Do New Drugs SIGNIFY a PARADIGM SHIFT? - Mayo Clinic PGR HF 10.18 Final.pdf2016 ACC/AHA/HFSA Focused Update NYHA class II-III (NSR, resting HR >70 bpm) ARNI: Angiotensin receptor-neprilysin

©2016 MFMER | slide-1

Do New Drugs SIGNIFY a PARADIGM SHIFT? Medication Updates in Heart Failure

Melissa Laub, PharmDPGY1 Pharmacy ResidentPharmacy Grand RoundsOctober 18, 2016


Objectives• Explain the impact of heart failure with reduced

ejection fraction in the United States. • Review the 2016 ACC/AHA/HFSA guideline

updates on new pharmacological therapy for heart failure.

• Describe the literature supporting guideline recommendations for the new medication classes (angiotensin receptor-neprilysininhibitor and If current inhibitor).


Heart Failure Disease Classifications

NYHA Functional Classification

Class Symptoms

I No limitation of physical activity.

II Slight limitation of physical activity. Comfortable at rest.

III Marked limitation of physical activity. Comfortable at rest.

IV Unable to carry out physical activity without discomfort. Symptoms at rest.

ACCF/AHA StagesStage Description

A At risk for HF but without structural heart disease or symptoms of HF.

B Structural heart disease but withoutsigns or symptoms of HF.

C Structural heart disease with prior orcurrent symptoms of HF.

D Refractory HF requiring specialized interventions.

Yancy CW. Circulation. Circulation. 2013 Oct 15;128(16):e240-327.ACCF: American College of Cardiology Foundation AHA: American Heart AssociationNYHA: New York Heart AssociationHF: Heart failure

• Heart failure with reduced ejection fraction (HFrEF): Ejection fraction < 40%

• Heart failure with preserved ejection fraction (HFpEF): Ejection fraction > 50%


QuestionIt is estimated what percentage of people with heart failure will die within 5 years of diagnosis?A. 10B. 30C. 50D. 70


Impact of Heart Failure

• 50% of people die within 5 years of diagnosis

• Lifetime risk in adults > 40 years old is 20%

• More than 14,500 heart failure patients receive care at Mayo Clinic, Rochester each year

Graphic from: http://CDC.gov.Mozaffarian D. Circulation. 2016 Jan 26;133(4):e38-360.

http://mayoclinic.org.


Eras of Heart Failure Pharmacotherapy

ACE-I: Angiotensin converting enzyme inhibitor, ARB: Angiotensin receptor blocker, -B: Beta blocker, Ald antag: Aldosterone antagonistRCT: Randomized control trial

Graphic modified from: Mentz, et al. Heart Failure, a Companion to Braunwald’s Heart Disease. 2014.

Fonarow GC. Am Heart J. 2011 Jun;161(6):1024-30.

0% -

10% -

20% -

30% -

40% -

50% -

60% -

70% -

Rel

ativ

e R

isk

Red

uctio

n (%

) in

Mor

talit

y:

Land

mar

k R

CTs

ACE-I or ARB

-B

Aldost.Antag.

ACE-I or ARB+

BB+

Aldost. Antag.

CONSENSUS, SOLVD, Val-HeFT

CIBIS, MERIT-HF,CORPERNICUS RALES,

EMPHASIS-HF

?

New Agents


Patient Case #1 Mr. GH• 61 year old Caucasian male diagnosed with HFrEF in 2011

• Admitted for urinary tract infection, but also has worsening edema and dyspnea

• Stage C Class III

• Home medications:• Lisinopril 40 mg daily• Metoprolol succinate 200 mg daily• Eplerenone 25 mg daily• Torsemide 10 mg daily

• Lab values:• EF: 30%• HR: 65 bpm• BP: 110/60 mmHg• SCr: 1.3 mg/dL• Potassium: 4.8 mEq/L

How can we advance his heart failure therapy?


Standards of Care: 2013 ACCF/AHA Guideline

Digoxin

Hydralazine + Isosorbide Dinitrate

Aldosterone Antagonist

ACE-I or ARB +-Blocker

Persistently symptomatic

NYHA class II-IV (CrCl >30ml/min +

<5.0 mEq/dL)

All HFrEF Stage C, Class I-IV

African Americans NYHA class III-IV

Loop diuretics(Symptom

management)

Yancy CW. Circulation. 2013 Oct 15;128(16):e240-327.ACCF: American College of Cardiology Foundation AHA: American Heart AssociationACE-I: Angiotensin converting enzyme inhibitorARB: Angiotensin receptor blocker


ACC: American College of CardiologyAHA: American Heart Association, HFSA: Heart Failure Society of AmericaACE-I: Angiotensin converting enzyme inhibitorARB: Angiotensin receptor blocker

Digoxin

If Current Inhibitor



ACE-I, ARB, or ARNI +-Blocker



<5.0 mEq/dL)



2016 ACC/AHA/HFSA Focused Update

NYHA class II-III (NSR, resting HR >70 bpm)

ARNI: Angiotensin receptor-neprilysin inhibitor


management)

Yancy CW. J Am Coll Cardiol. 2016 Sep 27;68(13):1476-88.


