Topic Discussion During Internal Medicine Rotation

1. 1
Classification of HF based on American Heart Association (AHA) stages (above)
or New York Heart Association (NYHA) classes (below)
Background and Terminology: A low output state
Etiology and Pathophysiology: A filling or ejection problem
Anna Sandler
Heart Failure
PharmD Candidate, 2023
 Heart failure (HF): Progressive, chronic condition in which the heart is
unable to pump blood efficiently and serve the body’s needs.
 2015-2018: ~ 6 million American adults were found to have HF
 One of the leading admission diagnoses worldwide (>1 million US
hospitalizations/year)1
, ~$350 billion US in healthcare expenditure
 High re-hospitalization rates
 ~9% of cardiovascular-related deaths in the US
 Presents with either a reduced (HFrEF) or preserved left ventricular
ejection fraction (LVEF), (HFpEF)
1: Most have cardiovascular comorbid conditions such as arterial hypertension, coronary artery disease, atrial fibrillation, and
about 40% of patients admitted for ADH have a history of diabetes mellitus while one fourth to one third have renal dysfunction
and COPD
2: HFmEF: Heart Failure with Mid-range ejection fraction, which may consist of mixed systolic and diastolic heart failure
HFrEF: </= 40%
Systolic HF
HFmEF2
: 41-49%
HFpEF: >/=50%
Systolic HF
I: No sx II: Mild sx, -
sx at rest
III. Mod. Sx, < normal
physical activity
IV: Severe sx,
sx at rest
A: at-risk B: Pre-HF C: Symptomatic D: Advanced
LVEF
Vasoconstriction
endothelial
dysfunction
Ischemia, valvular
disease,
arrhythmias
Ionotropic
dysfunction
Increased filling
pressures or
volume expansion
Intravascular
congestion
HF
Drug
Target
Compensatory Mechanisms
 HFrEF: Impaired ejection
 HFpEF: Impaired filling due to
inability of ventricles to full relax
CNS
ET-1
NE
cAMP
Myocard.
contractility
RAAS
ANG II
RAAS

2. 2
Mechanism S/sx
Fluid accumulation  Dyspnea, orthopnea,
edema, abdominal
discomfort, exercise
intolerance
 Fluid on CXR
 Increased NT-proBNP
Low output state  Fluid-filled lungs
 Cardiomegaly
 Hypotension
Right-sided heart
failure
 Hepatomegaly
 Elevated Jugular Venous
Pressure
Physical Exam  Pitting edema
HFmEF
Non-pharm
Rusk factors, Presentation, and Diagnosis
Increased
congestion+
adrenergic activity
Increased wall
stretch
Increased ANP
and BNP
Increased NT-
proBNP
 HFpEF rsik factors: Aging, hypertension,
obesity, diabetes
 HFrEF risk factors: Smoking, Ischemic
heart disease
 Right-sided heart failure risk factors:
Left-sided heart failure, congenital
defects
 BNP and NT-proBNP can both assist in
diagnosing HF3
 NT-proBNP preferred
o ARNi: neprilysin degrades BNP
Diagnosis= clinical features + ECHO+ Serum
natriuretic peptides
 NT-proBNP > 125 pg/mL
 BNP >/= 35 pg/mL
General Treatment Principles
HFrEF HFpEF
Guideline-
directed
medical
therapy
(GDMT)
 It is important to identify the cause of
HF
o Genetic, infectious, endocrine,
medications4
 Specific treatments based off HF stages
 Keep in mind level of evidence behind
each recommendation
ARNi: Angiotensin receptor-neprilysin inhibitor BNP: B-type natriuretic peptide; ECHO: echocardiogram, NT-proBNP: N-terminal pro-BNP
3. Not useful in patients with renal insufficiency due to accumulation-no clear cut-off values. Obesity is also associated with lower levels, reducing
diagnostic sensitivity. There is also insufficient evidence for utilizing serial measurements for guiding treatments. Rather these levels can help assist
diagnosis when the cause of dyspnea is unclear. Other causes may include myocarditis, renal failure, and atrial fibrillation.
4. These medications may include chemotherapies that cause cardiotoxicity (e.g., doxorubicin), TNF-alpha inhibitors

