What s New In The World Of Heart Failure?

9/27/2016 What’s New In The World Of Heart Failure? Sandra L Chase, BS, PharmD, FCCP Senior Medical Science Liaison Otsuka Product Development & Comm...
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9/27/2016

What’s New In The World Of Heart Failure? Sandra L Chase, BS, PharmD, FCCP Senior Medical Science Liaison Otsuka Product Development & Commercialization, Inc.

Learning Objectives  Pharmacist: - Explain the mechanism of action of the new medications approved for the management of heart. - List the indications, adverse effects, and drug interactions for the new medications approved for the management of heart failure. - Explain the role of the new medications in the updated “Guidelines for the Management of Patients with Heart Failure” in order to provide evidence based medical care for patients.

 Pharmacy technician: - Explain how the new medications work and how they compare to currently approved medications. - List the major adverse effects of the new medications approved for the management of heart failure. - Identify major drug interactions of the new medications for the management of heart failure.

Patient Case  AR is a 65 year old Caucasian male patient with stage C, NYHA class II heart failure and a reduced ejection fraction (EF 35%) secondary to ischemic cardiomyopathy. Today he presents to clinic for routine follow up. - Vitals: BP 132/75, HR 86, wt 76 kg - Medication profile:

137

102

22

4.2

27

1.2

102

 Lisinopril 20 mg daily

Aspirin 81 mg daily

 Carvedilol 25 mg twice daily

Atorvastatin 80 mg daily

 Eplerenone 25 mg daily

Furosemide 20 mg daily

 Digoxin 125 mcg daily

Omeprazole 20 mg daily

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Patient Case  AR is a 65 year old Caucasian male patient with stage C, NYHA class II heart failure and a reduced ejection fraction (EF 35%) secondary to ischemic cardiomyopathy. Today he presents to clinic for routine follow up. - Medication profile:    

Lisinopril 20 mg daily Carvedilol 25 mg twice daily Eplerenone 25 mg daily Digoxin 125 mcg daily

Aspirin 81 mg daily Atorvastatin 80 mg daily Furosemide 20 mg daily Omeprazole 20 mg daily

 Which of the following medication changes would you make for this patient? A. Increase lisinopril to 40 mg daily B. Switch lisinopril to sacubitril/valsartan 49/51 mg twice daily C. Increase carvedilol to 37.5 mg twice daily D. Add ivabradine 5 mg twice daily

Epidemiology of Heart Failure  Heart Failure (HF) currently afflicts over 5 million Americans .  Approximately 500,000 HF-related deaths each year in the United States.  Most common cause for hospitalizations in patients over age 65.  Significant cause for rehospitalization.  In 2012, the total cost for HF was estimated to be $30.7 billion. Of this total, 68% was attributable to direct medical costs.  Projections show that by 2030, the total cost of HF will increase almost 127% to $69.7 billion from 2012. This equals ≈$244 for every US adult. Circulation 2015;13:e29-322.

% of US population

2012 US Prevalence of Heart Failure

• 5.7 million Americans > 20 years of age were living with HF in 2012 • Projections show that the prevalence of HF will increase 46% and by 2030 > 8 million people > 18 years of age will have HF American Heart Association. Heart Disease & Stroke Statistics. 2015 Update. Dallas, TX: American Heart Association, 2015.

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Heart Failure: Here to Stay? Principle discharge Diagnoses for Medicare fee-for-service beneficiaries hospitalized in 1999 and 2013

JAMA 2015;314:355-365.

Dawn of a New Era…? "I think this is exciting and is a great new hope for our heart-failure patients…" Dr. Mariell Jessup (University of Pennsylvania)

"This is a large trial with convincing results and will be important for clinical practice. We're hoping for great things." Dr. John G Cleland (Imperial College London)

"I think they considered the data to be compelling and strong. And I think that when physicians look at the data, they will be convinced that this drug will become a cornerstone of treatment for heart failure.” Dr. Milton Packer (University of Texas Southwestern) http://www.medscape.com/viewarticle/848657#vp_3

Dual Inhibition of the Neuroendocrine System in Chronic Heart Failure

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Heart Failure: A Vicious Cycle Reduced Output

RAAS Activation

Activation SNS

Angiotensin II

Vasoconstriction

Aldosterone

Heart Failure Symptoms

Elevated Preload Cardiac Remodeling

Heart Failure Pathophysiology Neprilysin

BNP (Others*)

1. Vasodilation 2. Natiuresis 3.  Blood pressure 4.  Sympathetic tone 5.  Aldosterone levels

JACC Heart Fail 2014;2:663-70.

