PPT describes the pharmacotherapy of heart failure and treatment choices.

1. Heart Failure
Pharmacotherapy
Dr Bedeer Elsherbiny
PharmD MSc BCPS BCMTM
This Photo by Unknown Author is licensed under CC BY

2. Objectives
Definition signs and symptoms of heart failure
Stages and Classifications of heart failure
Diagnosis of heart failure
Drugs to avoid in HF
Goal of therapy of HF
ACCF/AHA Guideline for the Management of Heart Failure
Pharmacologic Treatment of stage B HF with reduced ejection fraction
New agents for heart failure
Pharmacist role in treatment of heart failure

3. What is Heart Failure?
• Fatigue
• Dyspnea
limit exercise tolerance
Fluid Retention
• Pulmonary Congestion
• Peripheral edema
HF is a clinical syndrome that results from any structural or functional impairment of
ventricular filling or ejection of blood,
resulting in insufficient perfusion to meet metabolic demands

4. Heart failure Prescription

5. Classification of heart failure
ACCF/AHA Stages of HF NYHA Functional Classification
A
At high risk for HF but without structural heart
disease or symptoms of HF
(DM, HTN, MS, Atherosclerosis)
None
B
Structural heart disease but without signs or
symptoms of HF(Previous MI,LVH)
I
No limitation of physical activity. Ordinary physical activity does
not cause symptoms of HF.
C
Structural heart disease with prior or current
symptoms of HF
I
No limitation of physical activity. Ordinary physical activity does
not cause symptoms of HF.
II
Slight limitation of physical activity. Comfortable at rest, but
ordinary physical activity results in symptoms of HF.
III
Marked limitation of physical activity. Comfortable at rest, but
less than ordinary activity causes symptoms of HF.
IV
Unable to carry on any physical activity without symptoms of HF,
or symptoms of HF at rest.
D Refractory HF requiring specialized interventions IV
Unable to carry on any physical activity without symptoms of HF,
or symptoms of HF at rest.
ACCF:American College of Cardiology Foundation; AHA, American Heart Association;
HF, heart failure; and NYHA, New York Heart Association.

6. Ejection Fraction
EF
Percentage of how much blood the left ventricle pumps out with each contraction
LVEF is a measure of the percentage of blood ejected during systole in relation to the total end-diastolic volume.
LVEF (percent) = SV / (LV end-diastolic volume) x 100

7. Classification of heart failure
Heart failure with preserved ejection fraction (HFPEF)
• EF(Ejection Fraction) >50%
• Impaired ventricular relaxation and filling
• Old term is diastolic heart failure
• common cause is HTN (60%–89%).
• left ventricular hypertrophy
• Treatment
optimising treatment of comorbidities,
e.g. hypertension, diabetes, and atrial fibrillation.
Heart failure with reduced ejection fraction (HFREF)
• EF(Ejection Fraction) ≤40%
• Contractility of ventricles is impaired
• Old term is systolic heart failure
• Main cause:Coronary artery disease
• left ventricular dilation
• Treatment
pharmacologic treatment to
improve symptoms
decrease morbidity and mortality
• modifying risk factors
stage A
• treating structural heart disease
stage B
• reducing morbidity and mortality
stages C and D
Treatment
Goals

8. Mortality and hospitalization of Heart Failure
Mortality
High mortality rates
In the ARIC study, the 30-day, 1-year, and 5-year case
fatality rates after hospitalization for HF were 10.4%, 22%, and 42.3%, respectively.
HF Mortality After Hospitalization
Jong P et al. Arch Intern Med . 2002 ; 162:1689 ‐94. Gordon HS et al. Am J Cardiol . 2010 ;
105:694 ‐700. O'Conner CM et al. Am Heart J. 2008 ; 156:662 ‐73.
0
10
20
30
40
50
60
30 1
days 5
year years
%
mortality
Hospitalizations
• HF is the primary diagnosis in >1 million
hospitalizations annually.
• Patients hospitalized for HF are at high risk
for all-cause rehospitalization,
with a 1-month readmission rate of 25%.

