2. Content
Introduction
•Classification of HF
•Stages of HF
Pathophysiology of ADHF
Diagnosis of acute heart failure
Risk and Challenge of ADHF
Preventing Heart Failure Readmissions:
A 3-phase Strategy
Impact of cardiac remodeling in ADHF patients
Evidence of ARNI in ADHF
3. Introduction
• Incidence of in-hospital mortality among patients admitted to the hospital for decompensated
heart failure is 6.4%
• In individuals aged 65 to 69 years, the prevalence of heart failure is roughly 20 per 1000,
• Among people >65 years of age presenting to primary care with breathlessness on
exertion, one in six will have unrecognized HF (mainly HFpEF)
• Prevalence jumps to more than 80 per 1000 in individuals older than 85 years.
Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure. Nat Rev Cardiol. 2011;8(1):30-41. doi:10.1038/nrcardio.2010.165
4. Classification of Heart Failure
• HF stages have been revised to emphasize symptomatic nature of HF as a clinical syndrome: At risk for HF (Stage A),
Pre‐HF (new!) (Stage B), Symptomatic HF (Stage C) and Advanced HF (Stage D).
left ventricular ejection fraction (LVEF)
Lam CSP, Yancy C. Universal Definition and Classification of Heart Failure: is it universal? Does it define heart failure? J Card Fail 2021;27:509-11.
6. Véronique L. Roger. Circulation Research. Epidemiology of Heart Failure, Volume: 128, Issue: 10,
Pages: 1421-1434, DOI: (10.1161/CIRCRESAHA.121.318172)
Syndemic framework applied to
heart failure.
• Syndemics is a conceptual framework for
understanding diseases or health conditions that
arise in populations and that are exacerbated by
• Social,
• Economic,
• Environmental,
• Political milieu in which a population is
immersed.
• The integration of social and environmental factors
expands our comprehension of the HF epidemic
beyond the boundaries of disease management
and health systems
7. Diagnosis of acute heart failure
• Early management of AHF should consist of three parts:
• Triage
• Diagnosis and initiation of treatment
• Reassessment
• AHF is a life threatening condition, current guidelines for
the management of AHF recommend that diagnosis and
initiation of treatment should occur as early as possible,
optimally during the first 30–60 min after hospital
admission
Early management of AHF
Eur Heart J Suppl, Volume 18, Issue suppl_G, December 2016, Pages G11–G18, https://doi.org/10.1093/eurheartj/suw044
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8. Clinical evaluation
• Initial clinical evaluation of dyspnoeic patients should help to
• Assess severity of AHF
• Confirm the diagnosis of AHF
• Identify precipitating factors of AHF
• Since congestion is a typical feature of AHF, patient history and physical examination should
primarily focus on the presence of congestion which would support the diagnosis of AHF.
9. Pathophysiology of ADHF
• The pathophysiology of ADHF is pleiotropic
and dependent on a number of factors
including
• Degree of systolic and diastolic cardiac
dysfunction
• Relative involvement of the right and left
ventricles
• Arterial and venous vascular tone
• Neurohormonal and inflammatory
activation state
• Comorbid contributing influences
Joyce N. Njoroge. Circulation Research. Pathophysiology and Therapeutic Approaches to Acute Decompensated Heart Failure, Volume: 128, Issue: 10, Pages:
1468-1486, DOI: (10.1161/CIRCRESAHA.121.318186)
10. Risk and challenge of ADHF
CHALLENGES IN PREDICTING HEART FAILURE READMISSION
• Readmission rate Over 1 million hospitalizations per year for HF in US and Europe
• 24% within 30 days
• 50% within 6 months
• One in 6 patients admitted for HF die within 30 days of hospitalization
• Patients with readmission for cardiovascular disease within 90 days of discharge for HF
hospitalization have a higher risk of mortality independent of the exact amount of time from
discharge
• Levels of cardiac biomarkers including natriuretic peptides and cardiac troponins may also anticipate
readmission risk, particularly if they remain high at hospital discharge.
Joyce N. Njoroge. Circulation Research. Pathophysiology and Therapeutic Approaches to Acute Decompensated Heart Failure, Volume: 128, Issue: 10, Pages:
1468-1486, DOI: (10.1161/CIRCRESAHA.121.318186)
11. PREVENTING HEART FAILURE READMISSIONS:
A 3-PHASE STRATEGY
• The Transition Phase: From Hospital to Home
• The Plateau Phase
• Phase of Palliation and Priorities
Desai AS, Stevenson LW. Rehospitalization for heart failure: predict or prevent? Circulation. 2012 Jul 24;126(4):501-6. doi: 10.1161/CIRCULATIONAHA.112.125435. PMID: 22825412.
