Expanding the Role of ARNIs in Treating Heart Failure

Barry Greenberg, M.D.Distinguished Professor of Medicine

Director, Advanced Heart Failure Treatment ProgramUniversity of California, San Diego

20th Annual UCSD Heart Failure Symposium for Primary Care and

Internal Medicine Physicians

New Strategies for Detecting, Preventing and Treating

Heart Failure

La Jolla, California

January 10-11, 2020

Myocardial injury to the heart (CAD, HTN, CMP, valvular disease)

Initial fall in LV performance, ­ wall stress

Morbidity and mortality

Arrhythmias

Pump failure

Peripheral vasoconstriction

Hemodynamic alterations

Remodeling and progressive

worsening of LV function

Fibrosis, apoptosis,

hypertrophy, cellular/

molecular alterations,

myotoxicity

Heart failure symptoms

Fatigue

Activity altered

Chest congestion

Edema

Shortness of breath

Activation of RAAS and SNS

Neurohormonal Activation in

Heart Failure

RAAS = renin-angiotensin-aldosterone system; SNS = sympathetic nervous system;

CMP = cardiomyopathy.

Fonarow GC. Rev Cardiovasc Med. 2001;2:7-12.

2013 ACC/AHA Guideline

Recommendations for Treating

Chronic HFrEF Patients

HFrEF Stage CNYHA Class I – IV

Treatment:

For NYHA class II-IV patients. Provided estimated creatinine

>30 mL/min and K+ <5.0 mEq/dL

For persistently symptomatic African Americans, NYHA class III-IV

Class I, LOE AACEI or ARB AND

Beta Blocker

Class I, LOE CLoop Diuretics

Class I, LOE AHydral-Nitrates

Class I, LOE AAldosterone Antagonist

AddAdd Add

For all volume overload, NYHA class II-IV patients

Yancy, et al. Circulation 2013;128:e240–319

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

Widespread Neurohormonal ActivationOccurs 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)

• In addition to the RAAS and SNS, counter-regulatory neurohormonalsystems are also activated

• These systems modulate adverse effects of the RAAS and SNS

• However, many compensatory peptide mediators are degraded by neprilysin

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

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

Sacubitril/Valsartan (LCZ696)Mechanism of Action

Sac/Val = Sacubitril/Valsartan; HR = hazard ratio.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 HF Hospitalization

Number at RiskSac/ValEnalapril

0 180 540 900Days 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

abilit

y

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<0.001

− 20%

ARNI Therapy Reduces Both SCD

and Worsening HF Death

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

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.

Combined Angiotensin Neprilysin Inhibition Doubles Effect on CV Death of Current RAAS Inhibitors

10

20

30

ACEInhibitor2

AngiotensinReceptorBlocker1

0

Dec

reas

e in

Mor

talit

y (%

)

18%

20%

AngiotensinNeprilysinInhibitor3

15%

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

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

All PatientsAge

<65 years≥65 years

SexMaleFemale

NYHA ClassI or IIIII or IV

Estimated GFR<60 mL/min/1.73 m2

≥60 mL/min/1.73 m2

Ejection fraction≤35%>35%

NT-proBNP≤Median>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

2016 ACC/AHA/HFSA Heart Failure Guideline Update

Pharmacological Treatment for Stage C HFrEF

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

Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e147-239.

Will Stable Patients Benefit?PARADIGM-HF: Prespecified Subgroup Analyses

McMurray JJ et al. N Engl J Med 2014

Jhund PS et al. Eu Heart J2015 Oct 7; 36(38): 2576–2584

Does Superiority of Sacubitril-Valsartan Vary According to Age?

Does Reduced Dose Offer Similar Benefits?

Eur J Heart Fail. 2016 Oct; 18(10): 1228–1234.

Kevin Damman et al. JCHF 2018;6:489-498

What Effect Does Sacubitril/Valsartan Have on Renal Function?

Other Issues

• Does starting sacubitril/valsartan in the hospital offer benefits?

