Biykem Bozkurt, MD, PhD Baylor College of Medicine

1. Biykem Bozkurt, MD PhD, FHFSA, FACC, FAHA, FESC
Associate Provost for Faculty Affairs, Senior Associate Dean for Faculty Development
The Mary and Gordon Cain Chair & Professor of Medicine
Director, Winters Center for HF Research, Associate Director, Cardiovascular Research Institute
Baylor College of Medicine, Houston, TX
Medicine Chief, Michael E. DeBakey VA Medical Center
Past President, Heart Failure Society of America
@BiykemB
Update in HF Definition and Classification:
Universal Definition and Stages of HF (UDHF)
Treatment Implications and Knowledge Gaps

2. • Clinical Event Committee: Abbott, GUIDE HF
Trial
• Consultation: scPharmaceuticals, Amgen, Vifor,
• Relypsa, Respicardia
• DSMC: Anthem Trial, Liva Nova
Disclosures

3. Universal Definition of HF (UDHF)
Chinese Heart Failure Association
Bozkurt, et al. Universal Definition and Classification of Heart Failure, Journal of Cardiac Failure, 2021

4. Overarching
definition
EF Phenotype
Stages
Syndrome dx,
Trials,
Research
Successful
GDMT
Initially to
Emphasize
Prevention
Existing Definitions and Classifications

5. “Textbook” definition :
“A clinical syndrome caused by the inability of the
heart to meet tissue metabolic requirements”
Former Definitions of Heart Failure

6. Heart failure is a condition in which the heart can't pump enough blood
to meet the body's needs.
Circa 1977: “Abnormality of cardiac structure or function leading to failure of the heart to deliver oxygen at a rate
commensurate with the requirements of the metabolizing tissues”
Wagner S, Cohn K. Heart failure. A proposed definition and classification. Arch Intern Med 1977;137:675–678.
Braunwald E. Heart failure. JACC Heart Fail 2013;1:1–20
Francis GS, Wilson Tang WH, Walsh RA. Pathophysiology of heart failure. In: Fuster V, Walsh RA, Harrington RA, eds. Hurst’s The Heart, 13th ed; 2011.pp719–738
Adamo L, Nassif ME, Novak E, LaRue SJ, Mann DL. Prevalence of lactic acidemia in patients with advanced heart failure and depressed cardiac output. Eur J Heart Fail. 2017;19(8):1027‐1033
1 %
Few HF Patients Meet the Historical HF Definition:

7. HF is a syndrome caused by cardiac dysfunction,
generally resulting from myocardial muscle
dysfunction or loss and characterized by either LV
dilation or hypertrophy or both. Whether the
dysfunction is primarily systolic or diastolic or
mixed, it leads to neuro-hormonal and circulatory
abnormalities, usually resulting in characteristic
symptoms such as fluid retention, shortness of
breath, and fatigue, especially on exertion.
HF is a complex clinical syndrome that results
from any structural or functional impairment of
ventricular filling or ejection of blood
HF is a clinical syndrome characterized by typical
symptoms (e.g. breathlessness, ankle swelling and
fatigue) that may be accompanied by signs (e.g.
elevated jugular venous pressure, pulmonary
crackles and peripheral oedema) caused by a
structural and/or functional cardiac abnormality,
resulting in a reduced cardiac output and/or
elevated intracardiac pressures at rest or during
stress.
Heart failure is defined as a clinical syndrome
consisting of dyspnea, malaise, swelling and/or
decreased exercise capacity due to the loss of
compensation for cardiac pumping function due
to structural and/or functional abnormalities of
the heart
HF Definition in Guidelines Differed

8. ICD-10-CMP I42.9:
 Cardiomyopathy (familial) (idiopathic) I42.9
 secondary I42.9
 idiopathic I42.9
 primary (idiopathic) I42.9
 Myocardiopathy (congestive) (constrictive) (familial)
(hypertrophic nonobstructive) (idiopathic) (infiltrative)
(obstructive) (restrictive) (sporadic) I42.9
CMP
Stage
C/D
ICD-10-HF I50: Coding guidance states first code following
 HF complicating abortion or ectopic pregnancy
 HF due to hypertension (I11.0);
 HF due to hypertension with CKD (I13.-);
 rheumatic heart failure (I09.81)
 HF following surgery
 I50.2: Systolic (congestive) heart failure
 I50.4 Combined systolic (congestive) and diastolic (congestive)
heart failure
No code for at-risk for HF or pre-HF
• to capture Stage A /at-risk / preHF prevalence
• to treat for specific risk
At-risk
for
HF
Stage
A
Stage
B
Stage
C/
D
Chaos in Documentation/Administrative Coding

