean Change from Baseline (b) VO2 at AT (ml/min/kg) Mean change from baseline (SE) P=0.235 P< Time since randomisation (months) # of available values Control Algisyl Control Algisyl AT is independent of patient motivation or effort. Algisyl was superior to SMT with a mean treatment effect of 2.34 ml/kg/min (CI ) at 12 months (p<0.001). 9

10 Post-hoc Analysis Impact of Missing Peak VO 2 Data This is an advanced HF patient population with a high 1 year mortality, hence loss of patient data over this period is a concern. Shown here is a post-hoc analysis of the repeated measures model for Peak VO 2 including only paired data; those 58 patients with both a baseline and a 12 months assessment. 10

11 Six Minute Walk Test - Change from Baseline 220 P<0.001* P<0.001* 6MWT Distance (m) Median change [25% - 75% range] Time since randomisation (months) Control Algisyl # of available values Control Algisyl Treatment effect (vs. SMT) of 101 meters for median 6MWT distance 11

12 NYHA Functional Class at 12 months Control (n=32) Algisyl (n=26) Odds Ratio: (CI ); P < No. of Patients Class I Class II Class III Class IV Control (n=32) Algisyl (n=26) At 12 months, 85% of patients in the Algisyl group were NYHA functional class I or II compared to 25% of patients on SMT. Only 4 patients in the Algisyl group remained in NYHA class III at 12 months. These differences were highly statistically significant. The odds ratio favoring improvement by one class for Algisyl was (CI ); P <

13 AUGMENT-HF Summary of 12 Month Outcomes Outcomes Mean Difference Algisyl vs. Standard Medical Therapy P Value Algisyl vs. Standard Medical Therapy Peak VO 2 (ml/kg/min) 2.10 < Anaerobic Threshold (ml/kg/min) 2.34 < Peak WaXs Total Exercise Time (min) min walk test distance (m) a 101 a < NYHA class < KCCQ Overall Summary score KCCQ quality of life score a non- parametric test 13 13

14 All Adverse Events at 12 months Safety popula=on SMT (N=38) Algisyl- LVR (N=40) Total # of events # of pa&ents with events (%) Total # of events # of pa&ents with events (%) P All adverse events (66) (85) <0.001 # Serious adverse events (47) (53) # # p- value calculated by the log- rank test of the hazard rano (hazard rate per 100 panent years at risk) 14

15 MACE and Mortality Blinded CEC Adjudication Safety population SMT (N=38) Algisyl-LVR (N=40) Event Total # of events # of patients (%) Total # of events # of patients (%) Death 4 4 (10.5%) 9 9 (22.5%) Cardiovascular death 4 4 (10.5%) 8 8 (20.0%) Non-cardiovascular death 0 0 (0.0%) 1 1 (2.5%) MACE events (excluding index hospitalization) (39.5%) (25.0%) Cardiovascular death 4 4 (10.5%) 6 6 (15.0%) Cardiac arrest 3 3 (7.9%) 2 2 (5.0%) Worsening heart failure (34.2%) 11 6 (15.0%) Sustained ventricular arrhythmias 8 5 (13.2%) 1 1 (2.5%) The study was not powered to detect differences in event rates and there were no statistically significant differences between groups for any of these event categories 15

16 The Future of Algisyl AUGMENT-HF II Large US PMA Study (recent FDA cleared IDE) Sample size of 240 patients, randomized 1:1 versus usual care Endpoints essentially identical to the prior AUGMENT-HF study Peak VO2 and Combined HF hospitalization and mortality Algisyl as a Percutaneous Intervention 16

17 Conclusions We previously reported that Algisyl injections can be administered safely in patients with advanced HF, with an acceptable 30 day post-operative morbidity & mortality. The one-year follow-up results from AUGMENT-HF trail demonstrate sustained long term benefits of the Algisyl implant procedure in patients with advanced HF Algisyl combined with SMT provided substantial improvements in functional capacity & HF symptoms when compared to patients on SMT alone at 1 year post treatment. The 1 year MACE suggest a potential favorable reduction in HF hospitalization in patients treated with Algisyl. However there was a trend towards higher CV mortality at 1 year for patients receiving Algisyl. Longer term observations for this patient cohort and larger studies will provide important insights into clinical outcomes such as HF hospitalization and CV mortality 17

18 These results of the one year follow-up will be published online as an Epub ahead of print in the European Journal of Heart Failure following this presentation 18