Heart Failure New Drugs- Updated Guidelines

Heart Failure New Drugs- Updated Guidelines Eileen Handberg, PhD, ANP-BC, FAHA, FACC Professor of Medicine Division of Cardiovascular Medicine University of Florida

Disclosures

1. 3 2. 6 3. 8 4. 11 Dunlay et al. Mayo Clin Proc. 2011 Apr; 86(4): 273 281.

Current Evidence Based Recommended HF Therapy ACE-I ARB if ACE Intolerant Beta Blocker mineralocorticoid receptor antagonist Diuretic- for volume overload Digoxin +/ICD and/or CRT

What Percentage of Your HF Patients Are On Optimal Medical Therapy? 1. 100% 2. 80% 3. 75% 4. 50%

Drugs That Reduce Mortality in Heart Failure With Reduced Ejection Fraction Angiotensin receptor blocker ACE inhibitor Beta blocker Mineralocorticoid receptor antagonist % Decrease in Mortality 0% 10% 20% 30% Drugs that inhibit the renin-angiotensin system have modest effects on survival 40% Based on results of SOLVD-Treatment, CHARM-Alternative, COPERNICUS, MERIT-HF, CIBIS II, RALES and EMPHASIS-HF

New Data/New Guidelines

LCZ696: Angiotensin Receptor Neprilysin Inhibition LCZ696 Angiotensin receptor blocker Inhibition of neprilysin

Sacubitril/Valsartan First-in-class angiotensin receptor neprilysin inhibitor. Neprilysin is an enzyme that breaks down biologically active natriuretic peptides and other vasoactive compounds. NPs contribute to the regulation of sodium and water balance, blood volume, arterial pressure, and sympathetic inhibition through their effects on the venous system, kidneys, and brain. Inhibition of neprilysin increases levels of NP s, countering the neurohormonal overactivation that contributes to vasoconstriction, sodium retention, and maladaptive remodeling Soon after oral ingestion, the drug dissociates into sacubitril (a neprilysin inhibitor prodrug which is enzymatically cleaved to the active form, LBQ657 and valsartan Designed to have a reduced risk for angioedema because it inhibits only one of the enzymes responsible for bradykinin breakdown.

PARADIGM-HF: Entry Criteria NYHA class II-IV heart failure LV ejection fraction 40% 35% BNP 150 (or NT-proBNP 600), but one-third lower if hospitalized for heart failure within 12 months Any use of ACE inhibitor or ARB, but able to tolerate stable dose equivalent to at least enalapril 10 mg daily for at least 4 weeks Guideline-recommended use of beta-blockers and mineralocorticoid receptor antagonists Systolic BP 95 mm Hg, egfr 30 ml/min/1.73 m2 and serum K 5.4 meq/l at randomization

Angiotensin Neprilysin Inhibition With LCZ696 Doubles Effect on Cardiovascular Death of Current Inhibitors of the Renin-Angiotensin System % Decrease in Mortality 0% 10% Angiotensin receptor blocker Angiotensin neprilysin inhibition ACE inhibitor 15% 18% 20% 20% 30% 40% Effect of ARB vs placebo derived from CHARM-Alternative trial Effect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial Effect of LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial

Guidelines

Sacubitril/valsartan Bioavailability >60% Steady state in 3 days Peak plasma S-0.5 hr V- 1.5 hr Protein bound 94-97% for S/V S excretion 52-68% urine prodrug 37-48 %in feces V 13% urine, 86% feces

Adverse Effects Occurrence Rates Hypotension 18% Hyperkalemia 12% Cough 9% Dizzy 6% Fall 1.9% Angioedema <0.5% In blacks 2.4% Black box for pregnancy

Dosing/Administration Recommended starting dose: 49 mg/51 mg PO BID 3 available doses 24/26, 49/51, 97/103 Target maintenance dose: After 2-4 weeks, double the dose to the target maintenance dose of 97 mg/103 mg PO BID as tolerated With or without food Severe (egfr <30 ml/min/1.73 m²): Reduce starting dose to 24 mg/26 mg BID; double the dose every 2-4 weeks to target maintenance dose of 97 mg/103 mg BID as tolerated

Case 45 yr old b/m with Ischemic Cardiomyopathy EF 35%--Class III NYHA Hx HTN, HLD, CAD-AMI with PCI to LAD, Cx with DES 6 months ago ECG-RSR, with q waves anterior leads, qrs 80 ms HR 66, BP 110/70, wt 180 lbs, 5 11 BMI Hospitalized 2 weeks ago with new onset HF

Case Current medications Losartan 50 mg daily stopped ACE-I due to persistent, life impacting cough Carvedilol 25 mg bid Lasix 20 mg qd Simvastatin 40 mg qd Clopidogrel 75 mg qd ASA 81 mg qd Social History Married with 5 children all 16 and younger Hospital mid level manager, wife is a school teacher Good heath insurance with prescription plan Nonsmoker, rare social ETOH

Does He Meet Criteria for S/V? 1. Yes 2. No

Why or Why Not? 1. Meet Criteria? 2. Are Medications Optimized? 3. What do we need to watch out for?

