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PHARMACOLOGICAL MANAGEMENT

NON NEUROHORMONAL ANTAGONISTS

Heart Failure Classification

ACC/AHA, 2001
NYHA
A

At high risk of developing HF, but without structural heart disease or symptoms of HF.

None
.
B

Structural heart disease, but without symptoms of HF.

I

Asymptomatic.

C

Structural heart disease with prior or current symptoms of HF.

II

Symptomatic with moderate exertion.

III

Symptomatic with minimal exertion.

IV

Symptomatic at rest.

IV
D

Refractory HF requiring specialized interventions.

ACC = American College of Cardiology.
AHA = Americal Heart Association.
NYHA = New York Heart Association.

HF = Heart Failure

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Medicines and when should they be prescribed

MEDICINES
INDICATION
Improve Symptoms
Decrease Hosp
Decrease Mortality
ACE Inhibitor

- NYHA I - IV.
-
Only medicine proved benefit in NYHA I.
-  First medicine to start.

Y
Y
Y
Beta Blocker- NYHA II - IV.
- Do not start in unstable patients.
- Should start early but not before ACEI.
Y
Y
Y
Aldosterone Antagonist

- NYHA (III) IV in RALES study (Spironolactone)
- Recent MI with heart failure in EPHESUS study (Eplerenone)

Y
Y
Y
Angiotensin II Receptor Blocker

- Substitute for patients that cannot use ACEI.
- Benefit when add to ACEI, beta blocker and aldosterone (CHARM, 2003)

a
a
a
Hydralazine+ISDN

- Substitute for patients that cannot use ACEI and ARB.

Y
.
Y
Diuretic

- NYHA II - IV
- For symptomatic patients with fluid retention.

Y
Y
b
Digitalis

- NYHA II -III (IV)
- For symptomatic patients already on ACEI, beta blocker and diuretic.

Y
Y
.
Antiarrhythmic Agent

- Amiodarone, (some) beta blocker, and dofetilide do not have deleterious effect on depressed LV systolic function.

.
.
.
Anticoagulation

- No conclusive recommendation for patients with EF <30%.
- Usual indications i.e.., atrial fibrillation, history of systemic emboli.

.
.
.
Calcium Channel Blocker

- No indication for heart failure treatment.
- Only amlodipine and felodipine do not have deleterious effect on depressed LV systolic function.

.
.
.
Medicines not recommend- NSAIDs, Cox 2 inhibitors, Class 1A and 1C antiarrhythmic agents , calcium channel blocker except amlodipine and felodipine, glitazones (avandia and actose in Heart failure with fluid retention, cardiotoxic agents.
- Others include coticosteroid, lithium, tricyclic antidepressants.

a = Appears to have similar result and not better than ACEI.
b = Essential for treatment of fluid retention, but no study on mortality to date.

Medicines and when should they be prescribed

.III         III    IV
IV Inotropic. .
Digitalis
. . 1
Diuretic
. .
Aldosterone antagonist
. 2
Beta blocker
34
ARB
5
ACE Inhibitor
.

1. Digitalis should not be started during this NYHA class.   2. Spironolactone adds to ACEI, Beta blocker (RALES Trial). May prescribe Eplerenone soon after MI with heart failure (EPHESUS Trial).  3. Prescribe after acute MI with or without heart failure symptoms.   4. Add to ACEI. Do not have to wait until reach ACEI target dose.   5a. Prescribe when patient is intolerable or contraindicate to ACEI.   5b. Add to ACEI, Beta blocker. (CHARM, 2003)

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ACC/AHA Stages, Progression, and Treatment of HF, 2001

This new HF staging also includes incorporation of conditions which potentially leading to HF and cardiac structural abnormality, which should lead to more appropriate management to slow down the progression of disease and improvement of quality of life.

Stage A
- At high risk for developing of HF but without structural heart disease or symptom of HF.

.

Stage B
- Structural heart disease but without symptoms of HF.

