Heart Failure Hospitalization:

Racing to Break the Cycle

Javed Butler, MD, MPH, MBA

Professor and Chairman of the Department of Medicine at the University of Mississippi, US
Patrick H. Lehan Chair in Cardiovascular Research

MA-M_VER-ALL-0167-1 Date of preparation: June 2021

Disclosures

• Served as consultant to: Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer,

Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Impulse
Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis,
Novo Nordisk, Relypsa, Roche and Vifor

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Heart Failure Is a Progressive Condition
Advanced
Worsening HF risk
HF risk
Baseline
No heart HF risk Residual Refractory/intolerant
failure HF risk to GDMT

Consideration for heart

transplantation,
Clinical risk

mechanical
Initial diagnosis and circulatory support
treatment (outpatient or IV inotrope therapy
or hospital)
Initiation and Palliative care
titration of GDMT Worsening HF
despite
ICD/CRT as optimal medical
indicated and device
therapy

Variable Variable Variable Variable

(months – years) Time 3–6 months (months – years) (months) (months)

Personal communication from Javed Butler, June 2021.

CRT, cardiac resynchronization therapy; GDMT, guideline-directed medical therapy; HF, heart failure; ICD, implantable cardioverter defibrillator; IV, intravenous.
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Despite the Use of HF Medication, Patients Still Develop
Worsening HF and Remain at Risk of HFH1–4

5%
Worsening HF
17%
15% De novo HF
Advanced or
end-stage HF
N=11,064 HFH

83% 80%

~1 in 6 patients with HFrEF in a large

1st Qtr 2nd Qtr Chronic worsening HF accounts for
US registry developed worsening HF
~80% of HFH cases6
≤18 months after HF diagnosis5

CV, cardiovascular; HF, heart failure; HFH, heart failure hospitalization; HFrEF, heart failure with reduced ejection fraction; US, United States.
1. McMurray JJV et al. N Engl J Med. 2014;371:993–1004; 2. McMurray JJV et al. N Engl J Med. 2019;381:1995–2008; 3. Packer M et al. N Engl J Med. 2020;383:1413–1424;
4. Teerlink JR et al. N Engl J Med. 2021;384:105–116; 5. Butler J et al. J Am Coll Cardiol. 2019;73:935–944; 6. Gheorghiade M et al. J Am Coll Cardiol. 2013;61:391–403.
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Worsening HF Is Characterized by Repeated HF Events,
Resulting in Reduced Cardiac Function1–5

HF is a progressive
condition1–4
Worsening HF events3–5
Characterized by:
• Progressive signs and symptoms of HF for
Cardiac function

which medical treatment is warranted despite

the use of GDMT
Worsening HF • Experience of a prior worsening HF event
event
– Need for IV diuretics, regardless of setting
Worsening HF – HFH
event – Need for an urgent HF visit

Worsening HF
event
Death
Time (months–years)
Adapted from Gheorghiade et al. Am J Cardiol. 2005 and Cowie et al. ESC Heart Fail. 2014.
GDMT, guideline-directed medical therapy; HF, heart failure; HFH, heart failure hospitalization; IV, intravenous.
1. Gheorghiade M et al. Am J Cardiol. 2005;96:11G–17G; 2. Cowie MR et al. ESC Heart Fail. 2014;1:110–145; 3. Greene SJ et al. JAMA Cardiol. 2018;3:252–259;
4. Butler J et al. J Am Coll Cardiol. 2019;73:935–944; 5. European Medicines Agency. 2017. CPMP/EWP/235/95, Rev.2. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-
investigation-medicinal-products-treatment-chronic-heart-failure-revision-2_en.pdf [accessed June 2021].
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Impact of Hospitalizations on the Survival of Patients
with HF1

Median survival in patients with HF after each hospitalization*

4.0
3.5
Median survival (years)

3.0
2.5
2.0
1.5
1.0
0.5
0
1st 2nd 3rd 4th
hospitalization hospitalization hospitalization hospitalization
(n=14,374) (n=3358) (n=1123) (n=417)
*After the initial worsening HF event, each subsequent event becomes longer in duration and is separated by shorter intervals.2
HF, heart failure.
1. Setoguchi S et al. Am Heart J. 2007;154:260–206; 2. Cowie MR et al. ESC Heart Fail. 2014;1:110–145.
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Worsening HF Events Are Associated with Increased
Mortality Risk, Regardless of Care Location1

Risk of mortality after a worsening HF event treated in the outpatient setting, in the ED or in hospital

40
35
All-cause mortality rate

◼
(per 100 patient-years)

Outpatient worsening HF
30 ◼ ED visit
◼ HFH
25
◼ No worsening HF
20

15

10

0 *
MADIT-CRT PARADIGM-HF

*Data for ED visits in MADIT-CRT were not reported.