9. 83
79.8
85.1
73.4
66.3
61.7
54
86.2
92.2
67
80.2 81.7
43
34.4
60.3
33.4 33.7
35.7
13 13.6
19.8
0
20
40
60
80
100
EuroHeart GDMT Among
Indicated %
IMPROVE-Baseline GDMT Use
%
IMPROVE- GDMT Use 24
Months Post Intervention %
CHAMP Original-Baseline
GDMT Use Among Eligible
Patients %
CHAMP Longitudinal- Baseline
GDMT Use Among Eligible
Patients (%)
CHAMP Longitudinal- GDMT
Use at 12 Months Among
Eligible Patients (%)
2001 2009 2009 2017 2017 2017
Prescription Rates for HF Medications in Heart Failure Registries
ACEI/ARB BB MRA ARNI
Bozkurt B. J Am Coll Cardiol. 2019 May 21;73(19):2384-2387
Failure: Treatment of HF in the Last 2 Decades

10. Major Criteria (need 1 or more)
• Acute pulmonary edema
• Cardiomegaly
• HJR
• JVD
• PND/Orthopnea
• Rales
• S3
Minor Criteria (need 2 or more)
• Ankle edema
• Dyspnea on exertion
• Hepatomegaly
• Nocturnal cough
• Pleural effusion
• Tachycardia (HR > 120)
Clinical Trials: Framingham Criteria
Episodes of Care: Hospitalization, ER visits
Objective Criteria: NP levels

11. Other Disease Definitions with Objective
Quantitative Markers
• BP consistently higher than 130/80
Hypertension
• Fasting glucose ≥126 mg/dL or non-fasting ≥200 mg/dL or Hb A1c ≥6.5%
Diabetes
• eGFR <60 ml/min/1.73m2 on at least 2 occasions 90 days apart
CKD
• GOLD grades by FEV1 % predicted thresholds
COPD
• BMD ≥2.5 SD below the normal mean for young-adult women
Osteoporosis:

12. European Heart Journal (2021) 42, 2331–2343

14. Symptoms and/or signs
of HF caused by a
structural and/or
functional cardiac
abnormality
Elevated natriuretic
peptide levels
Objective evidence of
cardiogenic pulmonary or
systemic congestion
and corroborated by at least one of the following
or
HF is a clinical syndrome with current
or prior
• Symptoms and or signs caused by a
structural and/or functional cardiac
abnormality (as determined by EF<50%, abnormal cardiac
chamber enlargement, E/E’ >15, moderate/severe ventricular
hypertrophy or moderate/severe valvular obstructive or regurgitant
lesion)
• and corroborated by at least one of the
following:
 elevated natriuretic peptide levels
 objective evidence of cardiogenic pulmonary
or systemic congestion by diagnostic
modalities such as imaging (e.g. by CXR or elevated
filling pressures by echocardiography) or hemodynamic
measurement (e.g. right heart catheterization, PA
catheter) at rest or with provocation (e.g. exercise)
Bozkurt, et al. Universal Definition and Classification of Heart Failure, Journal of Cardiac Failure, 2021, ISSN 1071-9164, https://doi.org/10.1016/j.cardfail.2021.01.022.
The Universal Definition of HF UDHF)

15. Stage A
• At high risk for HF but without structural heart disease or
symptoms of HF
Stage B
• Structural heart disease but without signs or symptoms of HF
Stage C
• Structural heart disease with prior or current symptoms of HF
Stage D
• Refractory HF requiring specialized interventions
Yancy CW, et al. Circulation. 2013;128(16):e240-327.
ACC/AHA HF Stages

16. HEALTHY
AT RISK
(STAGE A)
PRE-HF
(STAGE B)
Treatment Strategies According to Stages of HF
HF (STAGE C)
Risk
Treatment
Primordial
Prevention
Specific for risk:
SGLT2i for DM,
ACEi/ARB/
thiazide +LSM
for HTN
GDMT
for LVSD
BB, ACEi/
ARB, ICD
GDMT for HF: BB,
ACEI/ARB, ARNi,
MRA, ICD, SGLT2i,
Hyd+ISDN
Vericiguat
Reverse
remodeling
/
neurohormonal
antagonism
Treatment
for
symptoms.
reverse
remodeling
/
neurohormonal
antagonism
Specific for etio,
risk/ injury/
stretch
neurohormonal
antagonism
Higher
Risk
Treatment
HIGHER RISK
PHENOTYPE
NT-proBNP
microalbumiuria

