Download The Pharmacology of Heart Failure

The Pharmacology of Heart Failure
with Reduced Ejection Fraction
(HFrEF)
CHRONIC AND ACUTE
ANITA RALSTIN, MS, CNS, BC, CNP-BC
I have no conflicts of interest.
HFrEF vs HFpEF
 Left ventricular failure with reduced EF is now noted
as HFrEF (heart failure with reduce ejection
fraction)
 Previous diastolic heart failure is now noted as
HFpEF (heart failure with preserved ejection
fraction)
Impact of Heart Failure (HF)
 Approximately 4.6 million American are living with
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heart failure.
Annual number diagnosed: 450,000
Mortality: decreasing, but remains high
Researchers predict > 8 million by 2030
2012 direct cost for HF was $20.9 billion, projected
to be $53 billion by 2030
Heart Failure Society of America; www.hfsa.org ; K. Fitch, P Pelizzari, B Pyenson;
The High Cost of Heart Failure for the Medicare Population: An Actuarial Cost
Analysis 2/2015
Complex Pathophysiology of HF
 The Frank-Starling mechanism, in which an
increased preload helps to sustain cardiac
performance
 Alterations in myocyte regeneration and death
 Myocardial hypertrophy with or without cardiac
chamber dilatation, in which the mass of
contractile tissue is augmented
 Activation of neurohumoral system
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Norepinephrine release
Activation of renin-angiotension-aldosterone system
Activation of sympathetic nervous system
Atrial natruetic peptide, vasopressin
Classification of HF
 New York Heart Classification
 I,II,III, IV
 ACC/AHA Stages
 Stage A
 Stage B
 Stage C
 Stage D
Stage A Pharmacology
 Prevention
 Hypertension management
 CAD prevention
 Diabetes management
 Metabolic syndrome management
 Treat ETOH abuse
Stage B Pharmacology
 Developed structural heart disease without
symptoms of HF
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Initiate ACE-I or ARB
Initiate Beta Blocker therapy
Aldosterone Blocking
ACE-I/ARB
 Renin-angiotension-aldosterone system (RAAS)
activation
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Compensatory mechanism to maintain cardiac output
Increasing evidence of local RAAS at the tissue level (heart,
kidney and vasculature)
Angiotension II is a potent vasoconstrictor, triggers SNS and
adrenal release of aldosterone
 Ace Inhibitors were found to improve survival in
CHF patients
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Delay onset & progression of HF in pts with asymptomatic LV
dysfunction
↓ cardiac remodeling
Common ACE-I
 benazepril (Lotensin)
 captopril (Capoten)
 enalapril (Vasotec, Epaned)
 fosinopril (Monopril)
 lisinopril (Prinivil, Zestril)
 moexipril (Univasc)
 perindopril (Aceon)
 quinapril (Accupril)
 ramipril (Altace)
 trandolapril (Mavik)
ACE-I Side Effects
 Angioedema
 Hypotension
 Renal insufficiency
 Rash
 Cough
 Monitor renal function and potassium levels
ARB
 Considered equivalent to ACE-I
 Less cough due to reduced bradykinin release.
 Minimal evidence supporting using ACE-I and ARB
together.
Common ARBs
 Azilsartan (Edarbi)
 Candesartan (Atacand)
 Eprosartan
 Irbesartan (Avapro)
 Losartan (Cozaar)
 Olmesartan (Benicar)
 Telmisartan (Micardis)
 Valsartan (Diovan)
ARB Side Effects
 Less cough than ACE-I
 Similar SE profile as ACE-I
Beta Blockers (BB)
 Reduce the effect of the sympathetic nervous system
(beta receptors)
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Reduce heart rate to allow improved left ventricular filling
Some relax blood vessels to reduce afterload.
 Start with ACE-I/ARB as there is a synergic effect
 Start with low doses and advance.
Approved BB for Heart Failure
 Carvedilol
 Bisoprolol
 Metoprolol XL
 These have shown to slow progression of HF,
prolong survival and reduce ventricular arrhythmias
Side Effects of BB
 Feeling fatigued
 Hypotension
 Bradycardia
 Cold hands/feet
 Worsening asthma s/s
 Hair loss
Stage C Heart Failure
 Structural changes with s/s of heart failure
 Continue use of approved BB and ACE-I/ARB
 Add aldosterone blocking agent
 Replace ACE-I/ARB with valsartan/sacubitril
(Entresto)
 Consider
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ivabradine (Corlanor)
Aldosterone Blockade
 Aldosterone has been shown to cause coronary
inflammation, cardiac hypertrophy, myocardial fibrosis,
ventricular arrhythmias, and ischemic lesions.