ED, emergency department; HF, heart failure; HFH, heart failure hospitalization.
1. Greene SJ et al. JAMA Cardiol. 2018;3:252–259.
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PINNACLE Registry: Real-World Data on Patients with Symptomatic
Chronic HF Who Had a Previous Worsening HF Event1

Patients with incident symptomatic chronic HF (LVEF ≤45%)

diagnosed 1 Jan 2011–31 Dec 2014 identified in the CV outpatient
registry and linked to pharmacy and medical claims data
An observational cohort study n=44,679

identified 11,064 adult patients

newly diagnosed with symptomatic Continuous healthcare activity and continuity of data contribution
chronic HF between January 2011 n=11,255
and December 2014 using the
Patients with exclusion criteria
NCDR PINNACLE registry n=191
in the US.
Among these patients, 1851 (17%) One-year symptomatic chronic HF cohort
n=11,064
developed symptomatic chronic HF
following a worsening HF event
Non-worsening subcohort Worsening subcohort*
n=9213 n=1851

Note that worsening HF is defined in the PINNACLE registry as the development of progressively escalating symptoms and signs of HF requiring IV diuretic treatment in the outpatient, emergency
department or hospitalized setting.
*HF event requiring HF-related IV diuretic administration and/or inpatient hospitalization; patients had continuous healthcare activity 6 months prior to worsening index date.
CV, cardiovascular; HF, heart failure; IV, intravenous; LVEF, left ventricular ejection fraction; NCDR, National Cardiovascular Data Registry; US, United States.
1. Butler J et al. J Am Coll Cardiol. 2019;73:935–944.
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Risk of Hospitalization Increases over Time Following a
Worsening HF Event1

Patients with hospitalizations and number of hospitalizations per patient through 2 years after worsening HF event

100 2.5

hospitalizations/patient
Percent of patients with

90
80

Mean number of
hospitalizations

2.0
70
60
50 1.5
40
30
1.0
20
10
0 0.5
First First First First
30 days 3 months 12 months 24 months
post index post index post index post index
(n=1851) (n=1761) (n=1538) (n=582)
Patients with hospitalizations Hospitalizations per patient

56% of patients were rehospitalized within 30 days of the worsening HF event, and the number of
HF-related hospitalizations increased with time
Note that worsening HF is defined in the PINNACLE registry as the development of progressively escalating symptoms and signs of HF requiring IV diuretic treatment in the outpatient, emergency
department or hospitalized setting.
HF, heart failure; IV, intravenous.
1. Butler J et al. J Am Coll Cardiol. 2019;73:935–944.
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Prognosis of Patients with HF Following a Worsening HF
Event Despite the Use of Current Therapies1

Days from worsening HF onset to death/censor in 2 years post onset

100
Survival probability (%)

90

80

70

60

50
0 60 120 180 240 300 360 420 480 540 600 660 720 730
Days from worsening HF onset
Number at risk: 1851 1303 912 589 373

>1 in 5 patients died within 2 years of the worsening HF event

Note that worsening HF is defined in the PINNACLE registry as the development of progressively escalating symptoms and signs of HF requiring IV diuretic treatment in the outpatient, emergency
department or hospitalized setting.
HF, heart failure; IV, intravenous.
1. Butler J et al. J Am Coll Cardiol. 2019;73:935–944.
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Current Therapies Target Established Pathways Activated
in HF1–6

RAAS inhibitor1,2
RAAS SNS β-blocker3
(ACEi, ARB, MRA) – –

Neprilysin
ARNi2,4 NPS SGLT2 SGLT2i5
inhibitor
–
+

Activated pathways
Impaired pathways

NO–sGC–cGMP HF MoA unconfirmed*6

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor–neprilysin inhibitor; cGMP, cyclic guanosine monophosphate; HF, heart failure;
MoA, mechanism of action; MRA, mineralocorticoid receptor antagonist; NO, nitric oxide; NPS, natriuretic peptide system; RAAS, renin–angiotensin–aldosterone system; sGC, soluble guanylate
cyclase; SGLT2, sodium–glucose cotransporter 2; SGLT2i, sodium–glucose cotransporter 2 inhibitor; SNS, sympathetic nervous system.
1. Mann DL et al. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 10th edn. Elsevier/Saunders; 2015; 2. Yancy CW et al. J Am Coll Cardiol. 2017;70:776–803; 3. Triposkiadis F et al. J Am
Coll Cardiol. 2009;54:1747–1762; 4. Ponikowski P et al. Eur J Heart Fail. 2016;18:891–975; 5. Matsumura K & Sugiura T. Cardiovasc Ultrasound. 2019;17:26; 6. Nightingale B. Cardiol Res. 2021;12:60–66.
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 Decreased Activity of the NO–sGC–cGMP Pathway Plays
a Key Role in HF Pathophysiology1–8