17. Persistent Heart
Failure
AT-RISK FOR
HEART FAILURE
(STAGE A)
PRE-HEART
FAILURE
(STAGE B)
HEART FAILURE
(STAGE C)
ADVANCED
HEART FAILURE
(STAGE D)
Patients with HTN,
CVD, DM, obesity,
known exposure to
cardiotoxins, family
history of
cardiomyopathy
Patients without
current or prior
symptoms or signs of
heart failure but
evidence of one of the
following
Patients at risk for HF
but without current or
prior symptoms or
signs of HF and
without structural,
biomarker, or genetic
markers of heart
disease. Structural Heart Disease:
e.g. LVH, chamber
enlargement, wall motion
abnormality, myocardial
tissue abnormality, valvular
heart disease
Abnormal cardiac function:
e.g. reduced LV or RV
ventricular systolic function,
evidence of increased filling
pressures or abnormal
diastolic dysfunction
Elevated natriuretic peptide
levels or elevated cardiac
troponin levels in the setting
of exposure to cardiotoxins
Patients with current
or prior symptoms
and/ or signs of HF
caused by
Severe symptoms and/
or signs of HF at rest,
recurrent
hospitalizations despite
GDMT, refractory or
intolerant to GDMT
structural and/or
functional cardiac
abnormality
requiring advanced
therapies such as
consideration for
transplant, mechanical
circulatory support, or
palliative care
with GDMT and risk factor modification
Heart
Failure in
Remission
Bozkurt, et al. Universal Definition and Classification of Heart Failure, Journal of Cardiac Failure, 2021,
ISSN 1071-9164, https://doi.org/10.1016/j.cardfail.2021.01.022.
Universal Definition Stages of HF

18. European Heart Journal (2021) 42, 2331–2343

19. European Heart Journal (2021) 42, 2331–2343
Asymptomatic+ NP elevation already defined
in UDHF
=Pre-HF Stage (Stage B)

20. New onset/ de novo
HF:
• Newly diagnosed HF
• No former history of
HF
Worsening HF:
• Worsening
symptom/signs/
functional capacity,
and/or requiring
escalation of
therapies such as IV
or other advanced
therapies
• and/or
hospitalization
Improving HF:
• Improving
symptoms/signs and
or functional
capacity
Persistent HF:
• Persistent HF with
ongoing
symptoms/signs and
or limited functional
capacity
HF in Remission:
• Resolution of
symptoms and signs
of HF, with
resolution of
previous
structural/functional
heart disease after a
phase of
symptomatic HF
Do not use
“Recovered HF”
instead, use “HF in
Remission”
Do not use
“Stable HF”,
instead,
use “Persistent”
Bozkurt, et al. Universal Definition and Classification of Heart Failure, Journal of Cardiac Failure, 2021,
ISSN 1071-9164, https://doi.org/10.1016/j.cardfail.2021.01.022.
Other Clinical Trajectory Terminologies in HF

21. • HF with LVEF ≤ 40%
HF with reduced EF (HFrEF):
• HF with LVEF 41-49%
HF with mildly reduced EF (HFmrEF):
• HF with LVEF > 50%
HF with preserved EF (HFpEF):
• HF with a baseline LVEF ≤ 40%, a ≥ 10 point increase from
baseline LVEF, and a second measurement of LVEF > 40%
HF with improved EF (HFimpEF):
Bozkurt, et al. Universal Definition and Classification of Heart Failure, Journal of Cardiac Failure, 2021, ISSN 1071-9164.
EF Classification of HF in Universal Definition

22. HFrEF
BB ACEi/ARB/ARNi MRA SGLT2i
Decongest
Current Standard Core Medical Therapy
STAGE C HFrEF

23. Benefit with ARB, MRA, ARNi, SGLT2i in HFrEF & HFmrEF
Spironolactone: TOPCAT
Solomon et al, 2016
EHJ ARB: CHARM-PRESERVED
Lund L et al, EJHF, 2018
ARNI: PARAGON-HF.
Solomon et al, Circulation, 2020
EMPEROR PRESERVED and PARAGON
Packer Circulation. 2021;143:337–349

24. Benefit higher in lower LVEF
Bozkurt & Ezekowitz Circulation. 2020;141:362–366. DOI:
10.1161/CIRCULATIONAHA.120.045008

25. Anker et al NEJM 2021 DOI: 10.1056/NEJMoa2107038
~3000 pts NYHA Class II-IV HF, LVEF > 40 % elevated BNP
ARNi (sacubitril valsartan) vs valsartan
HFpEF: EMPEROR-Preserved Trial
HR 0.79
(95% CI 0.69, 0.90)
P = 0.0003
Placebo:
511 patients with event
Rate: 8.7 per 100 patient-years
20
15
10
5
0
Estimated
Cumulative
Incidence
(%)
Placebo
Empagliflozin
Empagliflozin:
415 patients with event
Rate: 6.9 per 100 patient-years
NNT=31
RRR
21%
During a median
trial period of
26 months.