3. 3
Stage B
LVEF </= 40%
ACEi or ARB
Evidence-based
BB
Metoprolol
succinate
Carvedilol
Bisoprolol
Recent MI or
ACS
Statin
Heart Failure with Reduced Ejection Fraction: Stage B-Pre-HF
Recall: This stage represents clinically asymptomatic structural and functional cardiac abnormalities that increase
risk of developing symptomatic HF
Goal: Prevent symptomatic HF in patients with structural and functional cardiac abnormalities
ACS: Acute coronary syndrome; ACEi: Angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; BB: Beta
Blocker
CV: Cardiovascular; CVD: Cardiovascular disease; DMII: Diabetes Type II; MI: Myocardial infarction; SGLT2i: Sodium-Glucose 2
transport inhibitor
Heart Failure with Reduced Ejection Fraction: Stage A-At risk for HF
 Blood pressure control
 SGLT2i to prevent hospitalizations
o DMII + CVD or high-CV risk
 Regular physical activity
 Weight control

4. 4
Drug/Class Initial Dosing Target Dosing7
Indication and
Pearls
Mortality benefit
?
ACE inhibitors Lisinopril: 2.5-5 mg
PO once daily
Enalapril: 2.5 mg PO
BID
Lisinopril: 20-40 mg
PO once daily
Enalapril: 10-20 mg
PO BID
When ARNi is not
feasible
NYHA II-IV (C-1, A)
Angiotensin
receptor blockers
Losartan: 25-50 mg
PO once daily
Valsartan: 20-40 mg
once daily
Losartan: 50-150 mg
PO once daily
Valsartan: 160 mg
PO BID
Used in patients
intolerant to ACEi or
ARNi (C-1, A)
Angiotensin
receptor and
Neprilysin Inhibitor:
Sacubitril/Valsartan
49 mg/51 mg PO BID 97 mg/ 103 mg PO
BID
Sx+ NYHA II-III
36-hour washout
period required
when switching
from an ACEi
(C-1, A)
PARADIGM-HF
trial
Beta Blockers Carvedilol: 3.125 mg
PO BID
Carvedilol: 25-50
mg PO BID
Current or previous
sx (C-1, A)
Heart Failure with Reduced Ejection Fraction: GDMT
Heart Failure with Reduced Ejection Fraction: Stages C and D-Roadmap
Routine assessment, optimization, and titration
MRA
SGLT2i
ACEi, ARB, or ARNi
PRN diuretics5
Persistent sx,
LVEF </= 40%
GDMT: Titrated as appropriate very 1-2
weeks
Hydralazine +
Isosorbide dinitrate
ICD
CRT
Refractory
(Stage D)
Palliative care
Transplant
BB
Consider Additional Txs

5. 5
Metoprolol
succinate: 12.5-25
mg PO once daily
Metoprolol: 200 mg
PO once daily
Do not delay
therapy even when
patients are asx
COPERNICIS
MERIT-HF trials
MRA Spironolactone:
12.5-25 mg PO once
daily
Eplerenone: 25 mg
PO once daily
Spironolactone: 25-
50 mg PO once daily
Eplerenone: 50 mg
PO once daily
NYHA II-IV
eGFR > 30
mL/min/1.73m2
K < 5.0 mEq/L
(C1-A)
(C-1, A)
RALES and
EMPHASIS-HF
trials
SGLT2i Dapagliflozin: 10 mg
PO once daily
Empagliflozin: 10 mg
PO once daily
N/A Symptomatic,
chronic HFrEF
(C-1, A)
EMPEROR-
REDUCED
DAPA-HF
Loop diuretics Bumetanide: 0.1-1.0
mg once or twice
Furosemide: 20-40
mg once or twice
Torsemide: 10-20
mg once
Bumetanide total
daily dose (TDD):
10mg
Furosemide TDD:
600 mg
Torsemide: 200 mg
Monitoring: Renal
function, CMP, BP,
relief of congestion
The OPTIMIZE HF
study6
Reduced 30-day
mortality and
hospitalizations
Improved QOL
Thiazide diuretics Chlorthalidone:
12.5-25 mg once
Hydrochlorothiazide
(HCTZ): 25 mg once
or twice
Chlor: 100 mg
HCTZ: 200 mg
Congestive sx+
unresponsive to
loop diuretics
Drug Initial dose Target Dose Indication and Pearls Mortality Benefit?
Isosorbide
dinitrate
and
hydralazine
Fixed dose:
20 mg/37.5
mg PO TID
Fixed dose: 40
mg/75 mg TID
African American+ NYHA
III-IV + GDMT OR if
unable to receive ARNi,
ACEi, or ARB (2b, C)
Lots of ADRs and thus
low usage
Monitoring: hypotension,
palpitations, dizziness,
fluid/Na retention,
bradycardia,
V-HeFT I and A-HeFT
trials8
Heart Failure with Reduced Ejection Fraction: Hydralazine+ Isosorbide Dinitrate
CMP: Complete metabolic panel; K: Potassium; MRA: Mineralocorticoid receptor antagonist;
5. Consider maintenance diuretics in any patient with a history of congestion in order to avoid recurrent symptoms.
6. Non-randomized registry trial
7. Doses should be titrated to prevent the CV outcomes of HF, rather than to achieve a specific goal (e.g, BP)
8. However, benefit in these trials was seen at doses higher than what is typically used in practice with short-acting nitrates.
Heart Failure with Reduced Ejection Fraction: Additional Medical Therapies for Stage C

