PARADIGM HEART FAILURE Discussant Professeur Michel KOMAJDA - PowerPoint PPT Presentation

PARADIGM HEART FAILURE Discussant Professeur Michel KOMAJDA Université Pierre & Marie Curie Hôpital Pitié Salpétrière ICAN Institute Paris (France) Disclosure: • Consultant / Member of Advisory Boards and Committees: Bristol Myers Squibb, NILE Therapeutics, Novartis,Servier, Torrent • Speaker: AstraZeneca, BMS, GlaxoSmithKline, MSD, Menarini, Sanofi-Aventis, Servier

Primary Endpoint STRENGTHS 40 Kaplan-Meier Estimate of Cumulative Rates (%) 1117 32 Enalapril (n=4212) 914 24 LCZ696 (n=4187) 16 § Large sample size # 8 400 patients. 8 HR = 0.80 (0.73-0.87); P = 0.0000002 Number needed to treat = 21 0 0 180 360 540 720 900 1080 1260 § Bio-marker entry criterion. Days After Randomization Patients at Risk LCZ696 4187 3922 3663 3018 2257 1544 896 249 Enalapril 4212 3883 3579 2922 2123 1488 853 236 Relevant primary and secondary § 32 Cardiovascular Death Kaplan-Meier Estimate of Cumulative Rates (%) outcomes. 693 24 Enalapril (n=4212) § Acceptable rate of discontinuation (# 558 16 LCZ696 18%) for a F/U of 27 months. Few (n=4187) 8 HR = 0.80 (0.71-0.89), p = 0.00004 patients lost to F/U. Number need to treat = 32 0 0 180 360 540 720 900 1080 1260 Days After Randomization Patients at Risk § Significant risk reduction # 20% in a LCZ696 4187 4056 3891 3282 2478 1716 1005 280 Enalapril 4212 4051 3860 3231 2410 1726 994 279 well treated population (93% beta- All-Cause Mortality blockers). 32 835 Kaplan-Meier Estimate of Cumulative Rates (%) 24 Enalapril § Consistency across pre-specified 711 (n=4212) 16 subgroups. LCZ696 (n=4187) 8 HR = 0.84 (0.76-0.93), P<0.0001 0 0 180 360 540 720 900 1080 1260 Patients at Risk Days After Randomization LCZ696 4187 4056 3891 3282 2478 1716 1005 280 Enalapril 4212 4051 3860 3231 2410 1726 994 279

SAFETY § Good renal and K+ safety § More hypotensive episodes (588 vs 388) p < 0.001 but no more discontinuation (36 vs 29). § More angioedema (19 vs 10).

QUESTIONS (1) Why was PARADIGM positive and OVERTURE (Omapatrilat) neutral ? * Run in period  12% patients discontinued for intolerance. * Twice daily regimen  fewer post dose  BP. * Drug = ARB + NEPi vs   effect on Bradykinin ACE-I + NEPi  fewer angioedema

QUESTIONS (2) Does PARADIGM HF set a new standard for first line § therapy in HF with low EF? § Cost effectiveness? § Is benefit related to the action on natriuretic peptides? § Role of ARNi in HFpEF? § Role of ARNi in acute HF? § How will ARNi compare to direct renin inhibitors? ( ATMOSPHERE) § PARADIGM HF is the first modern trial proposing a substitution rather than an add on strategy in chronic HF .