26. HR (95% CI)
Empagliflozin Placebo
n with event/N analysed
415/2997 511/2991 0.79 (0.69–0.90)
258/2298
157/699
319/2321
192/670
0.81 (0.68–0.95)
0.73 (0.59–0.90)
157/1079
258/1917
177/1038
334/1953
0.85 (0.69–1.06)
0.75 (0.64–0.89)
Overall
HF hospitalization in ≤12 months
No
Yes
Cause of HF
Ischaemic
Non-ischaemic
Baseline NYHA class*
II
III/IV
275/2435
140/562
361/2452
150/539
0.75 (0.64–0.87)
0.86 (0.68–1.09)
Baseline LVEF
<50%
≥50% to <60%
≥60%
145/995
138/1028
132/974
193/988
173/1030
145/973
0.71 (0.57–0.88)
0.80 (0.64–0.99)
0.87 (0.69–1.10)
Baseline NT-proBNP (calculated by AF/flutter status)
126/1477
288/1516
168/1508
341/1476
0.76 (0.61–0.96)
0.78 (0.67–0.91)
<Median
≥Median
Baseline use of MRA
No
Yes
233/1878
182/1119
306/1866
205/1125
0.73 (0.62–0.87)
0.87 (0.71–1.06)
Baseline use of ACE-inhibitor, ARB or ARNI
No 90/569 121/587
Yes 325/2428
*NYHA class I are counted in class II
390/2404
0.75 (0.57–0.99)
0.80 (0.69–0.93)
Placebo better
Empagliflozin better
HR (95% CI)
0.25 0.5 1 2
EMPEROR-Preserved-Primary Endpoint:
Effects in Subgroups
P-trend = 0.21

27. EMPEROR-Preserved: HF Total Hospitalizations

28. www.escardio.org/guidelines
©ESC
2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure
(European Heart Journal 2021 – doi:10.1093/eurheartj/ehab368)
Recommendations Class Level
Diuretics are recommended in patients with congestion and HFmrEF in order to
alleviate symptoms and signs.
I C
An ACE-I may be considered for patients with HFmrEF to reduce the risk of HF
hospitalization and death.
IIb C
An ARB may be considered for patients with HFmrEF to reduce the risk of HF
hospitalization and death.
IIb C
A beta-blocker may be considered for patients with HFmrEF to reduce the risk of
HF hospitalization and death.
IIb C
An MRA may be considered for patients with HFmrEF to reduce the risk of HF
hospitalization and death.
IIb C
Sacubitril/valsartan may be considered for patients with HFmrEF to reduce the
risk of HF hospitalization and death.
IIb C
Pharmacological treatments to be considered in patients with
(NYHA class II-IV) heart failure with mildly reduced ejection fraction
ACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; HF = heart failure; HFmrEF = heart failure with mildly reduced ejection fraction; MRA = mineralocorticoid receptor antagonist;
NYHA= New York Heart Association.

29. Gaps
EF was a tool for GDMT Implementation:
Limitations Well- Known
• Historical trial design: Targeting maladaptive mechanisms
associated with phenotypes &severity of HF
• Evidence prompted classification HFrEF &HFpEF categories
• Evolved as a standardization tool in guidelines for targeting
GDMT
• With evolving trial results and design changes, now
includes HFmrEF
• Phenotypic classification, not definition of HF
• Normal varies (not only for women vs men, hypertrophy,
mitral regurgitation)
• Not a reliable tool for phenotypic characterization
HFrEF
HFmrEF
HFprEF

30. Gaps
Future: EF will evolve into LV Systolic Dysfunction
• Benefit signal stronger for LVSD
• If widely available, reproducible, practical modalities to
detect LVSD
• LV global longitudinal strain (or other load independent
indices of contractile performance) and maladaptive LV
remodeling
• LVSD
• rEF, mrEF, impEF and/or
• Reduced LV strain and/or
• LV enlargement : LVESVI, LVEDVI