6. 6
Drug/MOA Starting Dose Target Dose Indications and
Pearls
Mortality
benefits?
Ivabradine/If
Channel Inhibitor
within sinoatrial
note 
prolonged
depolarization
and slowed
firing reduced
HR
5 mg PO BID 7.5 mg PO BID NYHA II-III + LVEF
</=35% + GDMT
w/ max dose BB+
NSR + HR >/=70
BPM (2a, B-R)
Monitoring: HR,
BP, EKG (afib)
CI in heart black,
concomitant use
with strong
CYP3A4 inhibitors
SHIFT trial:
Greatest benefit
in hospitalizations
Benefit results
from the
reduction in HR
Digoxin 0.125-0.25 mg PO
daily
Individualize
doses to maintain
conc. 0.5-< 0.9
ng/mL
Symptomatic
HFrEF despite
GDMT (2b-BR)
May decrease
hospitalizations
The DIG trial
Vericiguat
Guanylyl cyclase
stimulator
increased
cGMP
vasodilation,
improved
endothelial
function
2.5 mg PO once
daily
10 mg PO once
daily
NYHA II-IV; LVEF <
45%; recent
hospitalization or
IV diuretic use;
elevated NP levels
GDMT/intolerance
(2b, B-R)
Monitoring: BP,
daily weights
Warning: Not
studied in
patients with
longer-acting
nitrates or PDE-5
inhibitors
VICTORIA trial:
Reduction in
composite of
hospitalizations
or CV-death

7. 7
Symptomatic
HFmEF
PRN diuretics
SGLT2i
ACEi, ARB, or
ARNi
MRA
BB
Symptomatic
HFpEF
PRN diuretics
SGLT2i
ARNi
MRA
ARB
Drug Indications Evidence and
Pearls
SGLT2i:
Empagliflozin
2a, B-R
Reduce HF
hospitalizations
+CV mortality
EMPEROR
Preserved
trial
MRA 2b, B-R
Reduce HF
hospitalizations
TOP-CAT trial
ARB 2b, B-R
Reduce HF
hospitalizations
CHARM Trail
ARNi 2b, B-R
Reduce HF
hospitalizations
PARAGON-HF
trial
Drug Recommendation Evidence and Pearls
SGLT2i:
Empagliflozin
2a, B-R
Reduce HF
hospitalizations
+CV mortality
EMPEROR
Preserved trial
BBs: Evidence-
based
2b, B-NR
Reduce HF
hospitalizations
+CV mortality
ACEi, or ARB 2b, B-NR
Reduce HF
hospitalizations
+CV mortality
CHARM Trail
ARNi 2b, B-NR
Reduce HF
hospitalizations
+CV mortality
PARAGON-HF trial
MRA 2b, B-NR
Reduce HF
hospitalizations
+CV mortality
TOP-CAT trial
(+) HTN pts.
What about dapagliflozin?
What are the limitations and errors
associated with post-hoc analyses?
RCT: Randomized controlled trials
Heart Failure with Mildly Reduced or Preserved Ejection Fraction
 No prospective RCTs
 Patients on lower end of LVEF spectrum (LVEF 41-49%)
respond similarly as HFrEF patients
 Patients should have repeat LVEF evaluation to determine
trajectory of disease process
 Titrate medications to achieve BP targets
 Manage comorbidities (e.g., atrial fibrillation) to
improve sx