Oxidative stress NO deficiency Endothelial dysfunction

Extracellular NO

Intracellular cGMP
sGC

Low NO Decreased Decreased Decreased

availability NO sensitivity sGC activity cGMP production

Heart Vasculature Renal system

↑ Progressive myocardial stiffening
↑ Myocardial thickening ↑ Arterial constriction ↑ Na+ and fluid retention
↑ Ventricular remodeling ↑ Vascular stiffness ↓ Renal blood flow
↑ Fibrosis
cGMP, cyclic guanosine monophosphate; HF, heart failure; NO, nitric oxide; sGC, soluble guanylate cyclase.
1. Gheorghiade M et al. Heart Fail Rev. 2013;18:123–134; 2. Mann DL et al. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 10th edn. Elsevier/Saunders; 2015; 3. Boerrigter G et al. Handb Exp Pharmacol.
2009;191:485–506; 4. Breitenstein S et al. Handb Exp Pharmacol. 2017;243:225–247; 5. Felker G & Mann D. Heart Failure: A Companion to Braunwald’s Heart Disease. Elsevier; 2020; 6. Armstrong PW et al. JACC Heart Fail.
2018;6:96–104; 7. Follmann M et al. J Med Chem. 2017;60:5146–5161; 8. Mathar I et al. Circulation. 2018;138:A15553. 12
 Vericiguat Stimulates sGC to Restore the Impaired
NO–sGC–cGMP Pathway1–8

Extracellular NO

Vericiguat

Intracellular
sGC cGMP
PKG
Low NO Increased Increased Increased
availability NO sensitivity sGC activity cGMP production

Heart Vasculature Renal system

↓ Progressive myocardial stiffening
↓ Myocardial thickening ↓ Arterial constriction ↓ Na+ and fluid retention
↓ Ventricular remodeling ↓ Vascular stiffness ↑ Renal blood flow
↓ Fibrosis
cGMP, cyclic guanosine monophosphate; HF, heart failure; NO, nitric oxide; PKG, protein kinase G; sGC, soluble guanylate cyclase.
1. Gheorghiade M et al. Heart Fail Rev. 2013;18:123–134; 2. Mann DL et al. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 10th edn. Elsevier/Saunders; 2015; 3. Boerrigter G et al. Handb Exp Pharmacol.
2009;191:485–506; 4. Breitenstein S et al. Handb Exp Pharmacol. 2017;243:225–247; 5. Felker G & Mann D. Heart Failure: A Companion to Braunwald’s Heart Disease. Elsevier; 2020; 6. Armstrong PW et al. JACC Heart Fail.
2018;6:96–104; 7. Follmann M et al. J Med Chem. 2017;60:5146–5161; 8. Mathar I et al. Circulation. 2018;138:A15553. 13
Summary

In the real-world setting, 1 in 6 patients with HFrEF develop worsening HF within

18 months of HF diagnosis1

It is important to optimize existing HF treatment to delay the development of

worsening HF or its complications1

New options are required for patients following worsening HF events to improve
outcomes1

Vericiguat restores the impaired NO–sGC–cGMP pathway, leading to improved

myocardial and vascular function in HF2‒9

cGMP, cyclic guanosine monophosphate; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; NO, nitric oxide; sGC, soluble guanylate cyclase.
1. Butler J et al. J Am Coll Cardiol. 2019;73:935–944; 2. Gheorghiade M et al. Heart Fail Rev. 2013;18:123–134; 3. Mann DL et al. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 10th edn. Elsevier/Saunders;
2015; 4. Boerrigter G et al. Handb Exp Pharmacol. 2009;191:485–506; 5. Breitenstein S et al. Handb Exp Pharmacol. 2017;243:225–247; 6. Felker G & Mann D. Heart Failure: A Companion to Braunwald’s Heart Disease. Elsevier;
2020; 7. Armstrong PW et al. JACC Heart Fail. 2018;6:96–104; 8. Follmann M et al. J Med Chem. 2017;60:5146–5161; 9. Mathar I et al. Circulation. 2018;138:A15553.
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