.
Stage C
- Structural heart disease with prior or current symptoms of HF.
.
Stage D
- Refractory HF required specialized interventions.
.
.
.
.
.
.
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e.g.. Patients with:
- Hypertension, coronary artery disease, diabetes mellitus, using cardiotoxins, FH of CM.
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e.g.. Patients with:
- previous MI, Left ventricular systolic dysfunction, asymptomatic valvular disease.
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e.g.., Patients with:
- known structural heart disease, shortness of breath and fatigue, reduced exercise tolerance.
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e.g.., Patients who:
- have marked symptom at rest despite maximal medical therapy (e.g... Those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions).
.
.
.
.
.
.
.
Therapy:
- Treat hypertension, encourage smoking cessation, treat lipid disorders, encourage regular exercise, discourage alcohol intake,
- ACEI in atherosclerotic vascular disease of diabetic patients.
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Therapy:
- All measures under Stage A.
- Heart failure education.
- ACEI and Beta blocker S/P MI patients regardless of EF.
- ACEI in low EF patients regardless of MI history.
- Beta blocker in symptomatic low EF regardless of MI history.
- ICD in appropriate patients.
.
Therapy:
- All measures under Stage A.
- Extensive heart failure education.
- Drugs for routine used: ACEI, beta blocker, diuretic, digitalis, spironolactone,ARB, hydralazine and nitrate, etc.
- ICD/biventricular pacing in appropriate patients.

.
Therapy:
- All measures under Stage A, B, and C.
- Mechanical assist devices.
- Heart transplantation.
- Continuous (not intermittent) IV inotropic infusion for palliation.
- Hospice care.
HF = Heart Failure, FH = Family History, CM = Cardiomyopathy, S/P = Status Post, MI = Myocardial Infarction,
ACEI = Angiotensin Converting Enzyme Inhibitor
, ARB = Angiotensin Receptor Blocker.

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NEUROHORMONAL ANTAGONISTS

NEUROHORMONE

NON NEUROHORMONAL ANTAGONISTS

To view medicine tablets / capsules

ACE INHIBITOR

Use in Clinical Practice

Adverse Reaction

(Some side effects may occur early in the therapy but should not generally prevent long term use of these drugs later).

Adverse Reaction
Management
Intolerable cough - Rule out other causes of cough, particularly pulmonary congestion.
- Change to or rechallenge with other ACEI. (Cough resolves within 1-2 weeks after discontinuation of ACEI and recurs with in days of rechallenge).
- Prescribe smaller dose.
- Prescribe ARB, if ACEI has to be discontinued.
Angioedema- More serious allergic reaction but rarely occurs.
- (Note that ARBs may cause this allergic reaction, but much less). (CHARM 2003)

Worsening of renal function

- Increase incidence in higher NYHA. class, volume depletion, hyponatremia, NSAIDs user.
- Increase in serum creatinine >0.5 mg/dL.

- Improve conditions associated with higher incidence of worsening renal function.
- Adjust diuretic dose, mostly reduction.
- Lower ACEI dose. May increase it later. Smaller dose of ACEI is better than not at all.
- Allow small degree of creatinine rise (i.e.. Up to 0.5 mg/dL provided that it becomes stable). Some guidelines allow increase in creatinine up to 50% of the baseline.
Hypotension, if symptomatic- Avoid low intravascular volume or hyponatremia (usually due to diuretic overuse).
- Lower the dose. May increase it later (smaller dose of ACEI is better than not at all).
- May adjust dose schedule, i.e, bid or tid instead of single dose; hs dose; or do not give medications that lower blood pressure at the same time.
- Discontinue the BP lowering medication that has less heart failure benefit.
Hyperkalemia- Potassium level should be <5.9 mEq/L.
- Potassium supplements are frequently not needed in patients taking ACEI.
- Seen more in patients with deteriorating renal function.
- Seen more with patients taking potassium supplements or taking potassium sparing diuretics (especially in diabetic patients). These medications should be discontinued.
- Careful monitoring paients taking aldosterone antagonist.

