Rationale and Practical Aspects of Sacubitril- Valsartan and Ivabradine Use in Heart Failure Patients

Rationale and Practical Aspects of Sacubitril- Valsartan and Ivabradine Use in Heart Failure Patients Javed Butler, MD, MPH, MBA Patrick H. Lehan Professor of Medicine Professor of Physiology Chairman, Department of Medicine University of Mississippi

Disclosures Research Support NIH European Union PCORI Industry: Multiple clinical trials Consultant Amgen, Adrenomed, Astra Zeneca, Bayer, Berlin Cures, Bristol Myers Squibb, Boehringer Ingelheim, CVRx, Janssen, Luitpold, Medtronic, Merck, Novartis, Relypsa, Sanofi, SC Pharma, StealthPeptide, Vifor, ZS Pharma

Counter-Regulatory Systems Are Also Activated ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; CNP, C-type natriuretic peptide; NEP, neutral endopeptidase (neprilysin). 1. Klabunde R. Cardiovascular Physiology Concepts. 2nd ed. Philadelphia, PA: Lippincott, Williams, & Wilkins; 2012. 2. Mann DL et al. Braunwald s Heart Disease. 10th ed. Philadelphia, PA: Saunders; 2015. 3. Tsutamoto T et al. Circulation. 1997;96:509-516. 4. Erdos, Skidgel. FASEB J. 1989;3:145-151. 5. Stephenson et al. Biochem J. 1987;241:237-247. 6. Kenny et al. Biochem J. 1993;291:83-88. 7. Lisy O et al. Am J Physiol. 1998;275:F410-414.

Counterregulatory Peptide Systems Activated in Heart Failure Patients Prostaglandin Bradykinin These peptides promote vasodilation, salt and water diuresis and have antiremodeling effects that modulate the adverse effects of the RAAS and SNS Adrenomedullin NPs (Natriuretic peptides) Since neprilysin breaks down these peptides, inhibitors of this enzyme should increase their levels and effects in heart failure ANP BNP CNP Urodilatin Dendroaspis ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; CNP, C-type natriuretic peptide; NP, natriuretic peptide; NPS, natriuretic peptide system. Mann DL et al. Braunwald s Heart Disease. 10th ed. Philadelphia, PA: Saunders; 2015.

ANGIOTENSIN II 1-3 1,2 ANGIOTENSIN RECEPTOR 1-3 VASOCONSTRICTION 1-3 NEPRILYSIN 1,2 sacubitril 1-3 valsartan 2,3 sacubitril/valsartan inhibits neprilysin and blocks the AT1 receptor 3 NATRIURETIC VASODILATION PEPTIDES 1,2 1-3 1-3 AT1, angiotensin type 1 receptor. 1. Howell EH, Cameron SJ. Cardiol J. 2016;23(6):591-598. 2. Volpe M, et al. Clin Sci. 2016;130(2):57-77. 3. ENTRESTO [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; November 2017.

PARADIGM-HF Study LCZ696 (Sacubitril/valsartan) in HFrEF Patients Phase III RCT evaluating the efficacy and safety profile of LCZ696 vs enalapril in 8,436 patients with NYHA Class II-IV symptoms, EF <35% and elevated BNP level. Primary endpoint - LCZ696 is superior to enalapril in delaying time to composite of CV mortality and HF hospitalization. PARADIGM-HF was prematurely stopped by the DMC due to evidence that patients receiving LCZ696 lived longer without being hospitalized for heart failure than those who received standard care with ACE-inhibitor enalapril. McMurray JJ, et al. N Engl J Med. 2014 Sep 11;371(11):993-1004

PARADIGM-HF: Outcomes McMurray JJ, et al. N Engl J Med. 2014 Sep 11;371(11):993-1004

PARADIGM-HF: Prespecified Subgroup Analyses McMurray JJ et al. N Engl J Med 2014

25.0 Enalapril HF Readmission Rate After Index HF Hospitalization (%) 20.0 15.0 10.0 5.0 ENTRESTO 13.4% n=175/1302 OR (95% CI): 0.62 (0.45, 0.87) 9.7% n=104/1074 38 % ENTRESTO reduced 30-day readmission by 38% 3.7% ARR 0.0 30-Day HF Readmission Data are from a PARADIGM-HF post-hoc analysis (hospital readmission rate was not a primary end point). *The primary unit of analysis was hospitalizations, including repeat hospitalizations, rather than patients. Among patients hospitalized at least once for HF, patient characteristics were similar at baseline between treatment groups. OR, odds ratio. 1. Desai AS, et al. J Am Coll Cardiol. 2016;68(3):241-248. 9

