A New Future In Heart Failure (Should we reshuffle the deck?)

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1 A New Future In Heart Failure (Should we reshuffle the deck?) DR. HEMANT SAHA, MD, MRCP(UK) AGA KHAN UNIVERSITY HOSPITAL, NAIROBI

2 Disclosures Nothing to disclose.

3 Objectives 1. Historical Perspectives 2. Heart Failure to date (GDMT in HFrEF) 3. Un Met Needs 4. HF Neuroendocrine Disease 5. Case Presentations 6. PARADIGM HF 7. Conclusions

4 If I have seen further, it is by standing on the shoulder of giants. Isaac Newton, 1676

5 1. Historical Perspectives

6 Historical Perspectives The Romans foxglove (digoxin) William Harvey HF related to circulatory system 1819 Rene Laennec Stethoscope/EKG 1960s Christian Barnard 1 st Heart Transplant/ LVADs 1950 s Modern diuretics 1920 s Diuretics (toxic) st CABG (USA) 1970s Vasodilators (V HeFT I) st percutaneous coronary angioplasty

1980s HF becomes a neuroendocrine disease.

1990s ICDs, CRT devices Post 2000 PCSK 9,

7 1980s HF becomes a neuroendocrine disease Vasodilators Anti RAAS drugs (ACE I, ARBs). Positive Inotropes Negative Inotropes (B blockers); MRAs. 1990s ICDs, CRT devices Post 2000 PCSK 9, Ivabradine, Vaptans, Empagliflozin, LCZ s Molecular biology, genetics & stem cells.

8 2. Heart Failure To Date (GDMT in HFrEF)

9 Definition of HF HF Results from any structural or functional abnormalities that impairs the ability of ventricle to eject blood (SHF) or fill with blood (DHF) Definite HFrEF (LVEF <40%) HFmrEF (40% LVEF <50%) Definite HFpEF (LVEF 50%) 50% 14% 36% 0% 20% 40% 60% 80% 100% Steinberg et al. Circulation 2012;126:65 75 Proportion of patients

10 GDMT Ivabradine, HR>70bpm ICD +/ CRT in Eligible Pts ESC Guidelines until 2016 (modified)

11 REDUCTIONS IN ALL CAUSE MORTALITY AMONG COMMON HF RX

12 3. Un Met Needs

14 Residual Risk for HFrEF Despite Conventional GDMT

15 4. HF Neuroendocrine Disease

NEUROENDOCRINE MODEL Pharmacological Approaches Natriuretic peptide system 1 B

Sympathetic tone Vasopressin Aldosterone Fibrosis Hypertrophy NEPRILYSIN

Vasoconstriction RAAS activity Vasopressin Heart rate Contractility LCZ696 The

ARBs and MRAs 1 Benefits of β blockers indicate that the SNS also plays a key

Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy

Eur Heart J 2012;33:1787 847; Figure References: Levin et al.

16 NEUROENDOCRINE MODEL Pharmacological Approaches Natriuretic peptide system 1 B BLOCKER Sympathetic nervous system NPRs NPs Vasodilation Blood pressure Sympathetic tone Vasopressin Aldosterone Fibrosis Hypertrophy NEPRILYSIN SACUBUTRIL HFrEF Epinephrine Norepinephrine α 1, β 1, β 2 receptors Vasoconstriction RAAS activity Vasopressin Heart rate Contractility LCZ696 The crucial importance of the RAAS is supported by the beneficial effects of ACEIs, ARBs and MRAs 1 Benefits of β blockers indicate that the SNS also plays a key role 1 ARB ACE I VALSARTAN Renin angiotensinaldosterone system Ang II AT 1 R Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis 1. McMurray et al. Eur Heart J 2012;33: ; Figure References: Levin et al. N Engl J Med 1998;339:321 8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27 42; Kemp & Conte. Cardiovascular Pathology 2012;365 71; Schrier & Abraham. N Engl J Med 2009;341:577 85

17 ARNI CONCEPT Dual Acting ARNI Sacubutril (Neprilysin Inhibitor) Valsartan (ARB) ANP,BNP,CNP & Other Vasoactive Peptides Bradykinin Ang II AT 1 Receptor

18 Rationale of ARB Bradykinin Effect Bradykinin breakdown ACE APP NEP DPP-4 ACE I + NI = ARB + NI = Bradykinin Bradykinin ACE: angiotensin converting enzyme; APP: aminopeptidase P; AT 1 : angiotensin II type 1; DPP 4: dipeptidyl peptidase 4; NEP: neprilysin The information presented in this slide is from publicly available data and not head to head clinical trials 1. McMurray et al. Eur J Heart Fail. 2014;16:817 25; 2. Fryer et al. Br J Pharmacol 2008;153:947 55; 3. Semple. J Hypertens Suppl 1995;13:S17 21; 4. Gu et al. J Clin Pharmacol 2010;50:401 14; 5. McMurray et al. Eur J Heart Fail. 2013;15: ; 6. McMurray, et al. N Engl J Med 2014;371:

19 5. Case Presentations

20 Case 1 55 year old diplomat. Known to have anthracycline induced long standing DCM (EF 25%) Admitted with ADHF secondary to pneumonia This was a second admission within 3 months.

