PARADIGM HEART FAILURE Discussant Professeur Michel KOMAJDA - - PowerPoint PPT Presentation

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Dec 05, 2022 153 likes •217 views

PARADIGM HEART FAILURE Discussant Professeur Michel KOMAJDA Universit Pierre & Marie Curie Hpital Piti Salptrire ICAN Institute Paris (France) Disclosure: Consultant / Member of Advisory Boards and Committees: Bristol Myers

SLIDE 1

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

SLIDE 2

STRENGTHS

§ Large sample size # 8 400 patients. § Bio-marker entry criterion. § Relevant primary and secondary

utcomes.

§ Acceptable rate of discontinuation (# 18%) for a F/U of 27 months. Few patients lost to F/U. § Significant risk reduction # 20% in a well treated population (93% beta- blockers). § Consistency across pre-specified subgroups.

All-Cause Mortality

4187 4212 4056 4051 3891 3860 3282 3231 2478 2410 1716 1726 1005 994 280 279 LCZ696 Enalapril

Enalapril

(n=4212)

LCZ696

(n=4187) HR = 0.84 (0.76-0.93), P<0.0001 Kaplan-Meier Estimate of Cumulative Rates (%)

Days After Randomization Patients at Risk

360 720 1080 180 540 900 1260

16 32 24 8

835

711

Cardiovascular Death

Enalapril (n=4212) LCZ696 (n=4187)

HR = 0.80 (0.71-0.89), p = 0.00004 Number need to treat = 32

Kaplan-Meier Estimate of Cumulative Rates (%)

Days After Randomization 4187 4212 4056 4051 3891 3860 3282 3231 2478 2410 1716 1726 1005 994 280 279 LCZ696 Enalapril Patients at Risk

360 720 1080 180 540 900 1260 16 32 24 8

693 558 16 32 40 24 8 Enalapril (n=4212) LCZ696 (n=4187)

HR = 0.80 (0.73-0.87); P = 0.0000002 Number needed to treat = 21

360 720 1080 180 540 900 1260

Kaplan-Meier Estimate of Cumulative Rates (%)

Days After Randomization

Primary Endpoint

4187 4212 3922 3883 3663 3579 3018 2922 2257 2123 1544 1488 896 853 249 236 LCZ696 Enalapril Patients at Risk 1117 914

SLIDE 3

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).

SLIDE 4

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

SLIDE 5

§ 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.