Adverse Events During Randomized Treatment EVENT HYPOTENSION Symptomatic Symptomatic with systolic blood pressure <90 mm Hg ELEVATED SERUM CREATININE 2.5 mg/dl 3.0 mg/dl ELEVATED SERUM POTASSIUM > 5.5 mmol/liter > 6.0 mmol/liter Sacubitril/valsartan (N=4187) 588 (14.0) 112 (2.7) 139 (3.3) 63 (1.5) 674 (16.1) 181 (4.3) Enalapril (N=4212) 388 (9.2) 59 (1.4) 188 (4.5) 83 (2.0) 727 (17.3) 236 (5.6) COUGH 474 (11.3) 601 (14.3) ANGIOEDEMA** No treatment or use of antihistamines only Use of catecholamines or glucocorticoids without hospitalization Hospitalization without airway compromise Airway compromise 10 (0.2) 6 (0.1) 3 (0.1) 0 5 (0.1) 4 (0.1) 1 (<0.1) 0 * Shown are results of the analyses of prespecified safety events at any time after randomization. The numbers of patients who permanently discontinued a study drug were as follows: for hypotension, 36 (0.9%) in the LCZ696 group and 29 (0.7%) in the enalapril group (P = 0.38); for renal impairment, 29 (0.7%) and 59 (1.4%), respectively (P = 0.002); and for hyperkalemia, 11 (0.3%) and 15 (0.4%), respectively (P = 0.56). ** Angioedema was adjudicated in a blinded fashion by an expert committee. Adapted from: McMurray JJ, et al. N Engl J Med. 2014 Sep 11;371(11):993-1004.

FDA-Approved Sacubitril/Valsartan Brand name Indication Dosage Renal/hepatic impairment Switching from an ACE inhibitor Contraindications Side effects Sacubitril/Valsartan Entresto The fixed-dose combination of the neprilysin inhibitor sacubitril and the ARB valsartan is indicated to reduce the risk of CV death and HF hospitalization in patients with HF with reduced ejection fraction. Start with 49/51 mg twice daily. Double the dose after 2 4 weeks, as tolerated, to maintenance dose of 97/103 mg twice daily. For patients not currently taking an ACEI or ARB, or for those with severe renal impairment (egfr <30 ml/min/1.73 m 2 ) or moderate hepatic impairment, start with 24/26 mg twice daily. Stop ACE inhibitor for 36 hours before starting treatment. History of angioedema related to previous ACE inhibitor or ARB, concomitant use of ACE inhibitors, concomitant use of aliskiren in patients with diabetes. WARNING pregnancy, hyperkalemia. Hypotension, hyperkalemia, cough, dizziness, renal failure, and angioedema (0.5% sacubitril/valsartan vs. 0.2% enalapril). http://www.pdr.net/full-prescribing-information/entresto?druglabelid=3756. Accessed October 20, 2015.

COR = class of recommendation; LOR = level of recommendation; ARNI = angiotensin receptor blocker and neprilysin inhibitor. Yancy et al. Circulation. 2016;134(13):e282-93 [epub ahead of print] 2016 ACC/AHA/HFSA Heart Failure Guideline Update Pharmacological Treatment for Stage C HFrEF Recommendations for RAS Inhibition with ACE Inhibitor or ARB or ARNI COR LOR Recommendations I I III: Harm III: Harm ACE: A ARB: A ARNI: B-R ARNI: B-R B-R C-EO The clinical strategy of inhibition of the renin-angiotensin system with ACE inhibitors (Level of Evidence: A), OR ARBs (Level of Evidence: A), OR ARNI (Level of Evidence: B-R) (19) 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. 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. ARNI should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor. ARNI should not be administered to patients with a history of angioedema.

Sacubitril / Valsartan Dose Selection and Titration Equivalent of >10mg Enalapril: Lisinopril >10mg Ramipril >5mg Equivalent of 10mg Enalapril: Lisinopril 10mg Ramipril 5mg STOP ACEi for 36 hours before starting Valsartan/Sacubitril to prevent angioedema Start Valsartan/Sacubitril 49/51mg bid, increase to 97/103mg bid in 2-4 weeks Start Valsartan/Sacubitril 24/26mg bid, increase to 49/51mg bid in 2-4 weeks, and then 97/103mg bid Equivalent of > 160mg Valsartan: Losartan > 50mg Olmesartan > 10mg Equivalent of 160mg Valsartan: Losartan 50mg Olmesartan 10mg Start Valsartan/Sacubitril 49/51mg bid, increase to 97/103mg bid in 2-4 weeks Start Valsartan/Sacubitril 24/26mg bid, increase to 49/51mg bid in 2-4 weeks, and then 97/103mg bid Not currently taking ACEi s or ARB s Start Valsartan/Sacubitril 24/26mg bid, increase to 49/51mg bid in 2-4 weeks, and then 97/103mg bid

Impact of Heart Rate on Outcomes in HF 1 1. Castagno D et al. J Am Coll Cardiol. 2012;59:1785-1792.