9. Diagnosis of heart failure
• ECG: gold standard
• N-terminal pro b-type natriuretic peptide (NT-proBNP) is a protein that's an "ingredient" for
making the BNP hormone. Like BNP, your heart makes larger amounts of NT-proBNP when it
has to work harder to pump blood in response to stress or strain
NT-proBNP > 2000 ng/L
Urgent referral to specialist assessment for
echocardiography within two weeks
• NT-proBNP 400-2000 ng/L
refer to specialist assessment and
echocardiography within six weeks
NT-proBNP< 400ng/L HF not confirmed

10. Drugs that May Precipitate or Exacerbate Heart Failure
Negative inotropic,
and weaken cardiac
contractility
calcium antagonist
verapamil and diltiazem
Antiarrhythmics,
flecainide and
dronedarone.
promoting salt or water
retention and increasing
systemic vascular resistance
Non-steroidal anti-
inflammatory drugs
NSAIDs
Corticosteroids
Thiazolidinediones
Pioglitazone
Cardiotoxic
Chemotherapeutic
agents
Anthracyclines
Cyclophosphamide
(high dose)
Fluorouracil
Trastuzumab/
pertuzumab
Mitoxantrone

11. Modify or control risk factors (e.g., HTN, obesity, DM)
Manage structural heart disease
Reduce morbidity and mortality
Prevent or minimize Na and water retention
Eliminate or minimize HF symptoms
Block compensatory neurohormonal activation caused by reduced cardiac output (CO)
Slow progression of worsening cardiac function
Therapy goals of HF

13. Diuretics
Place in therapy: patients with evidence of fluid retention
Short-term benefit (days)
pulmonary congestion, peripheral edema
Intermediate-term benefits (months)
daily symptoms
exercise tolerance
Long-term benefits (months to years):
No benefit on mortality
For hospitalized patient with fluid overload, adjust therapy to achieve 0.5-1 kg of weight loss per day
Loop Diuretics Thiazides
↑ Na excretion by 20%‐25% ↑ Na excretion by 5%‐10%
Maintain effects unless renal
function is significantly impaired
Lose effectiveness in patients with
impaired renal function
Recommendations
Diuretics should be used for relief of symptoms due to volume overload in patients with HF
• K ≥4.0 mEq/L
• Magnesium ≥2.0 mEq/L
• Monitor SCr and renal function to avoid acute
kidney injury with over diuresis
Monitoring

14. Commonly used diuretics in HF
Agent
Oral
Bioavailability
(%)
Initial
Maximal Total
Daily Dose (mg)
Duration of
Action (hr)
Daily Dose
Loop Diuretics (inhibit 20%–25% of sodium reabsorption)
Furosemide 10–67 20–40 mg daily or BID 600 6–8
Bumetanide 80–100 0.5–1 mg daily or BID 10 4–6
Torsemide 80–100 10–20 mg daily 200 12–16
Thiazide Diuretics (inhibit 10%–15% of sodium reabsorption)
Hydrochlorothiazide 65–75 25 mg daily or BID 100 6–12
Metolazone 40–65 2.5 mg daily 20 12–24
Chlorthalidone 64 12.5–25 mg daily 100 24–72
Chlorothiazide 30–50 250–500 daily or BID 2000 6–12

15. Angiotensin Converting Enzyme
Inhibitor (ACEI)
Recommended in all patients
with heart failure with reduced
ejection fraction (HFrEF)
contraindicated to reduce
morbidity and mortality
Contraindications
• Angioedema
• Pregnancy
Precautions
• Low blood pressure (SBP <80 mm Hg)
• Markedly increased serum creatinine
(>3 mg/dL)
• Bilateral renal artery stenosis
• Elevated serum potassium (>5 mEq/L)
Titration: Increase dose every
2 weeks until target or maximum
tolerated dose is achieved
ACE inhibitors also inhibit
kininase and increase levels of
bradykinin, which can induce dry
cough
Recommendations
The use of ACE inhibitors is beneficial for patients with prior or current
symptoms of chronic HFrEF to reduce morbidity and mortality.

16. Angiotensin Converting Enzyme Inhibitor (ACEI)
Monitoring
•SCr and K for 1–2 weeks after initiating therapy or
increasing the dose
•SCr may rise (up to a 30% increase is acceptable)
Adverse Events
•Angioedema (less than 1%)
•Dry cough (20%)
Drug Starting Dosage Target Dosage Maximal Dosage
Captopril 6.25 mg three times daily 50 mg three times daily 50 mg three times daily
Enalapril 2.5 mg twice daily 10 mg twice daily 20 mg twice daily
Lisinopril 2.5–5 mg daily 20 mg daily 40 mg daily
Perindopril 2 mg daily 8 mg daily 16 mg daily
Ramipril 1.25–2.5 mg daily 10 mg daily 10 mg daily
Trandolapril 1 mg daily 4 mg daily 4 mg daily

17. Angiotensin Receptor Blockers ARBs
Reduce morbidity and mortality, especially in
ACE inhibitor–intolerant patients.
ARBs do not inhibit kininase
lower incidence of cough and angioedema
than ACE inhibitors
like ACE inhibitors, ARBs should be given with caution to
patients with
• low systemic blood pressure. (SBP <80 mm Hg)
• renal insufficiency (Scr >3 mg/dL)
• elevated serum potassium (>5.0 mEq/L)
Recommendations
The use of ARBs to reduce morbidity and mortality is recommended in patients with prior or current symptoms of chronic HFrEF
who are intolerant to ACE inhibitors because of cough or angioedema.