 Two medications
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spironolactone
eplerenone
 Indicated for those with EF 35% or less. Stage B or C.
 Do not use if CR 2.5 in men or 2.0 in women or
potassium 5.0 or higher.
 Stop potassium supplementation, monitor and restart if
needed.
spironolactone
 Non-selective blocker leads to increased incidence of
gynecomastia,
 Dose 12.5 to 25 mg daily.
 May reduce dose to QOD for GFR 30-49.
 Monitor renal function and potassium levels at onset
and 1 week post implementation, then monthly for
first 3 moths.
eplerenone
 Considered to be ½ as potent as spironolactone.
 Dose 25 mg daily.
 May reduce dose to QOD for GFR 30-49.
 Monitor renal function and potassium levels at onset
and 1 week post implementation, then monthly for
first 3 moths.
Valsartan/sacubitril
 ARB (valsartan) is combined with an inhibitor of
neprilysin, an enzyme that degrades natriuretic
peptides, bradykinin, adreno-medullin, and other
vasoactive peptides.
 In an RCT that compared the first approved ARNI,
valsartan/sacubitril, with enalapril in symptomatic
patients with HFrEF tolerating an adequate dose of
either ACE inhibitor or ARB, the ARNI reduced the
composite endpoint of cardiovascular death or HF
hospitalization significantly, by 20%
C. Yancy, et.al: 2016 ACC/AHA/HFSA Guideline for the
Management of Heart Failure
Valsartan/sacubitril
 On ACE-I/ARB
 Allow 36 hour washout
 Start at 49/51 BID dose
 Not on ACE-I/ARB or severe renal impairment
 Start at 24/26 BID
 Increase every 2-4 weeks to target maintenance dose
of 97/103 BID
Side Effects valsartan/sacubitril
 Hypotension
 Impaired renal function
 Angioedema
 Hyperkalemia
 Cost
 $12.50/day; $4500/year
ivabradine (Corlanor)
 Indications: heart rate reduction
 Corlanor
(ivabradine) is a hyperpolarizationactivated cyclic nucleotide-gated channel blocker
indicated to reduce the risk of hospitalization for
worsening heart failure in patients with stable,
symptomatic chronic heart failure with left
ventricular ejection fraction ≤ 35%, who are in sinus
rhythm with resting heart rate ≥ 70 beats per minute
and either are on maximally tolerated doses of betablockers or have a contraindication to beta-blocker
use
Corlaor Prescribing Information 1/2017
ivabradine (Corlanor)
 Up titrate BB first.
 For patients on maximum tolerated medical therapy
with sinus rhythm and resting heart rate > 70 BPM.
 Initiate at 5 mg BID, assess at 2 weeks and up titrate
to 7.5 mg BID to maintain resting HR between 50-60
BPM
 Reduce dose to 2.5 mg BID or stop medication if
resting HR < 50 BPM
ivabradine (Corlanor)
 Contraindications
 Acute decompensated HF
 BP < 90/50
 SSS, AV Block unless pacemaker in place
 Sinus bradycardia
 Use with strong CYP3A4 inhibitors -incomplete list

Alprazolam, carbamazepine, colchicine, cyclosporine,
dexamethasone, disopyramide, fluticasone, lovastatin, repaglinide,
sildenafil, simvastatin, tadalafil, triazolam
ivabradine (Corlanor)
 Side Effects
 Fetal toxicity
 Atrial fibrillation
 Bradycardia and conduction disturbances
 Syncope
 Ventricular arrhythmias
 Cost
 About $375/month
Diuretics
 Used for fluid volume management
 Use lifestyle changes to reduce the dependence on
diuretics.
 Loop diuretics are most effective.
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furosemide
torsemide
bumetanide
Pearls for Diuretics
 If loosing effectiveness, switch to another loop for a
time
 Add metolazone 2.5 to 5 mg PO 30 minutes before
diuretic dose.
