Neprilysin Inhibitors – The Mainstay for Heart Failure? Alison M. Walton, PharmD, BCPS Associate Professor of Pharmacy Practice – Butler University Clinical Pharmacy Specialist, Ambulatory Care – St. Vincent Indianapolis, IN

Email: [email protected]

Disclosure Statement

• No conflicts of interest to disclose. • I work for Butler University and St. Vincent in Indianapolis, Indiana.

Learning Objectives

• Define the mechanism of action of neprilysin inhibitors in the management of heart failure. • Explain the monitoring and toxicity of neprilysin inhibitors. • Discuss the place of neprilysin inhibitors in the heart failure treatment algorithm.

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Treatment Guidelines for Heart Failure

2013 ACCF/AHA Guideline for the Management of Heart Failure 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure Circulation 2013;128;e240-e327. Circulation 2016. DOI: 10.1161/CIR.0000000000000435 4 European Heart Journal 2016. DOI: 10.1093/eurheartj/ehw128

Goals of Heart Failure Therapy

Reduce mortality

Reduce hospitalizations

Relieve symptoms

Slow progression of disease

Improve quality of life

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Types of Heart Failure Classification

EF

Description

I. HF with reduced ejection fraction (HFrEF)

50%

Diastolic HF; Challenging diagnosis; Efficacy data for therapies not identified to date Intermediate group; Characteristics, treatment patterns, outcomes similar to HFpEF Recovery in EF; Further research needed

b. HFpEF, improved EF = Ejection fraction

41-49%

>40%

6 Circulation 2013;128;e240-e327.

Classifications of Heart Failure NYHA Functional Classification

ACCF/AHA Stages of HF A At high risk for HF but None without structural heart disease or symptoms B Structural heart disease I but without signs or symptoms of HF I C Structural heart disease with prior or current II symptoms of HF III D Refractory HF requiring specialized intervention

IV

Asymptomatic

Asymptomatic Symptomatic: moderate exertion Symptomatic: minimal exertion Symptomatic at rest 7

Circulation 2013;128;e240-e327.

Non-Pharmacologic Therapy

• • • • • • • •

Patient education and close follow-up Daily weight measurement Sodium restriction Exercise training Weight loss in obese patients Alcohol, illicit drug avoidance Fluid restriction in patients with severe HF Avoidance of offending medications (e.g. NSAIDs) Circulation 2013;128;e240-e327. 8 Circulation 2016. DOI: 10.1161/CIR.0000000000000426

Pearls of Drug Therapy for HFrEF Therapeutic Key Clinical Pearls Class ACE Inhibitor • Attempt to achieve target doses (At a minimum, achieve intermediate doses) ARB • Utilize if ACE Inhibitor intolerance (i.e. cough) and attempt to achieve target doses • Initiate switch but caution if previous ACE Inhibitor angioedema • Routine combined use of ACE Inhibitor, ARB, and Aldosterone Antagonist potentially harmful

Pearls of Drug Therapy for HFrEF continued Therapeutic Key Clinical Pearls Class Beta-blocker • Initiate clinical trial-proven agent (metoprolol succinate, carvedilol, bisoprolol) and achieve target doses • For patient on low dose ACE Inhibitor, addition of beta-blocker produces greater improvement in symptoms and reduction in risk of death than increase in ACE Inhibitor dose • Continue in most patients experiencing symptomatic exacerbation Vasodilator • Benefits African American patients on optimal therapy

Pearls of Drug Therapy for HFrEF continued Therapeutic Class Aldosterone Antagonist

Loop Diuretic

Key Clinical Pearls • Avoid if sCr >2.5mg/dL in men or >2mg/dL in women (CrCl5mEq/L • Evaluate risk vs benefit if close monitoring not feasible • Stop or reduce potassium supplements with initiation • No benefit on mortality thus never used as monotherapy • Optimal use of diuretics is cornerstone of symptom management and successful HF treatment

Dosing Recommendations for Common Agents Therapeutic Drug Class ACE Inhibitor lisinopril ARB losartan valsartan Beta-blocker metoprolol succinate (XL) carvedilol

Initial Dose

Target Dose

2.5-5mg daily 25-50mg daily 20-40mg BID 12.5-25mg daily 3.125mg BID

20-40mg daily 150mg daily 160mg BID 200mg daily

Aldosterone Antagonist

12.5-25mg daily

spironolactone

12

85kg: 50mg BID 25mg daily

Stage C HFrEF Pharmacologic Therapy

13 Circulation 2013;128;e240-e327.

Patient Case #1 74 year old white male presents to outpatient clinic to reestablish care after moving from Ohio. He complains of shortness of breath and fatigue when jogging at any pace above moderate. No symptoms of systematic congestion and concluded to be euvolemic on exam. • PMH: HFrEF (ACCF/AHA Stage C, NYHA FC II), Hypertension, Hyperlipidemia, Type 2 diabetes mellitus • Vitals: BP 132/88mmHg, HR 90bpm • Medications: unknown, son sets-up pillbox • Labs within normal limits except BNP 240pg/mL • Echo: LVH, estimated EF = 35% 14

Patient Case #1 Assessment – Hitting the Target What is the best next step for heart failure management? Current Medications aspirin 81 mg PO daily atorvastatin 40 mg PO QHS lisinopril 40 mg PO daily metoprolol succinate 50 mg PO daily insulin detemir 20 units SC QHS metformin ER 1000 mg PO BID acetaminophen 325 mg q4-6h PO PRN for pain (averages 1-2 tablets per day) 15

History of Neprilysin Inhibition

Neprilysin Inhibitors: Target for heart failure therapy in neurohormonal model • Neprilysin degrades natriuretic peptides and vasoactive peptides • Sole neprilysin inhibition likely failed due to increased levels of angiotensin II Dual inhibition of natriuretic peptide degradation and activation of renin-angiotensin-aldosterone system • Vasopeptidase Inhibitor (Neprilysin Inhibitor and ACE Inhibitor): omapatrilat was denied FDA approval, increased risk of angioedema 16 Pharmacotherapy 2002;22:27-42.

New Dual Target for Heart Failure

New Drug Class: Angiotensin receptor-neprilysin inhibitor (ARNI) • Effects on renin-angiotensin system, natriuretic-peptide system, and bradykinin

First New Drug in Class: sacubitril/valsartan (Entresto®) • Approved July 2015 17

Sacubitril/Valsartan: Mechanism of Action

http://www.nature.com/nrcardio/journal/v12/n2/images/nrcardio.2014.219-f1.jpg

New Role in Therapy: PARADIGM-HF Trial

Aim: To compare survival rates with the use of LCZ696 or enalapril in HF • Randomized, double blind trial • 8442 HF patients • 1043 sites in 47 countries • Median follow-up 27 months Angiotensin receptor-neprilysin inhibitor LCZ696 200mg twice daily vs. enalapril 10mg twice daily • LCZ696 200mg = sacubitril/valsartan 97/103mg

N Engl J Med 2014;371:993-1004.

PARADIGM-HF Trial: Entry Criteria Inclusion Criteria • Age > 18 yrs • NYHA FC II, III, IV • EF 600 pg/mL) • Stable dose for 4 weeks on ACE Inhibitor or ARB and beta-blocker – Equivalent to >10 mg enalapril

Exclusion Criteria • Symptomatic hypotension • Systolic blood pressure