Outline. Classification by LVEF Conventional Therapy New Therapies. Ivabradine Sacubitril/valsartan

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1 New Pharmacological Therapies for Heart Failure Mark Drazner, MD, MSc Clinical Chief of Cardiology Medical Director, CHF/VAD/Transplant James M. Wooten Chair in Cardiology UT Southwestern Medical Center April 28, 2017 Outline Classification by LVEF Conventional Therapy New Therapies Ivabradine Sacubitril/valsartan

2 Classification of HF by LVEF Heart Failure HFrEF (<40%) HFpEF ( 50%) Adapted: ESC Guidelines, 2016

3 Heart Failure HFrEF (<40%) HFpEF ( 50%) HFmrEF (40-49%) HFmrEF = mid-range EF Adapted: ESC Guidelines, 2016 HFrEF Accounts for One-Half of Patients Hospitalized for HF: AHA Get With the Guidelines Registry Steinberg, Circulation, 2012

4 Heart Failure HFrEF (<40%) HFpEF ( 50%) HFmrEF (40-49%) HFmrEF = mid-range EF Adapted: ESC Guidelines, 2016 Outline Classification by LVEF Conventional Therapy New Therapies Ivabradine Sacubitril/valsartan

5 Evidence-Based Treatment of HFrEF: Circa 2015 Control Volume Diuretics Sodium restriction ACEI (ARB) Reduce Mortality -Blocker CRT an ICD* Hyd/ISDN* Aldosterone Antagonist *For indicated patients Treat Residual Symptoms Digoxin Two New Pharmacological Therapies Approved by FDA for Heart Failure Ivabradine Sacubitril/Valsartan

6 Two New Pharmacological Therapies Approved by FDA for Heart Failure Ivabradine (April 15, 2015) Sacubitril/Valsartan (July 7, 2015) Being still and doing nothing are two very different things Jackie Chan, Karate Kid

7 Two New Pharmacological Therapies Approved by FDA for Heart Failure Ivabradine Sacubitril/Valsartan

8 Placebo Ivabradine Heart rate Lancet, 2010 Hospitalization for worsening HF

9 Ivabradine Selective sinus node inhibitor Reduces HR (10 bpm > placebo) FDA approved to reduce HF hospitalization in those with LVEF 35%, SR, HR 70, and either are on maximally tolerated doses of BBL or have a contraindication to BBL Phosphenes: 3% Ivabradine vs 1% Placebo No dose adjustment needed CrCL > 15 Reduction in HF hospitalization same whether egfr< 60 or no No difference on incident worsening renal function

10 SHIFT: Resting HR and Beta-Blocker Dose Subgroup: HR< 77 bpm less benefit (significant interaction for primary endpoint) Some question regarding degree of BBL 26% at target doses 56% at dose 50% target dose Two most common reasons for not reaching target doses: Hypotension (44-45%) (Entry SBP = mm Hg) Fatigue (32%) Limited Eligibility for Ivabradine After F/u in HF Clinic Heart, 2011 (Cullington et al) 9% eligible at end of 12-month f/u JACC HF, 2015 (Dierckx et al) 12% eligible after 6 months of f/u

11 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure Ivabradine can be beneficial to reduce HF hospitalizations for patients with symptomatic (Class 2-3) stable chronic HFrEF (LVEF 35%) who are receiving GDEM, including a beta blocker at maximum tolerated dose, and who are in SR with a HR of 70 bpm or greater at rest ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure Given the well proven mortality benefits of BBL therapy, it is important to initiate and uptitrate these agents to target doses, as tolerated, before assessing the resting HR for consideration of ivabradine treatment.

12 Two New Pharmacological Therapies Approved by FDA for Heart Failure Ivabradine Sacubitril/Valsartan

13 By inhibiting Neprilysin, you block its degradation of favorable neurohormones leading to an increase in their levels (neurohormonal agonism) BNP, ANP, CNP Bradykinin Adrenomedullin Favorable effects Vasodilation Decrease SNS Natriuresis/diuresis

14 BNP, ANP, CNP Bradykinin Adrenomedullin Neprilysin (neutral endopeptidase) Favorable effects Vasodilation Decrease SNS Natriuresis/diuresis Inactive fragments BNP, ANP, CNP Bradykinin Adrenomedullin Neprilysin (neutral endopeptidase) X NEP inhibitor Favorable effects Vasodilation Decrease SNS Natriuresis/diuresis Inactive fragments

15 ACE inhibitor X Inactive fragments BNP, ANP, CNP Bradykinin Adrenomedullin Neprilysin (neutral endopeptidase) X NEP inhibitor Favorable effects Vasodilation Decrease SNS Natriuresis/diuresis Inactive fragments Angioedema with Ompatrilat in the OCTAVE Trial (HTN) N=25,302 Kostis, Am J Htn, 2004

16 BNP, ANP, CNP Bradykinin Adrenomedullin Neprilysin (neutral endopeptidase) X NEP inhibitor Favorable effects Vasodilation Decrease SNS Natriuresis/diuresis Inactive fragments Ang II BNP, ANP, CNP Bradykinin Adrenomedullin Neprilysin (neutral endopeptidase) X NEP inhibitor Favorable effects Vasodilation Decrease SNS Natriuresis/diuresis Inactive fragments