Contraindications

Caution

Drug Interaction (see appendix)

Comparison of ACEI Table (Those with FDA approved for heart failure treatment)

Accupril
Altace
Capoten
Mavik

Mono
pril

Prinivil
Vasotec
Zestril
Generic name
Quinipril
Ramipril
Captopril
Trandola
pril
Fosino
pril
Lisinopril
Enalapril
Lisino
pril
FDA Indications
HTN, CHF
HTN, CHF
HTN, CHF, Asymp LV dysfunction
HTN,
S/P MI CHF
HTN, CHF
HTN, CHF
HTN, CHF, Asymp LV dysfunction
HTN, CHF
Tablet Size
5, 10, 20, 40
1.25, 2.5. 5, 10
12.5, 25, 50, 100
1, 2, 4
10, 20
5, 10, 20, 40
2.5, 5, 10, 20
5, 10, 20, 40
Starting Dose
5 mg bid
1.25-2.5 mg qd
6.25-12.5 mg tid
1 mg qd
5 mg qd
2.5-5 mg qd
2.5 mg bid
2.5-5 mg qd
Target Dose (a)
20 mg bid
10 mg qd
50 mg tid
2-4 mg qd
20 mg qd
20 mg qd
10 mg bid
20 mg qd
Maximum Dose
40 mg bid
10 mg bid
100 mg tid
8 mg qd
40 mg qd
40 mg qd
20 mg bid
40 mg qd
Can Tablet Be Broken in Half
(b)
Capsule
(b)
(b)
(b)
(b)
(b)
(b)

(a) = average maintenance dose used in clinical trials
(b) = Tablets are in all form and size. They can be cut in a half with good pill cutter and do it carefully. It may save money in many preparation and dosage.

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BETA BLOCKER

Use in Clinical Practice
  Tips on initiating beta blocker.

Beta Blockers with Proven Benefit in Heart Failure

Beta Blocker
Action
Starting Dose
Target Dose
FDA Approved
Carvedilol (Coreg) (a)
Beta 1; Beta 2, Alpha 1
3.125 mg bid
25 mg bid
Yes
Metoprolol Succinate CR (Toprol XL)
Beta 1 (c)
12.5 mg qd
100-200 mg qd
Yes
Metoprolol Tartrate (Lopressor) (b)
Beta 1 (c)
6.25 mg bid
50-75 mg bid
No
Bisoprolol (Zebeta)
Beta 1 (c)
1.25 mg qd
10 mg qd
No

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Adverse Reaction

(Some side effects may occur early in the therapy but should not generally prevent long term use of these drugs later).

Adverse Reaction
Management

Hypotension, symptomatic vasodilating effecting

(Carvedilol has vosodilating effect)

- Discontinue other BP lowering medication that has less heart failure benefit.
- Administer vasodilating medicines at different time.
- May temporary decrease other vasodilators doses (i.e.. ACEI).
- Lower the beta blocker dose.
Fluid retention, worsening of HF- Adjust diuretic dose, mostly increase.
- Lower the beta blocker dose.
- Monitor weight daily.
Bradycardia and heart block - Discontinue medications that may cause bradycardia.
- Lower the beta blocker dose.
- May require pacemaker to allow continuation of beta blocker.

Contraindications

Caution

Drug Interaction (see appendix)

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ALDOSTERONE ANTAGONIST

Use In Clinical Practice

Adverse Reaction (Spironolactone)

Adverse Reaction
Management
Hyperkalemia- Discontinue or readjust dose of potassium sparing medicine or potassium supplement.
- Check serum potassium level within first few weeks of initiation, and monitor there after.
- Improve condition causing renal insufficiency.
Gynecomastia (occur in 8-9% of Spironolactone) - May continue medicine if the problem is mild and the patient can tolerate it.
- Selective aldosterone antagonist, Eplerenone, rarely cause gynecomastia.