Heart Rate Reduction Through / f Current Inhibition Acts by dose-dependent specific inhibition of I f funny channels that are highly expressed in the SA node. Delayed diastolic depolarization results in HR reduction. In CAD patients with HR>70 bpm, Ivabradine reduced coronary events by 22%, MI by 36% and revascularization by 30%*. Ivabradine has been shown to increases stroke volume, fully preserve myocardial contractility and relaxation, atrioventricular conduction, and ventricular repolarization, and increase blood pressure. Adapted from: Thollon C, et al. Br J Pharmacol. 1994;112:37-42; DiFrancesco A, et al. Drugs. 2004;64:1757-1765; Fox K, et al. Lancet. 2008 Sep 6;372(9641):807-816. Ferrari R. Cardiology. 2014;128(2):226-230.

Ivabradine and Outcomes in Chronic HF: The SHIFT Study Double blind, placebo controlled RCT in symptomatic HF patients in NSR with HR >70 beats/min and EF <0.35. Patients were hospitalized within past year and on stable Rx including a beta blocker, if tolerated. Randomized to ivabradine 7.5 mg bid or placebo. Primary EP was CV death or HF hospitalization. Swedberg K, et al. Lancet.2010 Sep 11;376(9744):875-885.

Background Rx in Systolic Heart Failure Treatment with the / f Inhibitor Ivabradine Trial (SHIFT) Swedberg K, et al. Lancet.2010 Sep 11;376(9744):875-885.

Changes in HR Over Time in SHIFT Swedberg K, et al. Lancet.2010 Sep 11;376(9744):875-885.

Ivabradine Effects on Combined Cardiovascular Mortality and HF Hospitalization Swedberg K, et al. Lancet.2010 Sep 11;376(9744):875-885.

Ivabradine Effects on Combined Cardiovascular Mortality and HF Hospitalization Swedberg K, et al. Lancet.2010 Sep 11;376(9744):875-885.

Adverse Events in SHIFT PATIENTS WITH AN ADVERSE EVENT PATIENTS WITH AN ADVERSE EVENT LEADING TO DRUG WITHDRAWAL Ivabradine group (n=3232) Placebo group (n=3260) Ivabradine group (n=3232) Placebo group (n=3260) 2439 (75%) 2423 (74%) All 467 (14%) 416 (13%) 804 (25%) 937 (29%) Heart failure 70 (2%) 82 (3%) 150 (5%) 32 (1%) Symptomatic bradycardia 20 (1%) 5 (<1%) 184 (6%) 48 (1%) Asymptomatic bradycardia 28 (1%) 5 (<1%) 306 (9%) 251 (8%) Atrial fibrillation 135 (4%) 113 (3%) 89 (3%) 17 (1%) Phosphenes 7 (<1%) 3 (<1%) 17 (1%) 7 (<1%) Blurred vision 1 (<1%) 1 (<1%) Adapted from: Swedberg K, et al. Lancet.2010 Sep 11;376(9744):875-885.

SHIFT: Subgroup Analysis Swedberg K, et al. Lancet.2010 Sep 11;376(9744):875-85.

FDA-Approved Ivabradine Ivabradine Brand name Indication Dosage Contraindications Side effects Corlanor To reduce the risk of hospitalization for worsening HF in patients with stable, symptomatic chronic HF with LVEF 35% who are in sinus rhythm with resting HR 70 bpm and either are on maximum-tolerated doses of beta-blockers or have a contraindication to beta-blocker use. Start with 5 mg twice daily. After 2 weeks of treatment, adjust dose based on HR. Max is 7.5 mg twice daily. In patients with conduction defects or in whom bradycardia could lead to hemodynamic compromise, start with 2.5 mg twice daily. Acute decompensated HF; BP <90/50 mmhg; sick sinus syndrome or third-degree AV block unless a functioning demand pacemaker is present; resting HR < 60 bpm prior to treatment; severe hepatic impairment; pacemaker dependence. WARNING fetal toxicity. Occurring in 1% of patients are bradycardia, hypertension, atrial fibrillation, and luminous phenomena (phosphenes). http://www.pdr.net/full-prescribing-information/corlanor?druglabelid=3713. Accessed October 20, 2015.

2016 ACC/AHA/HFSA Heart Failure Guideline Update Pharmacological Treatment for Stage C HFrEF Recommendation for Ivabradine COR LOR Recommendations IIa B-R Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF 35%) who are receiving GDEM, including a beta-blocker at maximum-tolerated dose and who are in sinus rhythm with a heart rate of 70 bpm or greater at rest (37 40). COR = class of recommendation; LOR = level of recommendation; GDEM = guidelinedirected evaluation and management.