Three-phase terrain of lifetime readmission risk after heart
failure hospitalization.
12. High risk features in patients hospitalized with ADHF
(acute decompensated heart failure)
Lower systolic blood pressure
Elevated BUN
Hyponatremia
History of prior heart failure hospitalization
Elevated BNP or NT-proBNP
Elevated Troponin T or I
15. Patterns of ventricular remodeling in HFrEF
Volume overload
Increased diastolic pressure
Increased diastolic wall stress
Series addition of new sarcomeres
Chamber enlargement
–
HFrEF
Left ventricle:
volume
overload
Eccentric hypertrophy
Left ventricle:
normal
Characterized by eccentric hypertrophy resulting in:
Thinning of the LV walls
Decreased systolic function
Enlarged LV volume
HFrEF: Heart failure with reduced ejection fraction; LV: Left ventricle
Adapted from Colucci (Ed.). Atlas of Heart Failure, 5th ed. Springer 2008 Grossman et al. In: Perspectives in Cardiovascular Research;
Reference: Myocardial Hypertrophy and Failure. Vol 7. Edited by Alpert NR. New York: Raven Press;1993:1-15.
HFrEF – a condition of volume overload
16. Prognosis of patients with HF can be evaluated by
monitoring cardiac remodeling with echocardiogram1,2
LV systolic
function
LVEF: Is the most commonly utilized parameter, closely related to CV outcomes and
prognosis1-3
LVEDV or LVEDD: Is a parameter reflecting both LV systolic function and the degree of
structural remodeling1
LVESV or LVESD: Is the best parameter to evaluate the prognosis in patients with
lowered LV function after the occurrence of MI1,2
E/A, ratio of E and A-wave velocities; HF, heart failure; LV, left ventricle; LVEF, left ventricular ejection fraction; LVEDV, left ventricular end diastolic volume; LVEDD, left ventricular end-diastolic diameter; LVESV, left
ventricular end systolic volume; LVESD, left ventricular end systolic volume; MI, myocardial infarction
References: 1. Cohn JN, et al. J Am Coll Cardiol 2000;35:569-582; 2. Konstam MA, et al. JACC Cardiovasc Imaging 2011;4:98-108; 3. Solomon SD, et al. Circ Heart Fail 2016;9:e002744; 4. Ahmed MI, et al. Curr Probl
Cardiol 2009;34(3):93-136; 5. Nagueh SF, et al. J Am Soc Echocardiogr 2016;29(4):277-314.
Shape and
function of valve
Mitral valve regurgitation: Is one of the parameters that evaluates the severity of
mitral valve insufficiency that can be considered as the secondary change of HF4
LV diastolic
function
Mitral inflow: Is one of diastolic dysfunction variables and E/A ratio >2 is evaluated as
the indication of restrictive mitral inflow pattern5
17. Treatment goals for
Acute decompensated heart failure hospitalisation
Improve symptoms of congestion
Optimize volume status
Identify and address triggers for decompensation
Optimize chronic oral therapy
Minimize side effects
Identify patients who benefits from revascularization
Educate patients concerning medications and disease management
18. HF algorithmic treatment
• The primordial goals of HF therapy are the
following:
• Mitigate symptoms and signs
• Prevent first hospital admission and
subsequent readmissions
• Improve survival as well as quality of life.
• Since ADHF corresponds to worsening HF, the
main goal is to compensate the patient, i.e.
treat volume overload and promote transition
towards stabilization.
• On the other hand, the challenging
fundamental strategy in chronic HF is to
maintain stability and avoid decompensation
Rocha BML, Menezes Falcão L. Acute decompensated heart failure (ADHF): A comprehensive contemporary review on
preventing early readmissions and postdischarge death. Int J Cardiol. 2016 Nov 15;223:1035-1044. doi:
10.1016/j.ijcard.2016.07.259. Epub 2016 Aug 3. PMID: 27592046.
21. 21
Closely monitor serum creatinine, and down-titrate or
interrupt sacubitril/valsartan in patients who develop a
clinically significant decrease in renal function. In patients
with renal artery stenosis, monitor renal function.