.

ANGIOTENSIN RECEPTOR BLOCKER

Use in Clinical Practice

ARB
Initial Dose
Target Dose
FDA approved
Losartan (Cozaar) (1)
25 mg qd
50 mg qd  (4)
No
Valsartan (Diovan) (2)
80 mg qd
160 mg bid
Yes
Irbesartan (Avapro)
75 mg qd
150 - 300 qd  (5)
No
Candesartan (Atacan) (3)
4 mg qd
32 mg qd
Yes

(1) In ELETE II, 2000.  (2) In Val-Helf, 2001 and VALIANT, 2003.  (3) In CHARM, 2003.  (4) Dose of 100 mg qd may be better.   (5) Need to be confirmed.

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Contraindications and caution

BNP (B-TYPE NATRIURETIC PEPTIDE)

BNP (B-type natriuretic peptide) is a cardiac neurohormone secreted from cardiac ventricular myocyte in response to increased ventricular wall stretch or wall tension, increased ventricular volume or pressure. It is a potent vasodilator and it promotes diuresis. The half-live is short, about 18-22 minutes.

Potential usefulness are:

1. Diagnosis for HF

2. Follow up and Prognosis of heart failure

  • During inpatient treatment of heart failure. Rising of the discharged BNP level from the admission level is a good predictor of poor prognosis and near future unfavorable outcome i.e... early readmission.
  • During outpatient treatment followup, BNP guiding intensity of treatment may be useful.
  • During acute MI, rising of BNP level few days after admission level indicates poorer prognosis.
  • Baseline BNP is necessary for comparison
3. Treatment for acute decompensation

4. Potential outpatient intermittent treatment in severe heart failure

5.NT-proBNP (NT = N Terminal)

When cardiac myocyte Pro-BNP enter the circulation it split into BNP which is an active neurohormone and NT-proBNP which is inactive part but with longer half life. Level of NT-proBNP can be used for diagnosis, follow up and prognosis of heart failure the same way as BNP level. The physicians need to know whether the report are BNP or NT-proBNP since the level are significantly different and some laboratory may not label it correctly.

References
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HYDRALAZINE / ISDN

Use in Clinical Practice

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Initial Dose
Target Dose
Hydralazine
37.5 mg tid
75 mg tid
Isosorbide Dinitrate
20 mg qid
40 mg qid

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DIURETIC

Use in Clinical Practice
.
Initial dose
Target dose
Maximal dose
Loop Diuretics .

   Furosamide (Lasix)

20-40 mg qd
as needed
240 mg bid (a)

   Bumetanide (Bumex)

0.5-1.0 mg qd
as needed
10 mg qd

  Torsemide (Demedex)

10-20 mg qd
as needed
80-120 mg bid
Thiazide Diuretics .

  Hydrochlorothiazide

25-50 mg qd
as needed
100-200 mg qd
Thiazide-Related Diuretics .

  Metolazone (Zaroxolyn) (b)

2.5-5.0 mg qd
2.5-5.0 mg 2-3 time/wk
10 mg qd
Potassium Sparing Diuretics .

  Spironolactone

(See Aldosterone Antagonist section)

  Triamterene, Amiloride

(Not use in HF)

(a) = oral Furosamide up to 2500 mg/day has been reported without toxicity.
(b) = Metolazone may cause significant electrolyte imbalance.


