integrating arnis and other novel medical therapies into ... · integrating arnis and other novel...

Integrating ARNIs and Other Novel Medical Therapies into the Medical

Regimen to Improve Outcomes

Gregg C. Fonarow, MD FACC, FAHA, FHFSAEliot Corday Chair of Cardiovascular Medicine

Co-Chief UCLA Division of CardiologyDirector, Ahmanson-UCLA Cardiomyopathy Center

Los Angeles, CA

UCSD HF Symposium 2019

Disclosure

• Dr. Fonarow has consulted for Abbott, Amgen, Janssen, Medtronic, and Novartis, and has received research grants from the National Institutes of Health (NIH).

Scope of Heart Failure

• Heart failure (HF) is a major public health problem resulting in substantial morbidity, mortality, and healthcare expenditures

• Despite available effective treatments, a large number of eligible patients are not receiving optimal care

• Even with conventional therapy patients remain at risk for disease progression and adverse outcomes

Prevalence Incidence MortalityHospital

Discharges Cost

6,500,000 1,000,000308,976

(50% at 5 years)

900,000 $30.7 billion

American Heart Association. 2018 Heart and Stroke Statistical Update. Dallas, Tex: American Heart Association; 2018

Myocardial injury to the heart (CAD, HTN, CMP, valvular disease)Initial fall in LV performance, ↑ wall stress

Morbidity and mortalityArrhythmiasPump failure

Peripheral vasoconstrictionHemodynamic alterations

Remodeling and progressiveworsening of LV function

Fibrosis, apoptosis,hypertrophy,

cellular/molecular

alterations,myotoxicity

Heart failure symptomsFatigue

Activity altered Chest congestion

EdemaShortness of breath

Activation of RAAS and SNS

Neurohormonal Activation inHeart Failure

RAAS = renin-angiotensin-aldosterone system; SNS = sympathetic nervous system;CMP = cardiomyopathy. Fonarow GC. Rev Cardiovasc Med. 2001;2:7-12.

ACC/AHA HF Guidelines 2013:Management of HFrEF (Stage C)

Life-Prolonging Medical Therapy• ACE inhibitors or ARB (Class I, evidence A) in all patients

without contraindications or intolerance.

• Evidence-based beta-blockers (Class I, evidence A) in all patients without contraindications or intolerance. This would include carvedilol (immediate or extended release), metoprolol succinate, or bisoprolol.

• Aldosterone antagonists (Class I, evidence A) in all patients with Class II–IV HF without contraindications or intolerance when close monitoring can be ensured.

Yancy CW, et al. J Am Coll Cardiol. 2013;62:1495-1539.

Pharmacologic Treatment for Stage C HFrEF

Yancy CW, et al. J Am Coll Cardiol. 2013;62:1495-1539.

HFrEF Stage CNYHA Class I–IV

Treatment:

For persistently symptomaticAfrican Americans,NYHA Class III–IV

For NYHA Class II–IV patients.Provided estimated creatinine

>30 mL/min and K+

Residual Risk for HFrEF Despite Conventional GDMT

In PARADIGM-HF, study patients were followed over a median of 27 months.2,*

*Adult patients with NYHA class II–IV symptoms and an ejection fraction of 40% or less were required to take a stable dose of a beta blocker and an ACE inhibitor (or ARB) equivalent to at least 10 mg of enalapril daily, with most also receiving MRA.

McMurray J, et al. N Engl J Med. 2014;371:993-1004.

Of all patients randomized to enalapril, the absolute risk of CV death as a first event was 10.9% (n=459/4212)1

New Tools for HFrEF

Counterregulatory Peptide Systems Activated in Heart Failure Patients

Mann DL et al. Braunwald’s Heart Disease. 10th ed. Philadelphia, PA: Saunders; 2015.ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; CNP, C-type natriuretic peptide; NP, natriuretic peptide; NPS, natriuretic peptide system.