21 Additional history PMHx Breast cancer survivor DCM 20 years CRT D Systemic arterial hypertension CKD stage 3 Lifetime non smoker, no alcohol intake MEDICATIONS Carvedilol 25mg BD Lisinopril 20 mg OD Spironolactone 25mg BD Furosemide 40mg BD Ivabradine 7.5mg BD

22 Cardiac work up 12 lead ECG Sinus rhythm, LBBB, QRS 130msec 2D ECHO LVEF 25% Global hypokinesia Mild MR PASP 45mmHg

23 Sinus 65b/min BP 110/70mm Hg CVS Elevated JVP, S3,MR murmur Clear lung fields LABS Hb 12.6g/dl U/E/Cr Cr 154 mmol/l egfr 37ml/min/m2 Na 132mmol/l K 5.2mmol/l Others normal WHAT NEXT?

24 Case Presentation 2 D.W. - 75YRS, Male Co-morbids: HTN, IHD PCI LAD (2011), Ca. Prostate Presentation Dyspnea, NYHA IV, fluid overload state Previous Drug Regime Lasix 40mg OD Aldactone 25mg OD Ramipril 5mg OD Atorvastatin 20mg OD Aspirin 75mg OD Carvedilol 6.25mg BD

25 Examination HR 90bpm; RR 25/min; BP 108/60mmHg JVP raised, S3 gallop, no murmurs Right pleural effusion mild Tender hepatomegaly, ascites, gross scrotal edema. Neurological exam Normal X Ray Increased CTR, Right small pleural effusion, mild pulmonary edema Labs NTProBNP>3000 Hb 11.8 Creatinine 86 Urea 9.4 Na 130/ K 4.2 HsTrop x 2 <3.0 Others normal

26 ECG LAO PR 0.27 LAD Poor R wave progression V1 V6 No acute ST T wave changes 2D Cardiac ECHO LVEF 15% Ant, Anteroseptal & lateral wall hypokinesia MR moderate PA pressure 56mmHg IVC 2cm, non collapsible

27 This is what we did: Diureses with IV Lasix 40mg BD Introduced Eplerenone 25mg OD and Ivabradine 5mg BD Increased Ramipril 10mg OD Increased Carvedilol 12.5mg BD

28 Outcome HR stabilized 60bpm, occasional PVCs BP 108/65mmHg. Minimal pedal edema S3 positive, mild mitral systolic murmur No lung rales. Lab parameters remained normal with slight worsening UEC s. Urea 14; Creatinine 100; Na 137; K 4.0 LVEF 20%

29 Despite optimization of therapy both patients remained symptomatic with intermittent dyspnea and had repeated readmissions due to decompensated heart failure

30 Prospective comparison of ARNI with ACE I to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM HF)

31 PARADIGM HF: the most geographically diverse trial in patients with HFrEF 8,442 patients were randomized at 985 sites in 47 countries

32 ENTRESTO (LCZ696) Simultaneous neprilysin inhibition and AT 1 receptor blockade.

33 PARADIGM HF STUDY DESIGN Single blind active run in period Randomization n=8,442 Double blind Treatment period Enalapril 10 mg BID* Entresto 100 mg BID Entresto 200 mg BID Entresto 200 mg BID Enalapril 10 mg BID # 2 Weeks 1 2 Weeks 2 4 Weeks Median of 27 months follow up On top of standard HFrEF therapy (excluding ACEIs and ARBs)

34 Objectives Primary endpoint CV mortality/hf hospitalization. Secondary endpoint all cause mortality, AF, renal decline, KCCQ(symptom score)

35 PARADIGM HF: Inclusion Criteria Chronic HF NYHA II IV (LVEF 40%) NT probnp: 600 pg/ml or 400 pg/ml, HFrEF hospitalization in the last 12 months 4 weeks stable treatment with ACEI/ARB + β blocker Consider MRA for all patients (stable dose for 4 weeks) Exclusion Criteria SBP <100 mmhg OR SBP <95 mmhg at end of enalapril run in. egfr <30ml/min/ >35% reduction after enalapril. K>5.2 mmol/l / >5.4 mmol/l after enalapril/lcz696 run in. H/O angioedema ADHF; severe pulmonary disease. Prior intolerance to ACE I, ARB