ARNI: Sacubitril-ValsartanRenin-Angiotensin-Aldosterone System Natriuretic Peptide System

Angiotensin I

Angiotensin II

Angiotensin II Type 1

Receptor

• Vasoconstriction• Increased aldosterone• Increased sympathetic tone• Cardiac fibrosis

Valsartan Sacubitril

Pro-BNP

BNP: B-type natriuretic peptideARNI: Angiotensin receptor-neprilysin inhibitor

BNP

Heart Failure

NT-pro-BNP

Neprilysin

Inactive fragments

• Vasodilation• Decreased aldosterone• Decreased sympathetic tone• Decreased cardiac fibrosis

Graphic adapted from Langenickel TH. Drug Discovery Today. 2012.

Neprilysin

Inactive fragments


QuestionSacubitril-valsartan has been shown to improve which of the following outcomes in patients with HFrEF?A. Hospitalization rates for HFB. Death from cardiovascular causesC. A & B independentlyD. None of the above


PARADIGM-HF Design• RCT of 8,442 patients NYHA class II-IV HF with EF < 40%

and elevated BNP

• Randomized to

Baseline DemographicsAge 64 years oldGender 79% maleRace 66% CaucasianNYHA Class II 72%NYHA Class III 24%Systolic BP 120 + 15 mmHg

Baseline Therapy Continued-Blocker 93%

Diuretics 80%

Aldosterone Antagonist 55%

ICD 15%

Sacubitril-valsartan 200 mg BID

Enalapril 10 mg BID

Mcmurray JJ. N Engl J Med 2014; 371:993-1004..RCT: Randomized control trialICD: Implantable cardioverter difibrilator


PARADIGM-HF ResultsEfficacy

All p values <0.0001

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

0%

5%

10%

15%

20%

25%

30%

Composite** CV death** HF hospitalization**

21.8%

26.5%

13.3%16.5%

12.8%

15.8%

Sacubitril-valsartan (N=4187)Enalapril (N=4212)

Composite (CV death +

HF hospitalization)

CV death HF hospitalization


PARADIGM-HF Results

All p values <0.01

Safety

0%

2%

4%

6%

8%

10%

12%

14%

16%

Symptomatichypotension**

SCr > 2.5 mg/dL** Serum K+ > 6mmol/L**

Cough**

9.2%

3.3%4.5% 4.3%

5.6%

11.3%

14.3%

Sacubitril-valsartan (N=4187)Enalapril (N=4212)

14%

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

Symptomatic hypotension

SCr >2.5 mg/dL Serum K + >6mmol/L

Cough


Additional Support• Compared to enalapril, sacubitril-valsartan:

• Decreased 30-day hospital readmission rates for any cause

• Prevented clinical progression of surviving patients

• No difference in effectiveness regardless of:• Ejection fraction (5%-42%)• Background therapy

Packer M. Circulation. 2015 Jan 6;131(1):54-61. Desai AS. J Am Coll Cardiol. 2016 Jul 19;68(3):241-8.Soloman SD. Circ Heart Failure. 2016 Mar;9(3):e002744.

Okumura N. Circ Heart Fail. 2016;9:e003212.


Patient Case #1Mr. GH

• 61 year old Caucasian male diagnosed with HFrEF in 2011 admitted for urinary tract infection. Now stable and being discharged.


Cardiology recommended to start sacubitril-valsartan after discharge and follow up with his primary care doctor. What is your initiation recommendation?


Sacubitril-Valsartan Dosing PearlsDescription DoseStarting Dose 49/51 mg (100 mg) BIDTarget/Max Dose

Adjusted Starting Dose• ACE-I/ARB naïve or on equivalent of < 10

mg/day enalapril or < 160 mg/day valsartan• CrCl < 30 ml/min• Moderate hepatic impairment

Entresto [package insert]. Novartis 2015.Senni M. Europ J Heart Fail. 2016 Sep;18(9):1193-202.