Prostaglandin

Bradykinin

Adrenomedullin

ANP BNP CNP Urodilatin Dendroaspis

NPs (Natriuretic peptides)

Since neprilysin breaks down thesepeptides, inhibitors of this enzymeshould increase their levels and effectsin heart failure

These peptides promote vasodilation,salt and water diuresis and have anti-remodeling effects that modulatethe adverse effects of the RAAS and SNS

Endogenousvasoactive peptides

(natriuretic peptides, adrenomedullin,bradykinin, substance P,

calcitonin gene-related peptide)

Inactive metabolites

Neurohormonal activation

Vascular tone

Cardiac fibrosis, hypertrophy

Sodium retention

Neprilysin Neprilysininhibition

McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

Effects of Neprilysin Inhibition in Heart Failure

NEP < medianNEP < median

NEP ≥ median

NEP ≥ median

Bayés-Genís A et al. JACC 65: 657-665, 2014

Neprilysin Levels in Blood PredictOutcomes in HF Patients

Buggey et al. Journal of Cardiac Failure, Volume 21, Issue 9, 2015, 741–750

Sacubitril/Valsartan (LCZ696)Mechanism of Action

Prospective comparison of ARNI with ACEI toDetermine Impact on Global Mortality and

morbidity in Heart Failure trial (PARADIGM-HF)

Sacubitril/Valsartan 97/103 mg twice daily

Enalapril10 mg twice daily

Aim of the PARADIGM-HF Trial

SPECIFICALLY DESIGNED TO REPLACE CURRENT USEOF ACE INHIBITORS AND ANGIOTENSIN RECEPTOR

BLOCKERS AS THE CORNERSTONE OF THETREATMENT OF HEART FAILURE

PARADIGM-HF Trial: DesignEntry Criteria: • NYHA Class II-IV HF, LVEF ≤40% → amended to ≤35%• BNP ≥150 pg/mL (or NT-proBNP ≥ 600 pg/mL) or 1/3 lower if hospitalized for HF within 12 mos• On a stable dose of ACEI or ARB equivalent to ≥10 mg of enalapril daily for ≥4 weeks• Unless contraindicated, on stable dose of beta-blocker for ≥4 weeks• SBP ≥95 mm Hg, eGFR ≥30 mL/min/1.73 m2 and serum K ≤5.4 mmol/L at randomization

Sac/Val = Sacubitril/Valsartan.McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

34-month follow-up

Single-blind run-in period

HFPatients(n=8,442)

R

Enalapril 10 mg BID(n=4,212)

Sac/Val 97/103 mg BID(n=4,187)

Enalapril 10 mg BID(n=10,513)

Sac/Val49/51 mg to

97/103 mg BID(n=9,419)

2 Weeks 4–6 Weeks

Study stopped early after median follow-up of 27 mos

Primary endpoint: Death from CV causes or hospitalization for HF

Sac/Val(n=4187)

Enalapril(n=4212)

Age (years) 63.8 ± 11.5 63.8 ± 11.3Women (%) 21.0% 22.6%Ischemic cardiomyopathy (%) 59.9% 60.1%LV ejection fraction (%) 29.6 ± 6.1 29.4 ± 6.3NYHA functional Class II / III (%) 71.6% / 23.1% 69.4% /24.9%Systolic blood pressure (mm Hg) 122 ± 15 121 ± 15Heart rate (beats/min) 72 ± 12 73 ± 12N-terminal pro-BNP (pg/mL) 1631 (885–3154) 1594 (886–3305)B-type natriuretic peptide (pg/mL) 255 (155–474) 251 (153–465)History of diabetes 34.7% 34.6%Digitalis 29.3% 31.2%Beta-adrenergic blockers 93.1% 92.9%Mineralocorticoid antagonists 54.2% 57.0%ICD and/or CRT 21.9% 21.4%


PARADIGM-HF: Baseline Characteristics

Sac/Val = Sacubitril/Valsartan. McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

Number needed to treat = 21

PARADIGM-HF: Primary Endpoint of CV Death or Heart Failure Hospitalization

Number at RiskSac/ValEnalapril

0 180 540 900

Days since Randomization

0

0.1

0.2

0.4

0.6

1.0

Enalapril1117 events (26.5%)

Sac/Val914 events (21.8%)

1260

Cum

ulat

ive

Prob

abili

ty

41874212

36633579

22572123

15441488

896853

360 720 1080

0.3

0.5

39223883

30182922

249236

HR 0.80 (95% CI, 0.73–0.87), p

Sac/Val(n=4187)

Enalapril(n=4212)

Hazard Ratio(95% CI)

p-Value

Primary endpoint

914(21.8%)

1117(26.5%)

0.80(0.73–0.87)


Number needed to treat = 31


0 180 540 900


0

0.1

0.2

0.4

0.6

1.0



HR 0.80 (95% CI, 0.71–0.89), p

Influence of ARNI Therapy on Mode of Death: Reduces Both Sudden Death and Worsening HF Death1