17 Ang II BNP, ANP, CNP Bradykinin Adrenomedullin Neprilysin (neutral endopeptidase) X NEP inhibitor Inactive fragments Favorable effects Vasodilation Decrease SNS Natriuresis/diuresis Neprilysin inhibitors were NOT effective in HF Ang II BNP, ANP, CNP Bradykinin Adrenomedullin Neprilysin (neutral endopeptidase) X NEP inhibitor Inactive fragments Favorable effects Vasodilation Decrease SNS Natriuresis/diuresis Neprilysin inhibitors were NOT effective in HF

18 Ang II BNP, ANP, CNP Bradykinin Adrenomedullin Neprilysin (neutral endopeptidase) X NEP inhibitor Inactive fragments Favorable effects Vasodilation Decrease SNS Natriuresis/diuresis Combine ARB with Neprilysin Inhibitor PARADIGM HF Study Design Randomization (n=8399, EF <35 40%, stable ACE/ARB/BB) Single blind run in period Double blind period LCZ mg BID Enalapril 10 mg BID 100 mg BID LCZ mg BID 2 weeks 1-2 weeks 2-4 weeks *Doses based on SOLVD, Val HEFT, Valiant (1:1 randomization) Enalapril 10 mg BID Slide courtesy of Dr. Milton Packer

19 CV death or 1 st CHF hospitalization NEJM, 2014

20 CV death or 1 st CHF hospitalization 16% reduction in mortality (P<0.001) NEJM, 2014 ARNI Benefit Across Spectrum of LVEF 40% Solomon, Circ Heart Fail, 2016

21 Rapid Advantage of ARNI vs. ACEi: HF Hospitalization Within 30 Days Packer, Circ, 2015 ARNI Reduces Hospital Readmission P<0.05 for all P<0.05 for all

22 Some Possible Caveats Single trial All tolerated ACEi and ARNI during run in More symptomatic hypotension (14% vs 9%) Long term data lacking Trial only had 5% Blacks (angioedema) Neprilysin degrades Amyloid-β peptide in the brain in animal models (link to Alzheimer s disease) Cannon et al Median f/u 2.2 years (up to 4.3 years) Search of AE reports using terms related to dementia No difference between ARNI and ACEi Comparable to rates seen in Val-HeFT, ATMOSPHERE, and CORONA Further studies to address this question are warranted

23 Some Possible Caveats Single trial All tolerated ACEi and ARNI during run in More symptomatic hypotension (14% vs 9%) Long term data lacking Trial only had 5% Blacks (angioedema) Neprilysin degrades Amyloid-β peptide in the brain in animal models (link to Alzheimer s disease) Cost and associated paperwork Sacubitril/Valsartan (ARNI) 3 doses available (BID) of 1:1 ratio 50 mg (S 24 mg/v 26 mg) 100 mg (49/51 mg) 200 mg (97/103 mg) [equiv. to 160 mg Diovan] Do NOT use with h/o angioedema or with ACEinhibitor (stop ACEi for 36 hours before switch) Do NOT use with concomitant ARB (has valsartan in it) or Aliskiren (renin inhibitor) Do NOT use in pregnant patient

24 Biomarkers in PARADIGM-HF Sacubitril/Valsartan Enalapril Packer, Circulation, ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure The clinical strategy of inhibition of the reninangiotensin system with ACE inhibitors (LOE: A) or ARBs (LOE: A) or ARNI (LOE: B) in conjunction with evidence-based beta blockers, and aldosterone antagonists in selected patients, is recommended for patients with chronic HFrEF to reduce morbidity and mortality.

25 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality. - BNP > 150 or NT-proBNP 600 pg/ml - If hospitalized in last 12 months, then BNP 100 or NT-proBNP 400 pg/ml

26 European HF Guidelines Sacubitril/valsartan is recommended as a replacement for an ACE-I to further reduce the risk of HF hospitalization and death in ambulatory patients with HFrEF who remain symptomatic despite optimal treatment with an ACE-I, a beta-blocker and an MRA. Eur Heart J, 2016 Potassium and ARNI vs. ACEi Desai, JAMA Cardiol, 2017

27 Potassium and ARNI vs. ACEi Desai, JAMA Cardiol, 2017 ARNI and Renal Function (PARADIGM) 36% baseline CKD Excluded subjects if egfr 25% during run-in phase Mean egfr = 68 ml/min/1.73m 2 Decline in GFR (ARNI vs. ACEi) 5.4 vs 6.8 ml/min/1.73m 2 Nonsignificant effect on composite renal endpoints Mean increase of UACR 0.3 mg/mmol at 30 days with ARNI Benefits on clinical outcomes same irrespective baseline CKD Abstract, Medscape

28 Improving Survival in New-Onset Systolic HF Index hospitalization Diuretics ACE-I (or ARB) Beta-blocker when stable Discharge Uptitrate Beta-blocker Aldo blocker (K, Cr) Nitrates/Hydralazine (Black, 3-4) Switch to Sacubitril/Valsartan Assess for ICD/CRT Improving Survival in Chronic HFrEF Office Visit ACE-I (or ARB) Beta-blocker Aldo blocker (Cr, K) Nitrates/Hydralazine (Black, 3-4) CRT/ICD if appropriate Switch ACEi/ARB to Sacubitril/Valsartan

29 Evidence-Based Treatment of HFrEF in 2017 Control Volume Diuretics Sodium restriction Tolerating ACE or ARB, Class 2-3 ARNI (ACEI) (ARB) Reduce Mortality -Blocker Aldosterone Antagonist *For indicated patients CRT an ICD* Hyd/ISDN* (NSR, Class 2-3, HR 70) Reduce Morbidity (HF hosp.) Ivabradine; Digoxin