The Pharmacology of Heart Failure with Reduced Ejection Fraction HF r EF I have no conflicts of interest HF r EF vs HF p EF Left ventricular failure with reduced EF is now noted as ID: 932003
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Slide1
Chronic and AcuteAnita Ralstin, MS, CNS, BC, CNP-BC
The Pharmacology of Heart Failure with Reduced Ejection Fraction (
HF
r
EF
)
Slide2I have no conflicts of interest.
Slide3HFrEF vs HFp
EF
Left ventricular failure with reduced EF is now noted as
HF
r
EF
(heart failure with reduce ejection fraction)
Previous diastolic heart failure is
now
noted as
HF
p
EF
(heart failure with preserved ejection fraction)
Slide4Impact of Heart Failure (HF)Approximately 4.6 million American are living with 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
Slide5Complex 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
Norepinephrine release
Activation of renin-
angiotension
-aldosterone system
Activation of sympathetic nervous
system
Atrial
natruetic
peptide, vasopressin
Slide6Classification of HFNew York Heart Classification
I,II,III, IV
ACC/AHA
Stages
Stage A
Stage
B
Stage C
Stage D
Slide7Stage A PharmacologyPrevention
Hypertension management
CAD prevention
Diabetes management
Metabolic syndrome management
Treat ETOH abuse
Slide8Stage B PharmacologyDeveloped structural heart disease without symptoms of HF
Initiate ACE-I or ARB
Initiate Beta Blocker therapy
Aldosterone Blocking
Slide9ACE-I/ARBRenin-
angiotension
-aldosterone system (RAAS) activation
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
Delay onset & progression of HF in pts with asymptomatic LV dysfunction
↓ cardiac remodeling
Slide10Common ACE-Ibenazepril (
Lotensin
)
captopril (
Capoten
)
enalapril (Vasotec,
Epaned
)
fosinopril
(
Monopril
)
lisinopril
(
Prinivil
, Zestril)
moexipril
(
Univasc
)
perindopril (
Aceon
)
quinapril (
Accupril
)
ramipril
(
Altace
)
trandolapril
(
Mavik
)
Slide11ACE-I Side EffectsAngioedema
Hypotension
Renal insufficiency
Rash
Cough
Monitor renal function and potassium levels
Slide12ARBConsidered equivalent to ACE-I
Less cough due to reduced bradykinin release.
Minimal evidence supporting using ACE-I and ARB together.
Slide13Common ARBsAzilsartan (
Edarbi
)
Candesartan (
Atacand
)
EprosartanIrbesartan
(Avapro)
Losartan (
Cozaar
)
Olmesartan
(Benicar)
Telmisartan
(
Micardis
)
Valsartan (Diovan)
Slide14ARB Side EffectsLess cough than ACE-I
Similar SE profile as ACE-I
Slide15Beta Blockers (BB)Reduce the effect of the sympathetic nervous system (beta receptors)
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.
Slide16Approved BB for Heart FailureCarvedilol
Bisoprolol
Metoprolol XL
These have shown to slow progression of HF, prolong survival and reduce ventricular arrhythmias
Slide17Side Effects of BBFeeling fatigued
Hypotension
Bradycardia
Cold hands/feet
Worsening asthma s/s
Hair loss
Slide18Stage C Heart FailureStructural 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
ivabradine
(
Corlanor
)
Slide19Aldosterone BlockadeAldosterone has been shown to cause coronary inflammation, cardiac hypertrophy, myocardial fibrosis, ventricular arrhythmias, and ischemic
lesions
.
Two medications
s
pironolactone
e
plerenone
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.
Slide20spironolactoneNon-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.
Slide21eplerenoneConsidered 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.
Slide22Valsartan/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
HF
r
EF
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
Slide23Valsartan/sacubitrilOn 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
Slide24Side Effects valsartan/sacubitril
Hypotension
Impaired renal function
Angioedema
Hyperkalemia
Cost
$
12.50/day; $4500/year
Slide25ivabradine (Corlanor)
Indications: heart rate reduction
Corlanor
(
ivabradine
) is a hyperpolarization-activated 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 beta-blockers or have a contraindication to beta-blocker use
Corlaor
P
rescribing
I
nformation 1/2017
Slide26ivabradine (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
Slide27ivabradine (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
Slide29DiureticsUsed for fluid volume management
Use lifestyle changes to reduce the dependence on diuretics.
Loop diuretics are most effective.
f
urosemide
t
orsemide
b
umetanide
Slide30Pearls for DiureticsIf loosing effectiveness, switch to another loop for a time
Add
metolazone
2.5 to 5 mg PO 30 minutes before diuretic dose.
Educate the patient on s/s of dehydration
Prescribe just a few tablets
Monitor and replace potassium and magnesium.
Slide31DigoxinMay be considered in HF patients to reduce hospitalization.
Narrow therapeutic window
Toxicity
Anorexia
Nausea, vomiting
Headache
Disorientation.
Slide32VasodilatorsReduction of afterload
by arteriolar vasodilatation (hydralazine)
reduce LVEDP, O
2
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.
Slide33VasodilatorsMonitor BP and renal function.
Headache common SE of nitrates and hydralazine.
Hydralazine also can cause nausea, vomiting, diarrhea and orthostatic hypotension.
Slide34Stage DEnd 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.
Slide35Acute Decompensated Heart FailureCommon 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
Slide36Acute Decompensated Heart FailureTreatment 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
Slide37Diuresis and VasodilationMainstays 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
Slide38DiureticsIV preferred over PO because of better 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
Slide39VasodilatorsIV nitroglycerin or IV nitroprusside
Monitor BP to make sure hypotension does not develop
Nitrates are contraindicated with PDE-5 inhibitors like sildenafil
Nitroprusside
Don’t titrate above 400 mcg/min of nitroprusside (cyanide toxicity)
Can result in reflex tachycardia or rebound vasoconstriction
Slide40InotropesConsider if hypotensive with severe systolic dysfunction
Can lead to ischemia (increased HR and myocardial oxygen consumption) or arrhythmias
Worse mortality if given to patients who do not critically need these meds
Dobutamine and dopamine: primarily beta-1 agonists
Milrinone: phosphodiesterase inhibitor
Slide41Dopamine DobutamineCan 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
Slide42NorepinephrineCatecholamine with alpha receptor activity (vasoconstriction) to treat hypotension
Increases afterload which could reduce cardiac output.
Increases myocardial oxygen consumption.
Dose for acute hypotension
Initial 8-12 mcg/min IV and titrate to effect
Maintenance
2-4 mcg/min IV
Slide43MilrinoneA 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.
Slide44Thank you, Questions?