8. 8
HF Drug 2017 Recommendation 2022 recommendation
HFrEF ARNi ARNi only if cannot do
ACEi or ARB
ARNi > ACEi or ARB
HFrEF SGLT2i ? SGLT2i as initial GDMT
HFpEF SGLT2i ? SGLT2i could be used
HFpEF ACEi, ARB BBs May be considered
(2b-C)
May be reasonable (2b-
BR) – the BBs
HFpEF MRA ? May be considered
but confirmatory
studies needed
Might be considered to
decrease
hospitalizations (2b-BR)
1. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the
2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the
American College of Cardiology/American Heart Association Task Force on Clinical
Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6).
doi:10.1161/CIR.0000000000000509
2. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the
Management of Heart Failure. Journal of the American College of Cardiology.
2022;79(17):e263-e421. doi:10.1016/j.jacc.2021.12.012
3. Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin–Neprilysin Inhibition in
Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2019;381(17):1609-1620.
doi:10.1056/NEJMoa1908655
4. McMurray JJV, Packer M, Desai AS, et al. Angiotensin–Neprilysin Inhibition versus
Enalapril in Heart Failure. N Engl J Med. 2014;371(11):993-1004.
doi:10.1056/NEJMoa1409077
5. Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with
Empagliflozin in Heart Failure. N Engl J Med. 2020;383(15):1413-1424.
doi:10.1056/NEJMoa2022190
6. Wollert KC, Drexler H. Carvedilol Prospective Randomized Cumulative Survival
(COPERNICUS) Trial: Carvedilol as the Sun and Center of the β-Blocker World?
Circulation. 2002;106(17):2164-2166. doi:10.1161/01.CIR.0000038702.35084.D6
7. Taylor AL, Ziesche S, Yancy C, et al. Combination of Isosorbide Dinitrate and
Hydralazine in Blacks with Heart Failure. N Engl J Med. 2004;351(20):2049-2057.
doi:10.1056/NEJMoa042934
8. Malik A, Brito D, Vaqar S, Chhabra L. Congestive Heart Failure. In: StatPearls.
References
Blast from the Past: What has changes from the 2017 Focused Update Guidelines?

9. 9
StatPearls Publishing; 2022. Accessed September 7, 2022.
http://www.ncbi.nlm.nih.gov/books/NBK430873/
9. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart
Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008.
doi:10.1056/NEJMoa1911303
10. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised
Intervention Trial in-Congestive Heart Failure (MERIT-HF). The Lancet.
1999;353(9169):2001-2007. doi:10.1016/S0140-6736(99)04440-2
11. Cohn JN, Archibald DG, Ziesche S, et al. Effect of Vasodilator Therapy on Mortality in
Chronic Congestive Heart Failure. N Engl J Med. 1986;314(24):1547-1552.
doi:10.1056/NEJM198606123142404
12. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic
heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved
Trial. Lancet. 2003;362(9386):777-781. doi:10.1016/S0140-6736(03)14285-7
13. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in Heart Failure with a Preserved
Ejection Fraction. N Engl J Med. 2021;385(16):1451-1461.
doi:10.1056/NEJMoa2107038
14. Zannad F, McMurray JJV, Krum H, et al. Eplerenone in Patients with Systolic Heart
Failure and Mild Symptoms. N Engl J Med. 2011;364(1):11-21.
doi:10.1056/NEJMoa1009492
15. Fonarow GC, Abraham WT, Albert NM, et al. Organized program to initiate lifesaving
treatment in hospitalized patients with heart failure (OPTIMIZE-HF): rationale and
design. American Heart Journal. 2004;148(1):43-51. doi:10.1016/j.ahj.2004.03.004
16. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for Heart Failure with Preserved
Ejection Fraction. N Engl J Med. 2014;370(15):1383-1392.
doi:10.1056/NEJMoa1313731
17. The Effect of Digoxin on Mortality and Morbidity in Patients with Heart Failure. N Engl
J Med. 1997;336(8):525-533. doi:10.1056/NEJM199702203360801
18. Pitt B, Zannad F, Remme WJ, et al. The Effect of Spironolactone on Morbidity and
Mortality in Patients with Severe Heart Failure. N Engl J Med. 1999;341(10):709-717.
doi:10.1056/NEJM199909023411001
19. Armstrong PW, Pieske B, Anstrom KJ, et al. Vericiguat in Patients with Heart Failure
and Reduced Ejection Fraction. N Engl J Med. 2020;382(20):1883-1893.
doi:10.1056/NEJMoa1915928
UpToDate Link
https://www.uptodate.com/contents/natriuretic-peptide-measurement-in-heart-
failure?search=bnp%20and%20probnp&source=search_result&selectedTitle=1~150&usage_type=defaul
t&display_rank=1#H4

10. 10
Picture Links
https://www.nhlbi.nih.gov/health/heart-failure/causes
https://www.verywellhealth.com/congestive-heart-failure-vs-heart-failure-5212245
http://clipart-library.com/free/female-runners-silhouette.html
https://www.heartandstroke.ca/healthy-living/healthy-eating/healthy-eating-basics