36 Baseline characteristics Characteristic* Entresto (n=4,187) Enalapril (n=4,212) Age, years 63.8 ± ± 11.3 Women, n (%) 879 (21.0) 953 (22.6) Ischemic cardiomyopathy, n (%) 2,506 (59.9) 2,530 (60.1) LV ejection fraction, % 29.6 ± ± 6.3 NYHA functional class, n (%) II III 2,998 (71.6) 969 (23.1) 2,921 (69.3) 1,049 (24.9) SBP, mmhg 122 ± ± 15 Heart rate, beats/min 72 ± ± 12 NT probnp, pg/ml (IQR) 1,631 (885 3,154) 1,594 (886 3,305) BNP, pg/ml (IQR) 255 ( ) 251 ( ) History of diabetes, n (%) 1,451 (34.7) 1,456 (34.6) Treatments at randomization, n (%) Diuretics 3,363 (80.3) 3,375 (80.1) Digitalis 1,223 (29.2) 1,316 (31.2) β blockers 3,899 (93.1) 3,912 (92.9) Mineralocorticoid antagonists 2,271 (54.2) 2,400 (57.0) ICD 623 (14.9) 620 (14.7) CRT 292 (7.0) 282 (6.7) McMurray et al. N Engl Med 2014;371:

37 Primary Composite Endpoint Entresto Enalapril Cumulative probability No. at risk Entresto Enalapril ,080 1,260 Days since randomization 4,187 3,922 3,663 3,018 2,257 1, ,212 3,883 3,579 2,922 2,123 1, CI: confidence interval; CV: cardiovascular; HF: heart failure McMurray et al. N Engl Med 2014;371: Hazard ratio = 0.80 (95% CI: ) p<0.001

38 Death from CV Causes Entresto Enalapril Cumulative probability No. at risk Entresto Enalapril Hazard ratio = 0.80 (95% CI: ) p< ,080 1,260 Days since randomization 4,187 4,056 3,891 3,282 2,478 1,716 1, ,212 4,051 3,860 3,231 2,410 1, CI: confidence interval; CV: cardiovascular; HF: heart failure McMurray et al. N Engl Med 2014;371:

39 Death From Any Cause Entresto Enalapril 1.0 Cumulative probability Hazard ratio = 0.84 (95% CI: ) p< No. at risk ,080 1,260 Days since randomization Entresto Enalapril CI: confidence interval McMurray et al. N Engl Med 2014;371: ,187 4,056 3,891 3,282 2,478 1,716 1, ,212 4,051 3,860 3,231 2,410 1,

40 PARADIGM HF: Effect of LCZ696 vs Enalapril on Primary Endpoint and Its Components

41 Safety endpoints EVENT, N (%) ENTRESTO (N=4,187) ENALAPRIL (N=4,212) HYPOTENSION Symptomatic 588 (14.0) 388 (9.2) Symptomatic with SBP <90 mmhg 112 (2.7) 59 (1.4) ELEVATED SERUM CREATININE 2.5 mg/dl 139 (3.3) 188 (4.5) 3.0 mg/dl 63 (1.5) 83 (2.0) ELEVATED SERUM POTASSIUM >5.5 mmol/l 674 (16.1) 727 (17.3) >6.0 mmol/l 181 (4.3) 236 (5.6) COUGH 474 (11.3) 601 (14.3) ANGIOEDEMA No treatment or use of antihistamines only 10 (0.2) 5 (0.1) Catecholamines or glucocorticoids w/o hospitalization 6 (0.1) 4 (0.1) Hospitalized without airway compromise 3 (0.1) 1 (<0.1) Airway compromise 0 0

42 LCZ696 dosing Population Enalapril>10mg/day Valsartan>160mg/day Initial Dose 49/51mg twice daily Naïve to ACE I/ARB, or on Suboptimal ACE I/ARB GFR<30ml/min/1.73m 2 24/26 mg twice daily 24/26 mg twice daily Hepatic impairment (Child Pugh B) 24/26 twice daily Titration Schedule: Double the dose of sacubutril/valsartan every 2 4 weeks as tolerated to a target dose of 97/103mg twice daily

43 Critique Suboptimal background therapy. Efficacy and safety in specific subpopulations. Black patients NYHA Class I,IV, AHF Patients not previously on ACE inhibitors or ARBs Impact on Blood Pressure ProBNP and NT ProBNP monitoring Off target effects of neprilysin inhibition Alzheimer Disease Malignancy

44 Back to our Patients Introduced Entresto as per guidelines. Titrated dose upwards from 50mg BD to target 200mg BD. To date: No hospitalizations for ADHF. Marked symptomatic & clinical improvement.

45 STEPWISE RX OF PATIENTS - NYHA II IV HFREF

46 Conclusions 1. Inhibition of RAAS + SNS + MRA (if possible)is central. 2. Adding Neprilysin inhibition in PARADIGM HF to increase vasoactive peptides has unquestioned superiority. 3. ARNI reduces CVS death/hospitalization 20%, all cause mortality 16%. 4. Strong case for ARNI to replace ACE I/ARB in NYHA II IV HF. 5. Studies ongoing for ARNI in HFpEF, ADHF & CRS (PARAGON Trial)

47 Thank You.

From PARADIGM-HF to Clinical Practice. Waleed AlHabeeb, MD, MHA Associate Professor of Medicine President of the Saudi Heart Failure Group

From PARADIGM-HF to Clinical Practice Waleed AlHabeeb, MD, MHA Associate Professor of Medicine President of the Saudi Heart Failure Group PARADIGM-HF: Inclusion Criteria Chronic HF NYHA FC II IV with LVEF