Neprilysin Inhibition: Two Decades of Progress Candoxatril (1999) • No effect on BP or SVR  Abandoned Ecadotril (1998) • Numerically more deaths  Abandoned Omapatrilat: inhibits neprilysin and ACE (2004) • Equivalent to enalapril,  angioedema  Abandoned

JACC Heart Fail 2014;2:663-70.

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Dual Neuroendocrine Inhibition SNS

 RAAS  Heart Rate Beta-blockers BP  Remodeling

BNP/ANP

 BP  Natiuresis  Aldosterone  Remodeling

RAAS

 BP  Aldosterone ACE inhibitors  SNS ARBs  Remodeling MRAs

Neprilysin

Inactive Fragments

Sacubitril/valsartan

PARADIGM-HF: Methods

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

PARADIGM-HF: Patients Inclusion Criteria HF (NYHA Class II-IV)

Exclusion Criteria Hypotension (SBP < 100 mmHg at screening or < 95 mmHg at randomization)

Aged >18 years

Known history of angioedema

LVEF < 40% (within the past six months

Patients in acute decompensated HF

prior to randomization) – changed to < 35% in 12/10

BNP > 150 pg/mL or NT-proBNP > 600 pg/mL at visit 1

Estimated eGFR < 30 mL/min/1.73 m2 (MDRD)

Stable dose of an ACE-I or ARB for 4 weeks prior to visit 1

Serum potassium > 5.2 mmol/L (visit 1) or > 5.4 mmol/L at visit 3 or 5

Stable dose of beta-blocker for 4 weeks prior to visit 1 (unless contraindicated)

CVA, ACS, ventricular arrhythmia, or cardiac resynchronization device within the previous 3 months

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

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PARADIGM-HF: Demographics Characteristic

LCZ696 (n = 4187)

Enalapril (n = 4212)

310 (7.4%)

292 (6.9%)

Region North America NYHA Functional Class I

180 (4.3%)

209 (5.0%)

II

2998 (71.6%)

2921 (69.3%)

III

969 (23.1%)

1049 (24.9%)

IV

33 (0.8%)

27 (0.6%)

Implantable cardioverter-defibrillator

623 (14.9%)

620 (14.7%)

Cardiac resynchronization therapy (CRT)

292 (7.0%)

282 (6.7%)

Medical History

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

PARADIGM-HF: Outcomes

CV death

CV death or HF hospitalization

LCZ696 : 914 patients (21.8%) Enalapril 1117 patients (26.5%)

LCZ696 : 558 patients (13.3%) Enalapril 693 patients (16.5%)

NNT = 21

NNT = 31

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

PARADIGM-HF: Outcomes Time to first hospitalization

Emergency Department Visits LCZ696 : 151 visits Enalapril 208 visits HR 0.70, p=0.017

Cumulative number of hospitalizations

Intensification of Outpatient Therapy LCZ696 : 520 patients Enalapril 604 patients HR 0.84, p=0.003

Circulation 2015;131:54-61.

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PARADIGM-HF: Adverse Events Adverse Events

LCZ696 (n = 4187)

Enalapril (n = 4212)

P-Value

Symptomatic

588 (14%)

388 (9.2%)

< 0.001

Symptomatic (SBP < 90 mmHg)

112 (2.7%)

59 (1.4%)

< 0.001

> 2.5 mg/dL

139 (3.3%)

188 (4.5%)

0.007

> 3.0 mg/dL

63 (1.5%)

83 (2.0%)

0.10

474 (11.3%)

601 (14.3%)

< 0.001

Hypotension

Elevated SCr

Cough Angioedema No treatment

10 (0.2%)

5 (0.1%)

0.19

Hospitalization (no airway compromise)

3 (0.1%)

1 (