Disclosure- J Howlett

Transcription

1 Industry Contacts: AstraZeneca, Novartis, Merck, Servier, Pfizer, Medtronic, Abbott Research grants: Servier, CVS, Medtronic, Novartis I am a long serving member of CHEP and CCS HF Guidelines Disclosure- J Howlett I ALWAYS SEEM TO DISCUSS OFF LABEL USE OF MEDICATIONS!!!! CCC Oct 24, 2016

2 Sacubitril/Valsartan in HFrEF for All? NOPE Jonathan Howlett Calgary, AB CCC Oct 24, 2016

3 So Why not? There is a large proportion of Patients with HFrEF who are not studied CCC Oct 24, 2016

4 So Why not? There is a large proportion of Patients with HFrEF who are not studied We do not know the starting dose CCC Oct 24, 2016

5 PARADIGM-HF: Patient disposition 10,513 patients entered enalapril run-in phase (median duration, 15 days; interquartile range [IQR], 14 21) 9419 entered LCZ696 run-in phase (median duration, 29 days; IQR, 26 35) 8442 underwent randomization 1102 discontinued study: 591 (5.6%) had adverse event 66 (0.6%) had abnormal laboratory or other test result 171 (1.6%) withdrew consent 138 (1.3%) had protocol deviation, administrative problem or were lost to follow-up 49 (0.5%) died 87 (0.8%) had other reasons 977 discontinued study: 547 (5.8%) had adverse event 58 (0.6%) had abnormal laboratory or other test result 100 (1.1%) withdrew consent 146 (1.6%) had protocol deviation, had administrative problem, or were lost to follow-up 47 (0.5%) died 79 (0.8%) had other reasons 43 were excluded: 6 did not undergo valid randomization 37 were from four sites prematurely closed because of major Good Clinical Practice violations 4187 were assigned to receive LCZ had known final vital status 11 had unknown final vital status 4212 were assigned to receive enalapril 4203 had known final vital status 9 had unknown final vital status 14MDL252E McMurray, et al. N Engl J Med 2014; epub ahead of print: DOI: /NEJMoa

6 Health Canada Product Monograph, ENTRESTO 2015

7 TITRATION study: patient disposition 540 a entered run-in 498 randomized 42 b run-in failed AEs: 30 Protocol deviation: 7 88 c treatment failure (mainly renal dysfunction or hypotension) 378 completed randomization phase 32 non-ae, non-death related d/c Other reasons: 5 (administrative problem, or were lost to follow-up etc.) Completed open-label: 51 Deaths: 3 Discontinuations/ deviations: 34 Protocol deviation: 15 Withdrew consent: 7 Administrative problems: 4 Physician's decision: 5 On target dose: 19 d Not on target (incl. <2 wks on 200 mg b.i.d.): 32 AE d/c from open-label: 20 AE d/c without open-label: 11 Protocol deviation: 2 Administrative problem d/c from open-label: 1 Lost to follow-up: 1 15MDL % of patients had issues even with low dose switch Novartis Data on File: TITRATION study B2228

8 So Why not? There is a large proportion of Patients with HFrEF who are not studied We do not know the starting dose There may be harm in exposing these patients to the drug prematurely CCC Oct 24, 2016

9 Swedberg, NEJM 1992; 327:

10 So Why not? There is a large proportion of Patients with HFrEF who are not studied We do not know the starting dose There may be harm in exposing these patients to the drug prematurely They may not need it anyway. CCC Oct 24, 2016

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12 So Why not? There is a large proportion of Patients with HFrEF who are not studied We do not know the starting dose There may be harm in exposing these patients to the drug prematurely They may not need it anyway. Everyone else agrees with me! CCC Oct 24, 2016

13 2016 European Society of Cardiology Heart Failure Guidelines

14 Clyde Yancy et al ; JACC 2016

15 ACEi v. ARNi ACE Inhibitors > 30 years use > 1000 trials as de novo Randomized trials numerous settings, conditions Run in design No Run in design Large amount of registry data ARNIs 2 years use No trials as de novo Randomized trial in chronic stable HF Run in design onle No significant published registry data yet

16 ACE First Then Decide on ARNi CCC Oct 24, 2016 Howlett, CJC 2015

17 ARNis= Breakthrough advance in drug therapy for HFrEF.just not for everyone

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