1. Desai AS et al. Eur Heart J. 2015;36:1990-1997.



0 180 540 900


0

0.1

0.2

0.4

0.6

1.0



1260

Cum

ulat

ive

Prob

abili

ty

41874212

38913860

24782410

17161726

1005994

360 720 1080

0.3

0.5

40564051

32823231

280279

PARADIGM-HF:All-Cause Mortality

HR 0.84 (95% CI, 0.76–0.93), p


Sac/Val vs. Enalapril on Primary Endpoint and on CV Death by Subgroups

All PatientsAge

Median

HypertensionNoYes

Prior use of ACE inhibitorNoYes

Prior use of aldosterone antagonistNoYes

Prior hospitalization for heart failureNoYes

Death from Cardiovascular Causes

1.70.3

Sac/Val Better

Primary EndpointHazard Ratio

(95% CI)p-Value forInteraction

Hazard Ratio(95% CI)

p-Value forInteractionNo.

Sac/Val Enalapril

1.51.31.10.90.70.5

Enalapril Better

1.70.3

Sac/Val Better

1.51.31.10.90.70.5

Enalapril Better

4212

21682044

3259953

31301076

15202692

3722489

21162087

12412971

9463266

18122400

15452667

4187

21112076

3308879

31871002

15412646

3715472

20792103

12182969

9213266

19162271

15802607

0.47

0.63

0.03

0.91

0.36

0.16

0.87

0.09

0.10

0.10

0.70

0.92

0.76

0.73

0.36

0.33

0.14

0.06

0.32

0.19

Subgroup

PARADIGM-HF: Effect of Sacubitril/Valsartan According to Patient Age Category

CV Death or HF Hospitalization CV Death

HF Hospitalization All-Cause Death

Rate

Per

100

Pa

tient

Yea

rsRa

te P

er 1

00

Patie

nt Y

ears

Rate

Per

100

Pa

tient

Yea

rsRa

te P

er 1

00

Patie

nt Y

ears

Age, y

Age, y

Age, y

Age, y

EnalaprilSac/Val

Chart1

PARADIGM-HF Benefit Even in the Most Stable HF Patients1

1. Solomon SD et al. JACC Heart Fail. 2016;4:816-822.

Is Sacubitril/Valsartan Effective Across the Spectrum of Risk in HF? The MAGGIC Risk Score

1. ESC HF 2015, JACC 2015.

CV Death or HF Hospitalization

0

5

10

15

20

25

1 2 3 4 5

Enalapril LCZ696

Rat

e Pe

r 1,0

00 P

atie

nt Y

ears

Quintile of Risk Score

Sac/Val(n=4187)

Enalapril(n=4212)

p-Value

Prospectively identified adverse eventsSymptomatic hypotension 14.0% 9.2% 6.0 mmol/L 4.3% 5.6% 0.007

Serum creatinine ≥ 2.5 mg/dL 3.3% 4.5% 0.007

Cough 11.3% 14.3%

1. Granger CB, et al. Lancet. 2003;362:772-776. 2. The SOLVD Investigators. N Engl J Med. 1991;325:293-302. 3. McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

Angiotensin Neprilysin Inhibition with Sac/Val Doubles Effect on CV Death of Current Inhibitors

of the RAS

10

20

30

40

ACEInhibitor2

AngiotensinReceptorBlocker1

0

Dec

reas

e in

Mor

talit

y (%

)

18%

20%

AngiotensinNeprilysinInhibition3

15%

FDA-Approved Sacubitril/ValsartanSacubitril/Valsartan

Brand name Entresto

IndicationThe 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.

Dosage 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.

Renal/hepatic impairment

For patients not currently taking an ACEI or ARB, or for those with severe renal impairment (eGFR

Effect of Sacubitril/Valsartan on Early and Late Measures of HF Progression

Packer M et al. Circulation. 2015;131:54-61.

Hospitalization for HF in First 30 Days

Tim

e to

firs

t hos

pita

lizat

ion

for H

F

Cumulative Hospitalizations

41874212

41744192

41534166

41404143

24722408

17101724

1001993

279278

LCZ696Enalapril

Patients at Risk

41874212

40544049

38853857

32763228

1217

Days after Randomization Days after Randomization

Influence of Sacubitril/Valsartan on ReadmissionRates After HF Hospitalization: PARADIGM-HF

Desai, A.S. et al. J Am Coll Cardiol. 2016;68(3):241–8.

