1. Chronic and Acute Anita Ralstin, MS, CNS, BC, CNP-BC
The Pharmacology of Heart Failure with Reduced Ejection Fraction (HFrEF)
Chronic and Acute
Anita Ralstin, MS, CNS, BC, CNP-BC

2. I have no conflicts of interest.

3. 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)

4. Impact 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; ; K. Fitch, P Pelizzari, B Pyenson; The High Cost of Heart Failure for the Medicare Population: An Actuarial Cost Analysis 2/2015

5. 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
Norepinephrine release
Activation of renin-angiotension-aldosterone system
Activation of sympathetic nervous system
Atrial natruetic peptide, vasopressin

6. Classification of HF New York Heart Classification ACC/AHA Stages
I,II,III, IV
ACC/AHA Stages
Stage A
Stage B
Stage C
Stage D

7. Stage A Pharmacology Prevention Hypertension management CAD prevention
Diabetes management
Metabolic syndrome management
Treat ETOH abuse

8. Stage B Pharmacology
Developed structural heart disease without symptoms of HF
Initiate ACE-I or ARB
Initiate Beta Blocker therapy
Aldosterone Blocking

9. ACE-I/ARB Renin-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

10. 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)

11. ACE-I Side Effects Angioedema Hypotension Renal insufficiency Rash
Cough
Monitor renal function and potassium levels

12. ARB Considered equivalent to ACE-I
Less cough due to reduced bradykinin release.
Minimal evidence supporting using ACE-I and ARB together.

13. Common ARBs Azilsartan (Edarbi) Candesartan (Atacand) Eprosartan
Irbesartan (Avapro)
Losartan (Cozaar)
Olmesartan (Benicar)
Telmisartan (Micardis)
Valsartan (Diovan)

14. ARB Side Effects
Less cough than ACE-I
Similar SE profile as ACE-I

15. Beta 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.

16. Approved BB for Heart Failure
Carvedilol
Bisoprolol
Metoprolol XL
These have shown to slow progression of HF, prolong survival and reduce ventricular arrhythmias

17. Side Effects of BB Feeling fatigued Hypotension Bradycardia
Cold hands/feet
Worsening asthma s/s
Hair loss

18. 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
ivabradine (Corlanor)

19. Aldosterone Blockade
Aldosterone has been shown to cause coronary inflammation, cardiac hypertrophy, myocardial fibrosis, ventricular arrhythmias, and ischemic lesions. 
Two medications
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.

20. spironolactone
Non-selective blocker leads to increased incidence of gynecomastia,
Dose 12.5 to 25 mg daily.
May reduce dose to QOD for GFR
Monitor renal function and potassium levels at onset and 1 week post implementation, then monthly for first 3 moths.

21. eplerenone Considered to be ½ as potent as spironolactone.
Dose 25 mg daily.
May reduce dose to QOD for GFR
Monitor renal function and potassium levels at onset and 1 week post implementation, then monthly for first 3 moths.

22. 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: ACC/AHA/HFSA Guideline for the Management of Heart Failure

23. 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

24. Side Effects valsartan/sacubitril
Hypotension
Impaired renal function
Angioedema
Hyperkalemia
Cost
$12.50/day; $4500/year

25. ivabradine (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 Prescribing Information 1/2017

26. 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 BPM
Reduce dose to 2.5 mg BID or stop medication if resting HR < 50 BPM

27. 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

28. ivabradine (Corlanor)
Side Effects
Fetal toxicity
Atrial fibrillation
Bradycardia and conduction disturbances
Syncope
Ventricular arrhythmias
Cost
About $375/month

29. Diuretics Used for fluid volume management
Use lifestyle changes to reduce the dependence on diuretics.
Loop diuretics are most effective.
furosemide
torsemide
bumetanide

30. 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.
Educate the patient on s/s of dehydration
Prescribe just a few tablets
Monitor and replace potassium and magnesium.

31. Digoxin May be considered in HF patients to reduce hospitalization.
Narrow therapeutic window
Toxicity
Anorexia
Nausea, vomiting
Headache
Disorientation.

32. 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.

33. Vasodilators Monitor BP and renal function.
Headache common SE of nitrates and hydralazine.
Hydralazine also can cause nausea, vomiting, diarrhea and orthostatic hypotension.

34. 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.

35. 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

36. Acute Decompensated Heart Failure Treatment Goals
Hemodynamic stabilization
Support oxygenation and ventilation
Symptom relief
Modalities
Diuresis
Supplemental oxygen and assisted ventilation
Vasodilator therapy in some patients
Inotropes
Arrhythmia Management

37. 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

38. Diuretics
IV preferred over PO because of better bioavailability; bypasses GI congestion
Common initial doses: furosemide 40 mg, bumetanide 1 mg, torsemide mg
Rule of thumb: 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

39. 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
Don’t titrate above 400 mcg/min of nitroprusside (cyanide toxicity)
Can result in reflex tachycardia or rebound vasoconstriction

40. Inotropes Consider 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

41. 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 mcg/kg/min IV

42. 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
Initial 8-12 mcg/min IV and titrate to effect
Maintenance 2-4 mcg/min IV

43. 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 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.

44. Thank you, Questions?