31. ESC 2021 HF Guidelines Harmonized with
2021 Universal Definition
www.escardio.org/guidelines
©ESC
2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure
(European Heart Journal 2021 – doi:10.1093/eurheartj/ehab368)
Type of HF HFrEF HFmrEF HFpEF
CRITERIA
1 Symptoms ± Signsa Symptoms ± Signsa Symptoms ± Signsa
2 LVEF ≤40% LVEF 41–49%b LVEF ≥50%
3 - - Objective evidence of cardiac structural
and/or functional
abnormalities consistent with the
presence of LV diastolic
dysfunction/raised LV filling pressures,
including raised natriuretic peptidesc
Definition of heart failure with reduced ejection fraction, mildly reduced
ejection fraction and preserved ejection fraction
HF = heart failure; HFmrEF = heart failure with mildly reduced ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection
fraction; LV = left ventricle; LVEF = left ventricular ejection fraction.
aSigns may not be present in the early stages of HF (especially in HFpEF) and in optimally treated patients.
bFor the diagnosis of HFmrEF, the presence of other evidence of structural heart disease (e.g. increased left atrial size, LV hypertrophy or echocardiographic measures of
impaired LV filling) makes the diagnosis more likely.
cFor the diagnosis of HFpEF, the greater the number of abnormalities present, the higher the likelihood of HFpEF.

32. HFrEF
Stage
C-
Specific
Treatment
Modified from Bozkurt et al. Circulation. 2016 Dec 6;134(23):e579-e646
• HTN
• Ischemia
• Amyloidosis
• Valvular Heart disease
• Chemotherapy ,
immunomodulators
• COVID-19, Viral
• Illicit Drugs / ETOH
• Takotsubo/Tachycardia
• Metabolic
• MINOCA /Microvascul.
• RVF, PAH, RV Pacing
• Genetic
• Peripartum
Stage C HFrEF
BB ACEi/ARB/ARNi MRA SGLT2i
Treat Specific Etiology
Diagnose and Treat Specific etiology
Maurer et al.N Engl J Med 2018; 379:1007-1016

33. Practice Implications
First encounter
• Diagnose HF: Use UDHF to diagnose, confirm and
document HF
• Then Classify
• EF CLASSIFICATION: to initiate GDMT
• STAGES
• to initiate appropriate GDMT
• for prevention and treatment
• prognosis, communication with patient and referral

34. Practice Implications
Subsequent encounter
• HF Trajectory:
• Improving: Optimize GDMT
• Worsening: Optimize GDMT, consider referral
• Persistent (do not use stable HF): Optimize GDMT
• In Remission (do not use Recovered HF): Continue GDMT
• Reassess classification if symptoms/signs change or indicated for
new therapies:
• EF re-classification
• HFrEF HFrEF, HFmrEF, HFimpEF (not HFpEF or recovered EF)
• HFpEFHFrEF, HFmrEF, HpEF
• Stages reclassification to determine GDMT prognosis and referral

35. Implementation Steps for Standardization in Care
Coding and Documentation
• ICD codes to harmonize
• HF diagnosis
• Stages
• EF Classifications
Registries, administrative databases, research
• Reflect new definitions and classifications
• Payer /coverage to recognize complexity
• Quality measures and performance indicators
Timely updates in definitions as concepts and evidence evolve

36. Mentz R and Lala A. https://doi.org/10.1016/j.cardfail.2021.02.004
New Definition- Stakeholders

37. Standardization
of HF syndrome
definition
Symptoms / signs caused by
a structural / functional
cardiac abnormality and
corroborated by at least
one of the following:
• elevated NP levels
• objective evidence of
congestion by diagnostic
modalities
•to enhance
appropriate diagnosis
and optimization of
GDMT
•achieve uniformity of
care
New revised
classification of
HF
- At Risk for HF,
- Pre-HF
- HF
- Advanced HF
Easy to understand by
patients and clinicians
Clarify treatment
indications for pre-HF as
well as HF
EF
Classifications
HFrEF: LVEF ≤ 40%
HFmrEF : LVEF 41-49%
HFpEF: LVEF > 50%
HFimpEF: LVEF ≤ 40%, ≥
10 point , subsequent
LVEF>40%
Standardization & clarity
for treatment indications
Emphasis for improved,
not recovered EF
Trajectories
Persistent HF rather
than stable HF
HF in remission rather
than recovered HF
Summary: UDHF