2,383 investigator-reported HF hospitalizations, of which 1,076 (45.2%) occurred in subjects assigned to sacubitril/valsartan and 1,307 (54.8%) occurred in subjects assigned to enalapril.

30 Day All Cause Readmission

Odds Ratio: 0.74;95% CI 0.56-0.97

30 Day HF Readmission

Odds Ratio: 0.62;95% CI 0.45-0.87

Velazquez EJ, et al. Am Heart J. 2018;198:145-151.

Inclusion: • Admitted to the hospital with the primary diagnosis of HF,

NYHA class II-IV, including signs and symptoms of fluid overload

• At randomization (between 24 hours and 10 days from initial presentation), hospitalized patients were defined as stable by:• SBP ≥100 mmHg for 6 hours prior to randomization,

no symptomatic hypotension• No increase (intensification) in IV diuretic

dose within 6 hours prior to randomization• No IV inotropic drugs for 24 hours prior to randomization• No IV vasodilators including nitrates within

last 6 hours prior to randomization• LVEF ≤40%• NT-proBNP ≥1600 pg/mL OR BNP ≥400 pg/mL during current

hospitalization

PIONEER-HF: In-Hospital ARNI

Exclusion:• Hypersensitivity, contraindications or

intolerance to study drugs• Known history of angioedema with ACEi/ARB• eGFR 5.2mEq/L at screening• Primary dyspnea from non-cardiac, non-heart

failure cause• Implantation of cardiac resynchronization

device in 3 months prior or intent to implant• Pregnancy or potential to become pregnant

(not using two birth control methods)

Primary End PointTime-averaged proportional change in NT-proBNP at weeks 4 and 8

Safety AssessmentsWorsening renal function, Hyperkalemia, Symptomatic hypotension, Angioedema

Exploratory Clinical OutcomesTo examine the effect of sacubitril/valsartan vs Enalapril on incidence of rehospitalization through day 30

Goal: To Evaluate the In-Hospital Initiation of Sacubitril/Valsartan in Stabilized Patients Hospitalized with HFrEF irrespective of Prior HF Diagnosis or ACEI/ARB use

Sacubitril/Valsartan (n=440) Enalapril (n=441)

Age (years) 61 (50.5, 71) 63 (54, 72)

Women (%) 25.7 30.2

Black (%) 35.9 35.8

Prior HF Diagnosis (%) 67.7 63.0

LVEF 0.24 (0.18, 0.30) 0.25 (0.20, 0.30)

Systolic Pressure (mmHg) 118 (110, 133) 118 (109, 132)

NT-proBNP (pg/mL) 2883 (1610, 5403) 2536 (1363, 4917)

ACEi/ARB Therapy* (%) 47.3 48.5

Beta-adrenergic Blockers 59.6 59.6

PIONEER-HF: Baseline Characteristics

Velazquez EJ, et al. NEJM 2018 DOI: 10.1056/NEJMoa1812851


PIONEER-HF Change in NT-proBNP Levels

Safety of In-Hospital ARNI Initiation

Adverse events in stable hospitalized patients in PIONEER-HF were comparable to PARADIGM-HF and no new safety signals were seen

PIONEER-HF: AEs Occurring >5%

Sacubitril/Valsartan (n=440)Enalapril (n=441)

Perc

enta

ge†

(%)


Chart1

HypotensionHypotension

HyperkalemiaHyperkalemia

DizzinessDizziness

Cardiac failure congestiveCardiac failure congestive

Acute kidney injuryAcute kidney injury

Blood creatinine increasedBlood creatinine increased

PIONEER ENTRESTO

PIONEER ENALAPRIL

In-patient initiation

18

18.1

12.5

9.2

8.9

7.6

5

7.3

8.2

8.5

7

4

Sheet1

PIONEER ENTRESTOPIONEER ENALAPRILTRANSITION ENTRESTO

Hypotension1818.112.3

Hyperkalemia12.59.211.1

Dizziness8.97.65.6

Cardiac failure congestive57.36.8

Acute kidney injury8.28.51.2

Blood creatinine increased74

2.00.0 4.0

30-D

ay H

F R

eadm

issi

on

6.0 8.0 10.0 12.0 14.0HF Readmission Rate Through Day 30 (%)

HR: 0.56 (95% CI 0.37-0.84)