Monitor serum potassium periodically and treat
appropriately, especially in patients with risk factors for
hyperkalemia such as severe renal impairment, diabetes,
hypoaldosteronism, or a high potassium diet
Permanent discontinuation of sacubitril/valsartan &
Hypotension
therapy is usually NOT required
Every attempt should be made to achieve and maintain patients on the target sacubitril/valsartan &
Hypotension dose level of 200 mg b.i.d.; , however, if the following tolerability issues should occur:
Symptomatic
hypotension
Hyperkalemia
Renal dysfunction
AND
Closely follow up
the event until
resolution
Consider
1. Dose adjustment
of concomitant medications:
- diuretics, antihypertensive drugs,
- treatment of other causes of hypotension
(e.g., hypovolemia)
2. Down titration
or temporary discontinuation of
sacubitril/valsartan
(if adjustment of concomitant medication is
not possible or effective)
Discontinue sacubitril/valsartan immediately and permanently if angioedema occurs, and provide appropriate therapy and monitor for airway compromise.
Sacubitril/valsartan is contraindicated in patients with a history of angioedema related to previous ACEI or ARB therapy. Black patients may have increased
susceptibility to develop angioedema.
Angioedema
• ACEI and ARBs
• Direct renin inhibitors (such as aliskiren) in patients with Type 2 diabetes
Prohibited concomitant
medications
Before local implementation CPOs must ensure compliance with all applicable laws, regulations, local industry codes, and local Novartis companies’ policies.
For full information, guidelines, and references please refer to the local SmPC
ACEI= angiotensin-converting enzyme inhibitor; ARB= angiotensin receptor blocker;
b.i.d.= twice-daily; eGFR= estimated glomerular filtration rate; HF= heart failure
Sacubitril / Valsartan Tolerability Guidelines - Summary
1. Sacubitril/valsartan FDA USA PI. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=000dc81d-ab91-450c-8eae-8eb74e72296f; 2. Sacubitril/valsartan Core Data Sheet Version 1.1. Release date: 10-Aug-2015; 3. Sacubitril/valsartan EMA SmPC. Last
updated 17/03/2016. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004062/WC500197536.pdf
23. Background
23
PARADIGM-HF evaluated the effect of sacubitril/valsartan compared to enalapril
in patients with chronic HFrEF in delaying time to first occurrence of either CV
death or HF hospitalization3
• Patients were required to be on stable GDMT for HF for at least 4 weeks
• Patients with Acute Decompensated HF were excluded from PARADIGM-HF4
a Retrospective study of Medicare fee-for-service beneficiaries aged 65 years or older hospitalized with HF
b Based on survey data on hospitals that enrolled in either of 2 national quality initiatives to reduce readmission (ie, the Hospital to Home [H2H] National Quality
Improvement Initiative or the State Action on Avoidable Rehospitalizations Initiative [STAAR]) by July 1, 2010
HFrEF, Heart Failure with Reduced Ejection Fraction. CV, Cardiovascular. HF, Heart Failure. GDMT, Guideline Directed Medical Therapy.
1. Ambrosy AP. JACC 2014;63:1123-33.
2. Dharmarajan K. JAMA 2017;318(3):270-278.
3. McMurray JJ. NEJM. 2014;371:993-1004.
4. Data on File: PARADIGM-HF Protocol, Novartis Pharmaceutical Corp; December 2010
• Acute decompensated heart failure accounts for over 1M hospitalizations annually in the USa1
• 50%-60% of hospitalized HF population is classified as HFrEF1
• Approximately 25% of HF patients are readmitted within 30 days of dischargeb2
24. PARADIGM-HF
Primary outcome: To demonstrate superiority of sacubitril/valsartan over enalapril in reducing composite
of death from CV causes or a first hospitalization for HF
36 hour washout was required between enalapril and sac/val run-in and prior to randomization
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BID, twice daily; BNP, brain natriuretic peptide; NYHA, New York Heart Association; Sac/val, Sacubitril/valsartan.
aEnalapril 5 mg BID for 1–2 weeks followed by enalapril 10 mg BID was an optional starting run-in dose for patients treated with ARBs or with a low dose of ACEI.
bDosing in clinical trials was based on the total amount of both components of sac/val; 24/26 mg, 49/51 mg, and 97/103 mg were referred to as
50 mg, 100 mg, and 200 mg, respectively. Sac/val was formerly known as LCZ696 in clinical trials.