• Is it safe to start in-hospital?• Can drug be started in ACEI/ARB naïve

patients?

• Hospitalized for Acute Decompensated Heart Failure (ADHF)

• LVEF ≤40% within the last 6 months

• NT-proBNP ≥1600pg/mL or BNP ≥400 pg/mL*

• Stabilized while hospitalized

– SBP ≥100 mmHg in prior 6h; no symptomatic hypotension

– No increase in IV diuretics in prior 6h

– No IV vasodilators in prior 6h

– No IV inotropes in prior 24h

Key Entry Criteria

PIONEER-HF

Velazquez EJ et al. Late Breaker AHA 2018. Chicago, IL, USA November 10-12, 2018.

• Starting dose level based on SBP algorithm– If SBP 100 - <120 mm Hg: Sacubitril/Valsartan 24/26 mg or

Enalapril 2.5 mg twice daily

– If >120 mm Hg: Sacubitril/Valsartan 49/51 mg or Enalapril 5 mg twice daily

• At week 1, dose titrated upwards if SBP > 110 mm Hg

• At week 2,4,6, dose titrated upwards if SBP > 100 mmHg

• Target dose– Sacubitril/Valsartan 97/103 mm Hg or Enalapril 10 mg twice daily

• Clinical assessment and judgment permitted

Study Dose TitrationPIONEER-HF

Velazquez EJ et al. Late Breaker AHA 2018. Chicago, IL, USA November 10-12, 2018.

Primary Endpoint10

0

- 10

- 20

Perc

en

t C

han

ge f

rom

Baselin

e

- 30

- 40

- 50

- 60

- 70

Week since Randomization

Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8

Ratio of Change 0.71 (95% CI 0.63, 0.81)

P<0.001Enalapril

Sacubitril/Valsartan

Time-average proportional change of NT-proBNP from baseline*

PIONEER-HF

Velazquez EJ et al. Late Breaker AHA 2018. Chicago, IL, USA November 10-12, 2018.

Serious Clinical Composite Endpoint

HR = 0.54; 95% CI 0.37-0.79 P = 0.001NNT= 13

20

KM

est

imat

e of

Eve

nt R

ate

(%)

10

0

0 7

Sacubitril/ValsartanN=440

EnalaprilN=441

14 24 28 35 42 49 56

Days since Randomization

Composite of Death, HF re-hospitalization, LVAD, Listing for Transplant

• Serious Clinical Composite endpoints were driven by a reduction in death and HF re-hospitalizations

PIONEER-HF

Velazquez EJ et al. Late Breaker AHA 2018. Chicago, IL, USA November 10-12, 2018.

Safety Events (%) Sacubitril/

Valsartan

(n=440)

(%)

Enalapril

(n=441)

(%)

RR

(95% CI)

Worsening renal functiona 13.6 14.7 0.93 (0.67-1.28)

Hyperkalemia 11.6 9.3 1.25 (0.84-1.84)

Symptomatic hypotension 15.0 12.7 1.18 (0.85-1.64)

Angioedema eventsb 0.2% 1.4% 0.17 (0.02-1.38)

Safety

PIONEER-HF

Velazquez EJ et al. Late Breaker AHA 2018. Chicago, IL, USA November 10-12, 2018.

2019 ESC-HF Expert Consensus Update

• Sacubitril/valsartan is recommended as a replacement for ACEI/ARB to reduce the risk of HF hospitalization and death in ambulatory patients with HFrEF who remain symptomatic despite optimal medical treatment with an ACE-I, a beta-blocker and an MRA.

• Initiation of sacubitril/valsartan rather than an ACE-I or an ARB may be considered for patients hospitalized with new-onset HF or decompensated chronic HF to reduce the short-term risk of adverse events and to simplify management (by avoiding the need to titrate ACE-I first and then switch to sacubitril/valsartan).Seferovic PM et al. Clinical Practice Update on Heart Failure 2019 from the ESC-HFA. Eur J HF. 2019