P=.005

44%*

13.8%n=441

Enalapril

8.0%n=440

Sacubitril/Valsartan 5.8% Absolute Risk

Reduction

PIONEER-HF: Clinical Outcomes

All Patients

Prior HF

No

Yes

Prior ACEi/ARB

No

Yes

Subgroup

Change in NT-proBNP

0.1 0.3 0.5 0.7 0.9 1.1 1.3 1.5 1.7 1.9Favors

sacubitril /valsartan

Favorsenalapril

sacubitril/valsartanvs. enalapril mean

[95% CI]

0.71 [0.63, 0.81]

0.65 [0.53, 0.81]

0.72 [0.63, 0.83]

0.72 [0.60, 0.86]

0.72 [0.61, 0.85]

PIONEER-HF Key Subgroup Analyses

P value (interaction) = NSFavors

enalapril

Serious Composite Endpoint

0.1 0.3 0.5 0.7 0.9 1.1 1.3 1.5 1.7 1.9

Favorssacubitril /valsartan

0.54 [0.37, 0.79]

0.37 [0.12, 1.15]

0.53 [0.35, 0.80]

0.52 [0.29, 0.95]

0.56 [0.34, 0.92]

Hazard Ratio[95% CI]

All Patients

Prior HF

No

Yes

Prior ACEi/ARB

No

Yes

Subgroup

2016 ACC/AHA/HFSA Heart Failure Guideline Update

Reference: Yancy et al. Circulation. 2016;134:[ePub ahead of print].

Pharmacological Treatment for Stage C HFrEF

ARNI = angiotensin receptor blocker and neprilysin inhibitor; COR = class of recommendation; LOE = level of evidence.

Treatment of HFrEF Stage C and D

†Hydral-Nitrates green box: The combination of ISDN/HYD with ARNI has not been robustly tested. BP response should be carefully monitored. ‡See 2013 HF guideline. §Participation in investigational studies is also appropriate for stage C, NYHA class II and III HF.

Practical Points on Use of Sacubitril/Valsartan

• Starting dose is 24/26 mg twice daily, unless patient is tolerating full dose ACEI or ARB in which case start 49/51 mg twice daily

• Target dose is 97/103 mg twice daily• After 2-4 weeks uptitrate to next dose, aim for target dose• In-hospital initiation is safe, well tolerated, and markedly

improves early outcomes• Monitor SBP, renal function and K as you would with ACEI

or ARB use• Space out dosing from other vasoactive medications if

needed• Adjust diuretics doses based on volume status

Cost-Effectiveness and Value of Sacubitril/Valsartan Replacing ACEI or ARB in HFrEF1

1. Gaziano TA et al. JAMA Cardiol. 2016;16:666-672.

• For every 100 000 people receiving sacubitril/valsartan, this strategy could potentially reduce hospitalizations by 3000 and reduce deaths by nearly the same number over a 2-year period. Medical savings from reduced HF admissions would be more than $27 million.

What Value Do You and Your Patients Place on Being Able to Live 1-2 Years on Average Longer?

N Engl J Med 2015;373;23

Guideline

Recommended

Therapy

Relative Risk

Reduction in

Mortality

Number Needed

to Treat for

Mortality

NNT for Mortality

(standardized to

36 months)

Relative Risk

Reduction in HF

Hospitalizations

ACEI/ARB 17% 22 over 42 months 26 31%

ARNI (replacing ACEIor ARB) 16% 36 over 27 months 27 21%

Beta-blocker 34% 28 over 12 months 9 41%

AldosteroneAntagonist 30% 9 over 24 months 6 35%

Hydralazine/Nitrate 43% 25 over 10 months 7 33%

CRT 36% 12 over 24 months 8 52%

ICD 23% 14 over 60 months 23 NA

Ivabradine NA NA NA 26%

Updated from Fonarow GC, et al. Am Heart J 2011;161:1024-1030.