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Educate the patient on s/s of dehydration
Prescribe just a few tablets
 Monitor and replace potassium and magnesium.
Digoxin
 May be considered in HF patients to reduce
hospitalization.
 Narrow therapeutic window
 Toxicity
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Anorexia
Nausea, vomiting
Headache
Disorientation.
Vasodilators
 Reduction of afterload by arteriolar
vasodilatation (hydralazine)  reduce LVEDP, O2
consumption, improve myocardial perfusion, 
stroke volume and COP
 Reduction of preload By venous dilation
(nitrate)  ↓ the venous return ↓ the load on
both ventricles.
 Usually the maximum benefit is achieved by using
agents with both action.
 Use when intolerant to ACE-I/ARB.
Vasodilators
 Monitor BP and renal function.
 Headache common SE of nitrates and hydralazine.
 Hydralazine also can cause nausea, vomiting,
diarrhea and orthostatic hypotension.
Stage D
 End stage heart failure
 Medications continue as long as HR and BP can be sustained.
 Wean medications when BP cannot be sustained.
 Consider advanced heart failure therapies or inotropic
support.
Acute Decompensated Heart Failure
 Common and potentially fatal
 Maintain outpatient HF medications as possible
 Usually present with acute dyspnea from pulmonary
edema
 Can also present with signs of low output: fatigue,
marked exercise intolerance, anorexia, cognitive
impairment
Acute Decompensated Heart Failure
Treatment Goals
 Goals
 Hemodynamic stabilization
 Support oxygenation and ventilation
 Symptom relief
 Modalities
 Diuresis
 Supplemental oxygen and assisted ventilation
 Vasodilator therapy in some patients
 Inotropes
 Arrhythmia Management
Diuresis and Vasodilation
 Mainstays of therapy
 Flash pulmonary edema with HTN
 Diuresis and aggressive vasodilation
 Normotensive and volume overload
 Diuresis and vasodilation
 Hypotension and volume overload
 Diuresis +/- inotropes
 Aortic Stenosis
 Diuresis with caution
Diuretics
 IV preferred over PO because of better
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bioavailability; bypasses GI congestion
Common initial doses: furosemide 40 mg,
bumetanide 1 mg, torsemide 10-20 mg
Rule of thumb: 1-2.5 times their normal PO dose
Peak diuresis is 30 minutes after administration
Bolus and continuous IV infusions have similar
efficacy
Adding a thiazide diuretic (metolazone) can
potentiate the effects of the loop diuretics
Vasodilators
 IV nitroglycerin or IV nitroprusside
 Monitor BP to make sure hypotension does not
develop
 Nitrates are contraindicated with PDE-5 inhibitors
like sildenafil
 Nitroprusside
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Don’t titrate above 400 mcg/min of nitroprusside (cyanide
toxicity)
Can result in reflex tachycardia or rebound vasoconstriction
Inotropes
 Consider if hypotensive with severe systolic
dysfunction
 Can lead to ischemia (increased HR and myocardial
oxygen consumption) or arrhythmias
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Worse mortality if given to patients who do not critically need
these meds
 Dobutamine and dopamine: primarily beta-1
agonists
 Milrinone: phosphodiesterase inhibitor
Dopamine Dobutamine
 Can be used at low dose to improve renal blood flow
if diuresis is not adequate.
 For cardiogenic shock, inotropes are used to support
sufficient blood flow to preserve organ function.
 Dopamine to improve cardiac contractility, initiate at
5-10 mcg/kg/min IV
 Dobutamine has less MVO2 demand, may result in
tachycardia. 0.5-1 mcg/kg/min IV
Norepinephrine
 Catecholamine with alpha receptor activity
(vasoconstriction) to treat hypotension
 Increases afterload which could reduce cardiac
output.
 Increases myocardial oxygen consumption.
 Dose for acute hypotension
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Initial 8-12 mcg/min IV and titrate to effect
Maintenance 2-4 mcg/min IV
Milrinone
 A selective phosphodiesterase inhibitor in cardiac
and vascular tissue.
 Positive inotropic and vasodilator effects.
 Dose 50 mcg/kg loading dose by IV push over 10
minutes then 0.375-0.75 mcg/kg/min.
 Used in Stage D HF for symptom management as
home infusion. Must demonstrate improvement in
right heart pressures and symptoms to qualify.
Thank you, Questions?