18. ARBs and Recommended Dosage
Drug
Starting
Dosage
Target
Dosage
Valsartan
20–40 mg
twice daily
Losartan
25–50 mg
daily
Candesartan 4–8 mg daily 32 mg daily
150 mg daily
160 mg
twice daily

19. β-blockers
Contraindications
• Second- or third-degree atrioventricular (AV) block
• Heart rate <50 beats per minute
• Asthma
Dosing and
administration
considerations
• Recommended agents: , , and .
• Add to existing ACE inhibitor when HF symptoms are stable, and patients are euvolemic.
• Start low and double the dose every 2 weeks to achieve target dose in 8–12 weeks .
• Avoid abrupt discontinuation; can precipitate clinical deterioration
• Improvement in symptoms may take several months
Recommendations
Use of 1 of the 3 beta blockers proven to reduce mortality is recommended for all patients with current or prior symptoms of HFrEF,
unless contraindicated, to reduce morbidity and mortality

20. •monitor in 1–2 weeks
•lower the dose by 50%.
•higher β-blocker doses are associated with greater mortality reduction.
so, if hypotension alone is the problem, try reducing the ACE inhibitor (or another antihypertensive) first.
BP, HR, and symptoms of
hypotension or bradycardia
•monitor in 1–2 weeks
Increased edema or fluid
retention
Fatigue or weakness
Agent Starting Dosage Target Dosage
Bisoprolol 1.25 mg daily 10 mg daily
Carvedilol 3.125 mg twice daily 25 mg twice daily
Carvedilol CR 10 mg daily 80 mg daily
Metoprolol succinate 12.5–25 mg daily 200 mg daily
β-blockers
Monitoring

21. Aldosterone receptor antagonists ARAs :Aldosterone, Eplerenone
Benefits of spironolactone in NYHA class III and IV HF (RALES trial)
• Decrease mortality 30%
• Decrease hospitalizations for HF 35%
Recommendations
recommended in patients with NYHA class II–IV HF and who have LVEF of 35% or less,
unless contraindicated, to reduce morbidity and mortality

22. Aldosterone receptor antagonists ARAs
eGFR ≥ 50 mL/min
Drug Initial Dose Maintenance Dose
Eplerenone 25 mg daily 50 mg daily
Spironolactone 12.5–25 mg daily 25 mg daily or twice daily
eGFR 30‐49 mL/min
Drug Initial Dose Maintenance Dose
Eplerenone 12.5 once daily or every other day 12.5 ‐ 25 mg once daily
Spironolactone 25 mg every other day 25 mg once daily
If potassium rises above 5 mEq/L then treatment should be held for a minimum of 72 hours
until resolution of hyperkalemia (K < 5 mEq/L) and renal insufficiency
Dosage and adjustments

23. Aldosterone receptor antagonists ARAs
• within 2–3 days, 7 days after starting therapy,
• monthly for first 3 months, and every 3 months thereafter.
• If the dose of ACE inhibitor or ARB is increased, restart monitoring.
• Decrease dose by 50% or discontinue if K is greater than 5.5 mEq/L.
K and Scr
• Common with Spironolactone (10% in clinical trials)
• Eplerenone can be considered
Gynecomastia

24. Aldosterone receptor antagonists ARAs
The inappropriate use of aldosterone antagonists is potentially harmful due to
life‐threatening hyperkalemia or renal insufficiency when:
• serum creatinine is > 2.5 mg/dL in men
• serum creatinine is > 2.0 mg/dL in women
• estimated GFR < 30 mL/min
• serum potassium is > 5.0 mEq/L
Recommendations
The inappropriate use of aldosterone antagonists is potentially harmful due to life‐threatening hyperkalemia or renal insufficiency