1. Entresto (sacubitril/valsartan) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2015.
2. McMurray JJ et al. Eur J Heart Fail. 2013;15(9):1062-1073. 3. McMurray JJ et al. N Engl J Med. 2014;371(11):993-1004.
25. PARADIGM-HF
Effects of Sacubitril/Valsartan or Enalapril on NT-proBNP in Patients
with HFrEF
This was an exploratory endpoint of the PARADIGM-HF trial, measured in a subset of the overall trial population
NT-proBNP N-terminal pro–brain natriuretic peptide
Patients in both groups received the same single-blind treatment
Packer M, et al. Circulation. 2015;131:54–61
Data on File, PARADIGM-HF Clinical Study Report, Novartis Pharmaceuticals Corp; October 2014
Study Outcomes
Outcome, n %
Sac/val
(n=4187)
Enalapril
(n=4212)
Hazard ratio*
(95% CI)
p-
value‡
Primary composite outcome
Cardiovascular death or
heart failure hospitalization
914 (21.8)
1117
(26.5)
0.80 (0.73–
0.87)
<0.000
1
CV death as first event 377 (9.0) 459 (10.9)
HF hospitalization as first
event
537 (12.8) 658 (15.6)
Number of patients with events*:
Death from CV causes † 558 (13.3) 693 (16.5)
0.80 (0.71–
0.89)
Hospitalization for HF 537 (12.8) 658 (15.6)
0.79 (0.71–
0.89)
*Calculated with the use of stratified cox proportional-hazard models
‡Two-sided p-values calculated by means of a stratified log-rank test without adjustment for multiple
comparisons
†includes subjects who had heart failure hospitalization prior to death
*analyses of the components of the primary composite endpoint were not prospectively planned to be
adjusted for multiplicity
29. Wachter R et al., TRANSITION primary data poster presentation (P886) at ESC Congress 2018, Munich Germany
30. Wachter R et al., TRANSITION primary data poster presentation (P886) at ESC Congress 2018, Munich Germany
† ≥2 events in any treatment group; MedDRA Version 20.1 has been used for the reporting of preferred terms;
*Number of patients with at least one AE that lead to permanent discontinuation; Fischer’s Exact Test, Full analysis set
31.
32.
33. PIONEER-HF
33
Study Design
*Target Dose
HF, Heart Failure. EF, Ejection Fraction
Velazquez EJ et al. Late Breaker AHA 2018. Chicago, IL, USA November 10-12, 2018.
Sacubitril/valsartan
97/103 mg twice daily*
Enalapril
10 mg twice daily*
vs
In-hospital initiation
Hospitalized with Acute Decompensated HF with Reduced EF
Stabilized
• Evaluate biomarker surrogates of efficacy
• Evaluate safety and tolerability
• Explore clinical outcomes
Study Drug for 8 weeks
Key Entry Criteria
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
N=881
34. In-Hospital Settings(after patients become hemodynamically stable)
GreaterreductionintheNT-proBNPconcentrationfrombaselineto 4and8weeks and
improvedclinical outcomeswithsac/val
ADHF, acute decompensated heart failure; CV,
cardiovascular; HFrEF, heart failure with reduced
ejection fraction; HF, heart failure; HR, hazard ratio; NT-
proBNP, N-terminal pro b-type natriuretic peptide;
sac/val, sacubitril/valsartan
36
HR: 0.58 (95% CI, 0.39 to 0.87) P=0.007
Change in NT-proBNP1 Sac/val Enalapril CV death or re-hospitalization for HF2
Change
in
NT-proBNP
from
baseline
(%)
Percent
of
patients
with
CV
death/HHF
15.2%
9.2%
HR 0.58 (95% CI: 0.39 − 0.87) p=0.007
Ratio of change 0.71 (95% CI: 0.63 − 0.81) p<0.001
10
0
- 10
- 20
- 30
- 40
- 50
- 60
- 70
2 3 4 5
Weeks since randomization
0 1 6 7 8
-25.3%
17.5
15.0
12.5
10.0
7.5
5.0
2.5
0.0
0 3 4 5
Weeks from randomization
1 2 6 7 8
-46.7%
1. Velazquez EJ, et al. NEJM
2019;380:539-548; 2. Morrow et al.
Circulation 2019;139:2285–2288.
35.
36. Clinical implications
• These results support the in-hospital initiation of sacubiteril-valsartan
in stabilized patients with ADHF and reduced EF, irrespective of prior
ACEi/ARB use, or prior HF diagnosis
