ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITORS IN HEART FAILURE FROM CHD

Transcription

1 ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITORS IN HEART FAILURE FROM CHD Karen Stout, MD FACC Professor, Medicine/Pediatrics University of Washington Seattle, WA USA

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3 No disclosures

4 Case 35 year old man with TGA, listed for transplant Mustard repair Atrial flutter, ablated Atrial pacemaker NYHA Class II symptoms On carvedilol, lisinopril, furosemide and spironolactone HR 70, BP 104/75 Mildly volume overloaded, BNP 385

5 PVR 5.5 Wood units

6 Case Begun on milrinone with some improvement of PCWP, mpap and PVR HF Cardiologist proposes sacubitril/valsartan

7 topics What is the PARADIGM trial? What is sacubitril-valsartan, how does it work? Who was in the study What might apply to ACHD patients?

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10 Life s hard. It s harder when you re stupid. ~ John Wayne

11 PARADIGM First new FDA approved heart failure drug since % reduction in death from CV causes and HF Similar to that of ACEi trials McMurray NEJM 2014

12 WHAT IS SACUBITRIL?

13 Heart failure - harmful RAAS ANG II AT1 RECEPTOR SVR SYMPATHETIC TONE FIBROSIS HYPERTROPHY NATRIURESIS/DIURESIS ALDOSTERONE

14 Heart failure - beneficial NATRIURETIC PEPTIDES NPR-A RECEPTOR INCREASE CGMP SVR SYMPATHETIC TONE FIBROSIS HYPERTROPHY NATRIURESIS/DIURESIS ALDOSTERONE

15 Heart failure less harm RAAS ANG II AT1 RECEPTOR SVR SYMPATHETIC TONE FIBROSIS HYPERTROPHY NATRIURESIS/DIURESIS ALDOSTERONE

16 Heart failure less benefit NATRIURETIC PEPTIDES NPR-A RECEPTOR Inactive products Neprilysin targets ANP, BNP, angiotensins 1, 2, 3, adrenomedulin, bradykinin INCREASE CGMP SVR SYMPATHETIC TONE FIBROSIS HYPERTROPHY NATRIURESIS/DIURESIS ALDOSTERONE

17 Heart failure more benefit NATRIURETIC PEPTIDES NPR-A RECEPTOR Inactive products INCREASE CGMP SVR SYMPATHETIC TONE FIBROSIS HYPERTROPHY NATRIURESIS/DIURESIS ALDOSTERONE

18 Heart failure - combination NATRIURETIC PEPTIDES RAAS NPR-A RECEPTOR Inactive products ANG II INCREASE CGMP AT1 RECEPTOR SVR SYMPATHETIC TONE FIBROSIS HYPERTROPHY NATRIURESIS/DIURESIS ALDOSTERONE

19 Heart failure maximum benefit NATRIURETIC PEPTIDES RAAS NPR-A RECEPTOR Inactive products ANG II INCREASE CGMP AT1 RECEPTOR SVR SYMPATHETIC TONE FIBROSIS HYPERTROPHY NATRIURESIS/DIURESIS ALDOSTERONE

20 BACK TO PARADIGM

21 Who was enrolled? 18 years NYHA class II, III, or IV symptoms EF 35% or less BNP 150 pg/ml ( 100 pg/ml if hospitalized within last year) NT-proBNP 600 pg/ml ( 400 pg/ml if hospitalized within last year 4 weeks of stable dose of a beta-blocker and an ACE inhibitor (or ARB) 10 mg of enalapril daily McMurray NEJM 2014

22 Who wasn t enrolled? Symptomatic hypotension SBP 100 mm Hg at screening or 95 mm Hg at randomization egfr< 30 ml/min/1.73 m2 BSA serum potassium > 5.2 mmol/liter McMurray NEJM 2014

23 McMurray NEJM 2014

24 COULD THIS APPLY TO ACHD?

25 Stout et al Circulation 2016

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27 Acquired LV Dysfunction

28 Balance Data in ACHD Extrapolation

29 Frankly, I mess around until they feel better and their BNP decreases without destroying their kidneys. I then congratulate myself on my foresight and clinical acumen, until they get overloaded again at which point I blame the nephrologist. ONE OPTION -Esteemed ACHD physician

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31 ACHD? NATRIURETIC PEPTIDES NPR-A RECEPTOR INCREASE CGMP NEPRILYSIN Inactive products RAAS Giannakoulas Amer J Cardiol 2010 NEPRILYSIN ANG II AT1 RECEPTOR SVR SYMPATHETIC TONE FIBROSIS HYPERTROPHY NATRIURESIS/DIURESIS ALDOSTERONE

32 ACHD? NATRIURETIC PEPTIDES NPR-A RECEPTOR NEPRILYSIN Inactive products RAAS NEPRILYSIN ANG II INCREASE CGMP Bolger Circulation 2002 AT1 RECEPTOR SVR SYMPATHETIC TONE FIBROSIS HYPERTROPHY NATRIURESIS/DIURESIS ALDOSTERONE

33 ACHD? NATRIURETIC PEPTIDES NPR-A RECEPTOR NEPRILYSIN Inactive products RAAS NEPRILYSIN ANG II INCREASE CGMP AT1 RECEPTOR Babu-Naranyan Circulation 2005 SVR SYMPATHETIC TONE FIBROSIS HYPERTROPHY NATRIURESIS/DIURESIS ALDOSTERONE

34 ACHD? NATRIURETIC PEPTIDES NPR-A RECEPTOR NEPRILYSIN Inactive products RAAS NEPRILYSIN ANG II INCREASE CGMP AT1 RECEPTOR Van der bom Circulation 2013 SVR SYMPATHETIC TONE FIBROSIS HYPERTROPHY NATRIURESIS/DIURESIS ALDOSTERONE

35 Before and after PVR 1.7 Wu

36 Other bits Not cheap - US$4500/year not yet cost effective Possible impact on pulmonary hypertension May help diastolic dysfunction PARAMOUNT trial ongoing (HFpEF)

37 ACC/AHA/HFSA guidelines Yancy J Amer Coll Card 2016

38 ESC guidelines Ponikowski Eur Heart J 2016

39 Some ACHD patients might benefit Fibrosis, Elevated BNP, Ventricular dysfunction Other reasons for HF No HF

40 CONCLUSION ARNI are beneficial for patients with systolic dysfunction (and maybe diastolic dysfunction) There is no data on patients with ACHD In selected patients, there may be symptomatic and survival benefit, but INDIVIDUALIZE and FOLLOW CLOSELY If LV dysfunction exists, and no other reversible cause is found, reasonable to follow existing GL

41 conclusion A pessimist is one who makes difficulties of his opportunities and an optimist is one who makes opportunities of his difficulties. ~Harry Truman

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