25. HYDRALAZINE AND ISOSORBIDE DINITRATE
• African Americans with HFrEF who remain symptomatic despite use of ACE inhibitors, beta blockers, and
aldosterone antagonists
Selection of Patients
• 37.5 mg of hydralazine hydrochloride / 20 mg of isosorbide dinitrate 1 Tab TID.
Increase dose to 2 tablets TID
• Max dose :225 mg of hydralazine hydrochloride and 120 mg of isosorbide dinitrate
Initiation and Maintenance.
• Poor adherence large number of pills
Risks of Treatment
• headache
• dizziness
• gastrointestinal complaints.
• slow titration enhance tolerance of the therapy.
Common adverse effects
Recommendations
The combination of hydralazine and isosorbide dinitrate is recommended to reduce morbidity and mortality for African Americans with
NYHA class III–IV HFrEF receiving optimal therapy with ACE inhibitors and beta blockers, unless contraindicated

26. HF Treatment Guidelines

27. Digoxin in heart failure
Consider in patients with continuous
symptoms despite guideline
determined medical therapy (GDMT)
Common dosage 0.125 to 0.25 mg daily
• Do not load in HF
• Ideal plasma concentration 0.5 to 0.9 ng/mL
narrow therapeutic range
Recommendation
Digoxin can be beneficial in patients with HFrEF, unless contraindicated, to decrease hospitalizations for HF

28. Potential Digoxin Complications
Digoxin Toxicity
• Cardiac arrhythmias
• GI complaints: nausea, vomiting
• CNS manifestations
Toxicity can occur at lower levels due to:
• Low K or Mg levels
• Hypothyroidism
• Drugs
Amiodarone, dronedarone, verapamil, clarithromycin, erythromycin
Poor renal function can also elevate digoxin levels

29. Ivabradine
Recommendation
Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic
HFrEF (LVEF ≤35%) who are receiving GDMT, including a beta blocker at maximum tolerated dose, and who are in sinus
rhythm with a heart rate of 70 bpm or greater at rest
Place in Therapy
How does Ivabradine work
• patients with HFrEF with resting heart rate of 70 bpm or greater despite maximum
tolerated beta blocker dose up to target
• who have a contraindication to beta blocker use.
Inhibit the "funny" channel pacemaker current (If) in the sinoatrial node,
resulting in a lower heart rate and thus more blood to flow to the myocardium.

30. Ivabradine
Dosage
The recommended starting dose is 5 mg twice daily with meals,
may increase to 7.5 mg twice a day or decrease to 2.5 mg twice daily
depending on the patient’s heart rate and symptoms.
In patients > 75 years old, a lower starting dose of 2.5 mg twice daily
Treatment must be stopped if the heart rate is persistently below 50 beats per minute or if
symptoms of bradycardia continue despite dose reduction.
When used for angina, treatment should be stopped if symptoms do not improve after 3 months.

31. ARNI (ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITOR)
Sacubitril/Valsartan
Recommendations
In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB,
replacement by an ARNI is recommended to further reduce morbidity and mortality
Attenuate
negative effects
of angiotensin II
by blocking RAAS
system
Valsartan
Boost
positive effects of the
natriuretic
peptides& other
vasodilatory
Peptides by blocking its
degradation
Sacubitril

32. Sacubitril/Valsartan
Contraindications
• History of angioedema due to an ACEI/ARB
• Patients already on an ACEI
• ARNI should not be administered
concomitantly with ACE inhibitors or
within 36 hours of the last dose of an ACE
inhibitor
Side effects
• Angioedema
• Hypotension
• Impaired renal function
• Hyperkalemia

33. Sacubitril/Valsartan
• Systolic blood pressure (SBP) ≥100 mmHg
• Estimated glomerular filtration rate ≥30 mL/min/1.73 m2
Criteria for initiation
• Double after 2 ‐ 4 weeks to a target dose of 97 mg/103 mg
twice daily if tolerated
Starting dose:
49 mg/51 mg twice daily
• who have never taken an ACEI or ARB
• who are taking low dosages of an ACEI or ARB
• with a eGFR < 30 mL/min
• with moderate hepatic impairment (Child‐Pugh B classification)
Starting dose:
24 mg/26 mg twice daily

34. Sacubitril/Valsartan Dosing
Moderate to high dose ACE inhibitor
(>10 mg/day of enalapril or equivalent)
ARB (>160 mg/day of valsartan or equivalent)
low doses of an ACE inhibitor
(≤10 mg/day of enalapril or equivalent)
ARB (≤160 mg/day of valsartan or equivalent)
Sacubitril 49 mg/valsartan 51 mg BID
Double the dose after 2 to 4 weeks
Target maintenance dose:
sacubitril 97 mg/valsartan 103 mg BID
Sacubitril 24 mg/valsartan 26 mg BID
Double the dose every 2 to 4 weeks
Target maintenance dose:
sacubitril 97 mg/valsartan 103 mg BID