Evidence-Based HFrEF Therapies

Guideline Recommended

Therapy

HF Patient

Population

Eligible for

Treatment, n*

Current HF

Population

Eligible and

Untreated, n (%)

Potential Lives

Saved per Year

Potential Lives

Saved per Year

(Sensitivity Range*)

ACEI/ARB 2,459,644 501,767 (20.4) 6516 (3336-11,260)

Beta-blocker 2,512,560 361,809 (14.4) 12,922 (6616-22,329)

Aldosterone Antagonist 603,014 385,326 (63.9) 21,407 (10,960-36,991)

Hydralazine/Nitrate 150,754 139,749 (92.7) 6655 (3407-11,500)

CRT 326,151 199,604 (61.2) 8317 (4258-14,372)

ICD 1,725,732 852,512 (49.4) 12,179 (6236-21,045)

Total - - 67,996 (34,813-117,497)

ARNI (replacing ACEI/ARB) 2,287,296 2,287,296 (100) 28,484 (18,230-41,017)

Updated from Fonarow GC, et al. Am Heart J 2011;161:1024-1030. and JAMA Cardiology 2016

Potential Impact of Optimal Implementation of Evidence-Based HFrEF Therapies on Mortality

Fonarow GC, et al. JAMA Cardiol. 2016. doi:10.1001/jamacardio.2016.1724.

2,964,000 excluded with HFpEF

5,700,000 patients with HF in the United States

2,736,000 HFrEF

2,599,200 HFrEF

2,287,296 HFrEF eligible for ARNI

136,800 excluded•109,440 in hospice or comfort care

only•27,360 receiving advanced therapies

311,904 excluded•181,944 with contraindication for

or intolerance to ACE inhibitor/ARB/ARNI

•129,960 with SBP

Hospital Level Variation in the Early Adoption of ARNI in HFrEF

J Am Heart Assoc. 2019;8:e010484. DOI: 10.1161/JAHA.118.010484

Advances in the Treatment of HF• Increased attention to prevention

• ACEI /beta-blocker /aldosterone antagonist combination previously established as the “cornerstone” of therapy

• ARNI further reduces morbidity and mortality (start in-hospital)

• Evidence that beta-blockers’ effects are not homogeneous

• Ivabradine further reduces HF hospitalization risk

• Integration of CRT and ICD device therapy into the standard therapeutic regimen

• Recognition that “special populations” of HF patients may benefit from or require different approaches

• New strategies to improve utilization of evidence-based therapies

Slide Number 1DisclosureScope of Heart FailureNeurohormonal Activation in�Heart FailureACC/AHA HF Guidelines 2013:�Management of HFrEF (Stage C)Pharmacologic Treatment for Stage C HFrEFResidual Risk for HFrEF Despite �Conventional GDMTSlide Number 8Counterregulatory Peptide Systems Activated in Heart Failure PatientsEffects of Neprilysin Inhibition in Heart FailureSlide Number 11Slide Number 12Aim of the PARADIGM-HF TrialPARADIGM-HF Trial: DesignPARADIGM-HF: Baseline CharacteristicsPARADIGM-HF: Primary Endpoint of CV Death or Heart Failure HospitalizationPARADIGM-HF: Effect of Sac/Val vs. Enalapril on the Primary Endpoint and Its ComponentsPARADIGM-HF: CV DeathInfluence of ARNI Therapy on Mode of Death: Reduces Both Sudden Death and Worsening HF Death1PARADIGM-HF:�All-Cause MortalitySac/Val vs. Enalapril on Primary Endpoint and on CV Death by SubgroupsPARADIGM-HF: Effect of Sacubitril/Valsartan According to Patient Age CategoryPARADIGM-HF Benefit Even in the Most Stable HF Patients1Is Sacubitril/Valsartan Effective Across the Spectrum �of Risk in HF? The MAGGIC Risk ScorePARADIGM-HF: Adverse EventsAngiotensin Neprilysin Inhibition with Sac/Val Doubles Effect on CV Death of Current Inhibitors of the RASFDA-Approved Sacubitril/ValsartanEffect of Sacubitril/Valsartan on Early and Late Measures of HF ProgressionInfluence of Sacubitril/Valsartan on Readmission�Rates After HF Hospitalization: PARADIGM-HFSlide Number 30Slide Number 31PIONEER-HF Change in �NT-proBNP LevelsSafety of In-Hospital ARNI InitiationSlide Number 34PIONEER-HF: Clinical OutcomesPIONEER-HF �Key Subgroup Analyses2016 ACC/AHA/HFSA �Heart Failure Guideline Update Treatment of HFrEF Stage C and D Practical Points on Use of Sacubitril/ValsartanCost-Effectiveness and Value of Sacubitril/Valsartan Replacing ACEI or ARB in HFrEF1Slide Number 41Slide Number 42Slide Number 43Hospital Level Variation in the Early Adoption of ARNI in HFrEFAdvances in the Treatment of HF

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