HF Treatment Target

How Many of Your Heart Failure Patients are BB d to HR < 70? 1. 100% 2. 75% 3. 50% 4. 30%

Ivabradine 70% Protein bound Half life ~6 hrs Bioavailability-~40% (first pass elimination in gut/liver) Peak Plasma time = 1 hr fasting Food delays absorption ~1 hour, plasma exposure 2040% Take with meals

SHIFT Trial Inclusion criteria 18 years Class II to IV NYHA heart failure Ischaemic/non-ischaemic aetiology LV systolic dysfunction (EF 35%) Heart rate 70 bpm Sinus rhythm Documented hospital admission for worsening heart failure 12 months Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81

SHIFT Trial Chronic HF Background Treatment Patients (%) Ivabradine 100 90 89 90 91 91 84 Placebo 83 80 70 61 59 60 50 40 30 22 22 20 10 3 4 0 Beta-blockers ACEIs and/or ARBs Swedberg K, et al. Lancet. 2010;376(9744):875-885 Diuretics Aldosterone antagonists Digitalis ICD/CRT

Mean heart rate reduction 70% of patients on ivabradine 7.5 mg bid Heart rate (bpm) 90 80 80 Placebo 75 75 70 67 64 60 Ivabradine 50 0 2 weeks 1 4 8 12 16 20 24 28 32 Months Swedberg K, et al. Lancet. 2010;376(9744):875-885 www.shift-study.com

SHIFT Results 18% reduction in CV death or hospital admission for worsening HF 26% reduction in death from heart failure 26% reduction in hospital admission for worsening heart failure

Effect of ivabradine in prespecified subgroups Test for interaction Age <65 years 65 years Sex Male Female Beta-blockers No Yes Aetiology of heart failure Non-ischaemic Ischaemic NYHA class NYHA class II NYHA class III or IV Diabetes No Yes Hypertension No Yes Baseline heart rate P = 0.029 <77 bpm 77 bpm 0.5 1.0 Hazard ratio Favours ivabradine Swedberg K, et al. Lancet. 2010;376(9744):875-885 1.5 Favours placebo www.shift-study.com

Dosing/Administration Initial dosing 5 mg bid with meal After 2 weeks increase by 2.5 mg bid to target HR 5060 Synergistics effects with BB, antiarrhythmics, antianginals so monitor carefullly Metabolized via CYP3A4 so contraindicated with strong CYP3A4 metabolized drugs which would potentiate effects of ivabradine Contraindicated in pregnancy so adequate birth control is recommended No dosing changes for CrCl15-60ml/min

Side Effects Bradycardia- symptomatic and asymptomatic ~10% Increased BP 8.9% AF 8.3% Luminous phenomes 2.8% Rarely cause vision changes such as brief increased brightness, or seeing halos or colored bright lights. Sudden changes in light brightness may set off this effect. If vision changes happen, usually start within the first 2 months and may go away during treatment or after stopping medication.

Guidelines

Costs In one HF cohort, a $10 increase in ACEI copayment was associated with a 2.6% decrease in medication adherence, which correlated with an estimated 6.1% increase in hospitalizations for HF. Cole et al. Pharmacotherapy. 2006;26(8):1157-1164

Heart Failure Treatment Drug Dose Cost Location Drug Dose Cost Location Carvedilol 25 mg bid $10 Walmart Carvedilol 25 mg bid $20 Walgreen s Lisinopril 20 mg $10 Walmart Lisinopril 20 mg $10 Walgreen s Lasix 80 mg $10 Walmart Lasix 80 mg $10 Spirono 25 mg $10 Walmart Walgreen s Spirono 25 mg $20 Simvastatin 40 mg $30 Walgreens Walgreen s Simvastatin 40 mg $30 Walgreen s Clopidogrel 75 mg $9.83 Kroger Clopidogrel 75 mg $9.83 79.83 Kroger 99.83

New Drug Costs Sacubitril/Valsartan Ivabradine Kroger $412.23 Kroger CVS $422.29 CVS Walgreens $424.14 Walmart $425.07 $397.61 $407.32 Walgreens $409.11

2016 AHA Guidelines & Statements Drugs That May Cause or Exacerbate Heart Failure: A Scientific Statement From the American Heart Association

Name Drugs That May Cause or Exacerbate HF a. Ibuprofen b. Propofol c. Diltiazem d. None of the above e. a,b,c

Drugs That May Cause or Exacerbate HF

Questions?