35. Initiate, Add, or Switch to New Evidence-Based
Guideline-Directed Therapy for HFrEF

36. • Pharmacist Interventions
Nonadherence Worsening HF signs and symptoms due to nonadherence with lifestyle modifications (eg,
sodium restrictions)
Unnecessary medication
Duplicate therapy
(eg, ACEI and an ARB in HFpEF)
Need for additional
medication
A Back patient not taking an optimal regimen for HFrEF (add hydralazine/ISDN combination)
Suboptimal heart rate control in HFpEF and atrial fibrillation in a patient taking maximum BB
dose (add low-dose digoxin)
Ineffective medication Patient using metoprolol tartrate for HFrEF
A patient taking high-dose furosemide with worsening ascites, dyspnea on exertion, and
hepatomegaly (reduced oral absorption of furosemide)
Dosage too low Worsening ascites and dyspnea on exertion on torsemide 5 mg once every morning
Dosage too high Patient with CKD taking target dose of spironolactone and experiencing hyperkalemia
Symptomatic bradycardia on metoprolol succinate 150 mg daily
Adverse drug event Orthostatic hypotension on carvedilol
Hypokalemia and worsening renal function with a loop

37. PC (Presenting Complaint)
• I can’t seem to catch my breath.
• MK is a 68‐year‐old African American male who
is admitted to the ED with progressive,
worsening SOB.
HPI ( history of presenting complaint)
• Unable to climb a flight of stairs or walk more
than a block before developing SOB.
• Unable to sleep in bed due to SOB.
• These are new symptoms that have been
becoming progressively worse.
• 15 lb weight gain over the past week despite
having no appetite.
• Two weeks ago, able to walk more than 4‐5
blocks without a problem.
• MK reports compliance with all medications.
Patient Case

38. PMH (Past Medical History)
• HFrEF (EF 35% in August 2014)
• MI status‐post DES 2013
• HTN
• Dyslipidemia
• Type 2 Diabetes Mellitus
DES ‐ drug‐eluting stent
EF – ejection fraction
HFrEF ‐ heart failure with reduced ejection fraction
HTN – hypertension
Medications Prior to Admission
• Aspirin 81 mg daily
• Atorvastatin 40 mg daily
• Metoprolol tartrate 25 mg twice daily
• Lisinopril 10 mg daily
• Metformin 1000 mg twice daily
• Furosemide 40 mg daily
• Digoxin 250 mcg daily
Labs on admission
Na: 140 mmol/L (136 to 144 mmol/L)
K: 4.1 mmol/L (3.7 to 5.1 mmol/L)
Cl: 105 mmol/L (97 to 105 mmol/L)
• BP 95/68 mm Hg,
• HR 103 bpm
• T 37.1°C, RR 22/min
• Wt: 87 kg
(2 weeks ago 79 kg per patient)
Vital Signs:

39. On hospital discharge, which of the following would be an appropriate intervention to help optimize
HFrEF pharmacotherapy in MK?
• A. Discontinue digoxin
• B. Change metoprolol tartrate to metoprolol succinate 50 mg daily
• C. Change metoprolol tartrate to atenolol 50 mg daily
• D. Initiate Ivabradine

40. Which of the following medications should be added for MK at this time to reduce her risk of death?
• A. Valsartan
• B. Aliskiren
• C. Eplerenone
• D. Metolazone

41. Which of the following pharmacotherapy changes is appropriate to make and will further improve
survival in MK?
• A. Change lisinopril to valsartan 160 mg twice daily
• B. Add ivabradine 5 mg twice daily
• C. Change lisinopril to sacubitril/valsartan 49/51 mg twice daily
• D. Change lisinopril to sacubitril/valsartan 97/103 mg twice daily

42. ‫والتقدي‬ ‫التحية‬ ‫خالص‬ ‫مع‬
‫ر‬
Regards

43. Refernces
• Journal of the American College of Cardiology Volume 71, Issue 2, January 2018 DOI: 10.1016/j.jacc.2017.11.025
• 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure
JOU RNAL OF THE AME R I CAN COL L EG E OF CARD I OLOGY
h t t p : / / d x . d o i . o r g / 1 0 . 1 0 1 6 / j . j a c c . 20 1 7 . 0 4 . 0 2 5
• 2013 ACCF/AHA Guideline for the
• Management of Heart Failure A Report of the American College of Cardiology Foundation/American Heart Association
Task Force on Practice Guidelines
• ACCP Updates in Therapeutics® 2018: Pharmacotherapy Preparatory Review and Recertification Course Cardiology