Sacubitril-Valsartan Dosing PearlsDescription DoseStarting Dose 49/51 mg (100 mg) BIDTarget/Max Dose 97/103 mg (200 mg) BID





Sacubitril-Valsartan Dosing PearlsDescription DoseStarting Dose 49/51 mg (100 mg) BIDTarget/Max Dose 97/103 mg (200 mg) BID



24/26 mg (50 mg) BID



Sacubitril-Valsartan Dosing Pearls

• Titration• Conservative: low dose x 2 weeks medium dose x 3

weeks target dose • Condensed: medium dose x 2 weeks target dose

• All patients:• At least 36 hour washout period between ACE-I therapy

Description DoseStarting Dose 49/51 mg (100 mg) BIDTarget/Max Dose 97/103 mg (200 mg) BID



24/26 mg (50 mg) BID



Question• Following discontinuation of his lisinopril, which

dose of sacubitril-valsartan should Mr. GH be started on?

A. 24/26 mg BIDB. 49/51 mg BIDC. 97/103 mg BID


Patient Case #1 - Three Months LaterMr. GH• 61 year old Caucasian male diagnosed with HFrEF in 2011 admitted for

acute decompensated heart failure

• Stated he never started sacubitril-valsartan


• Lab values:• EF: 25%• HR: 60 bpm• BP: 95/50 mmHg

Why hasn’t sacubitril-valsartan gained more popularity?


PARADIGM-HFLimitations & Controversies

• Comparative dose of enalapril = 10 mg BID• Extended run-in phase criteria• Under-representation of certain ethnicities• Under-representation of advanced disease• Unknown long-term effects


Summary: Sacubitril-Valsartan• Reduces risk of CV death, symptom

progression, and hospitalization in HFrEF• Promising new class in HF despite slow

adoption• Eligible Patients:

• Established disease already on background therapy

• Newly diagnosed• Not for decompensated patients


Patient Case #2 Mrs. BC• 53 year old Caucasian female diagnosed with HFrEF in 2009

• Presents to clinic with worsening sleep orthopnea

• Stage C Class III

• Home medications:• Lisinopril 20 mg daily• Carvedilol 6.25 mg twice daily• Spironolactone 50 mg daily• Furosemide 60 mg daily• Digoxin 250 mcg daily

• Lab values:• EF: 33%• HR: 75 bpm, NSR• BP: 95/57 mmHg• SCr: 1.4 mg/dL• Potassium: 5.0 mEq/L

How can we advance her heart failure pharmacotherapy?


Digoxin

If Current Inhibitor



ACE-I, ARB, or ARNI +-Blocker



<5.0 mEq/dL)



2016 ACC/AHA/HFSA Focused Update

NYHA class II-III (NSR, resting HR >70 bpm)

ARNI: Angiotensin receptor-neprilysin inhibitor


management)

Yancy CW. J Am Coll Cardiol. 2016 Sep 27;68(13):1476-88..ACC: American College of CardiologyAHA: American Heart Association, HFSA: Heart Failure Society of AmericaACE-I: Angiotensin converting enzyme inhibitorARB: Angiotensin receptor blocker


If Current Inhibitor: Ivabradine

HCN: Hyperpolarization-activated cyclic nucleotide-gated channelSA node: Sinoatrial node

HCN Channel

Na+K+

Intracellular

Extracellular

Pacemaker cell in SA node

If Current


If Current Inhibitor: Ivabradine

HCN: Hyperpolarization-activated cyclic nucleotide-gated channelSA node: Sinoatrial node

HCN Channel

Na+K+

Intracellular

Extracellular

Pacemaker cell in SA node

Ivabradine


QuestionIvabradine has been shown to improve which of the following outcomes in certain patients with HFrEF?A. Hospitalization rates for HFB. Death from cardiovascular causesC. A & B independentlyD. None of the above


BEAUTIFUL Trial• RCT 12,473 patients with coronary artery disease and EF <40%

• Randomized to

• Did not meet significance for composite endpoint

• Did reduce hospitalizations for myocardial infarction in subgroup patients with heart rate > 70 bpm

Fox K. Lancet. 2008 Sep 6;372(9641):807-16.

Ivabradine (titrated to HR of 50-60 bpm)

Placebo


SHIFT Design• RCT of 6,558 patients EF < 35%, in NSR with resting HR >70 bpm on β-blocker

• Randomized to

Swedberg K. Lancet. 2010 Sep 11;376(9744):875-85.EF: Ejection fractionCV: CardiovascularNSR: Normal sinus rhythm, HR: heart rate

Baseline DemographicsAge 60 years oldGender 76% maleEthnicity 89% CaucasianNYHA Class II 49%NYHA Class III 50%Heart Rate 80 + 10 bpm

Baseline Therapy Continued-Blocker 89%

ACE-I 79%

ARB 14%

Diuretics 84%

Aldosterone Antagonist 61%

Ivabradine (titrated to HR of 50-60 bpm)

Placebo


SHIFT ResultsMean heart rate during the study

90 -

80 -

70 -

60 -

50 -

0 0 2 wks 1 4 8 12 16 20 24 28 32

64

7580

67

75

Follow-up (months)

Hea

rt ra

te (b

pm)

Ivabradine (N=3241)Placebo (N=3264)

Swedberg K. Lancet. 2010 Sep 11;376(9744):875-85.


SHIFT Results

CV: CardiovascularHF: Heart failure

Efficacy

0%

5%

10%

15%

20%

25%

30%

35%

Composite** CV death HF hospitalization**

24%

29%

14% 15% 16%

21%


**p <0.05

Composite(CV death +

HF hospitalization)**



0%

1%

2%

3%

4%

5%

6%

7%

8%

9%

10%

Symptomatic bradycardia** Asymptomatic bradycardia** Blurred vision** Atrial fibrillation**

1%

6%

1% 1% <1%

9%

8%

Symptomaticbradycardia

SHIFT ResultsSafety


All p values <0.05

Asymptomaticbradycardia

5%


Blurred vision Atrial fibrillation


Patient Case #2Mrs. BC• 53 year old Caucasian female diagnosed with HFrEF in 2009

• Presents to clinic with worsening sleep orthopnea

• Home medications:• Lisinopril 20 mg daily• Carvedilol 6.25 mg twice daily• Spironolactone 50 mg daily• Furosemide 60 mg daily• Digoxin 250 mcg daily

• Lab values:• HR: 75 bpm, NSR• BP: 95/57 mmHg

How do we start ivabradine?


Ivabradine Dosing Pearls

Heart Rate Dose Adjustment> 60 bpm Increase by 2.5 mg BID50-60 bpm Maintain< 50 bpm or symptoms of bradycardia

Decrease by 2.5 mg BID or discontinue

• Starting dose: 5 mg BID with meals• Maximum dose: 7.5 mg BID

Corlanor [package insert]. Amgen 2015.Swedberg K. Lancet. 2010 Sep 11;376(9744):875-85.


Summary: Ivabradine• Reduces risk of hospitalization in certain

HFrEF patients• Potential add on for stable HFrEF patients

with:• Resting heart rate > 70 bpm and in NSR

AND• Maximized or contraindication to

beta-blocker therapyAND

• Intolerance or contraindication to digoxin


Ivabradine: Beyond Heart Failure

Tardif J. Eur Heart J 2005. 2005 Dec;26(23):2529-36.Cappato R. J Am Coll Cardiol. 2012 Oct 9;60(15):1323-9.

Fox K. N Engl J Med. 2014 Sep 18;371(12):1091-9.

Trial Disease State Comparator Result

INITIATIVE Stable angina Atenolol Non-inferior

Cappato et al. Inappropriate sinus tachycardia Placebo Improved

symptoms

SIGNIFY Stable CAD withoutHF Placebo Did not improve

outcomes

CAD: Coronary artery disease


Future Directions

http://www.clinicaltrials.gov

• PARAGON-HF: Sacubitril-valsartan vs. valsartan (Mortality) NCT01920711

• Digoxin vs. ivabradine in HFpEF (Symptoms)NCT01796093

HFpEF

• Ivabradine + -blockers in patients with atrial fibrillationPreliminary results: International Journal of Cardiology

Atrial Fibrillation

• Sacubitril-valsartan vs. olmesartan for essential hypertension NCT01785472

• Sacubitril-valsartan vs. placebo in patients with essential hypertension NCT01193101

Hypertension

HFpEF: Heart failure with preserved ejection fraction


Questions & Discussion


Sacubitril/Valsartan: Cost Effectiveness• Estimated price = $380.00 per month• Added approximately 0.6 QALYs compared to

enalapril• Estimated $50,000 per QALY• Estimated 9% discount would keep within

budget impact threshold• Similar to other popular brand name drugs

• Advair $320.00• Crestor $300.00

QALY: Quality adjusted life year Ollendorf DA. JAMA 2016. Sandhu. Annals of Int. Med 2016.

Gaziano TA. JAMA Card 2016.


Ivabradine: Cost Effectiveness• Estimated price= $375.00 per month• Added approximately 0.24 QALYs compared to

placebo• Estimated $8,594 savings over 10 years with

private insurance based on single cost-effectiveness trial

QALY: Quality adjusted life year Kansal AR. J Am Heart Assoc. 2016 May 6;5(5).

Documents

Do New Drugs SIGNIFY a PARADIGM SHIFT? - Mayo Clinic PGR HF 10.18 Final.pdf2016 ACC/AHA/HFSA Focused Update NYHA class II-III (NSR, resting HR >70 bpm) ARNI: Angiotensin receptor-neprilysin