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Diuretic Refractory

  1. Medication noncompliance, excessive salt and fluid intake and NSAIDs are the common reasons that the patients become refractory to diuretics.
  2. Prescribe higher loop diuretic dose. Avoid single daily dose to decrease post diuretic sodium retention (Furosamide has short half life).
  3. Oral Torsemide has better absorption and bioavailability than Furosemide in symptomatic HF with fluid retention.
  4. Combine diuretics with different sites of action i.e... Metolazone (give 1/2 hour before) and Furosamide/Bumetanide/Torsamide. Use lowest effective Metolazone i.e.. 2.5-5.0 mg 2-3 times/week or prn per weight increase. For IV use, prescribe Chlorothiazide or hydrochlorothiazide 250-500 mg or 25-50 mg respectively, 1/2 hour before IV loop diuretic. Monitor electrolyte when use Metolazone.
  5. Intravenous loop diuretics, bolus. May be used as outpatient.
.
Dose depending on Creatinine Clearance
Dose Frequency
Furosamide
>40 mg ------ 160-240 mg (a)
q 8 hrs, q 12 hrs
Bumetanide
>2 mg ------
q 12 hrs
Torsemide
10-20 mg ------ 100 mg
q 12 hrs

(a) = bolus Furosemide up to 1000 mg has been reported.

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6. Intravenous loop diuretics, continuous infusion, is more effective and requires less total daily dose than bolus form.

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Loading Dose (mg)
Infusion Rate (mg/hr)
CrCl >75 ml/min
CrCl 25-75 ml/min
CrCl <25 ml/min
Furosamide (a)
40
10
10-20
20-40
Bumetanide
1
0.5
0.5-1
1-2
Torsemide
20
5
5-10
10-20

(a) = infusion Furosemide up to 4000 mg/day has been reported

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7. Combine diuretics and drugs that increase renal blood flow, i.e... Dobutamine, Milronone, Nesiritide, low dose Dopamine.
8. Ultrafiltration.

Adverse Reactions

Adverse Reaction
Management

Electrolyte imbalance (Increase incidence when combine loop and thiazide)
   
- Hypokalemia
    - Hyponatremia, hypomagnesemia

- Use of ACEI, potassium sparing diuretics, potassium supplement in case of hypokalemia.
- Potassium/magnesium replacement or supplement in case of hypokalemia and hypomagnesemia.
- Fluid restriction in case of hyponatremia.
Neurohormonal activation - Patient should be on neurohormonal antagonist medicine i.e... ACEI, beta blocker and aldosterone antagonist.

Hypotension, azotemia
   
- May occur in worsening of HF

 

- Should continue diuretic if there is evidence of fluid overload.
- May decrease ACEI or o ther medicines that lower the BP.
- May allow some degree of renal insufficiency if stable.
- Allows hypotension if asymptomatic, although too low BP ie.. <80 may decrease renal perfusion significantly in some patients.

Ototoxicity
   
- May occur in high IV dose of Furosamide

- Usually reversible except when combine with aminoglycoside.

Caution

Drug Interaction (see appendix)

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DIGITALIS

Use In Clinical Practice

Adverse Reaction

Adverse Reaction
Management

Cardiac arrhythmias
   
- ectopies, re-entrant rhythm, heart block

Gastrointestinal symptoms
   
- anorexia, nausea, vomiting

Neurological symptoms
   
- visual disturbance, confusion, disorientation

- Check blood level.
- Check renal function.
- Check interacting drugs, ie.. amiodarone, spironolactone.
- Check conditions that may potentiate digoxin side effects (hypokalemia. hypomagnesemia, hypothyroidism).

Contraindication

Caution

Drug Interaction (see appendix)

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ANTIARRHYTHMIC AGENT

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ANTICOAGULATION

Use in Clinical Practice

Drug Interaction (see appendix)

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ANTIPLATLETS

Aspirin (ASA)

ADP Antagonists (Ticlopidine, Clopidogrel)

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CALCIUM CHANNEL BLOCKER

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Medicines worsening/exacerbate heart failure

NSAIDs, Cox 2 inhibitors, class I antiarrhythmic agents, calcium channel blockers except amlodipine and felodipine, corticosteroid, lithium, tricyclic antidepressants, cardiotoxic agents, glitazones (avandia and actose in HF with fluid retention).

.

IV INOTROPIC

Data: There is no evidence that IV inotropic treatment prolongs life. In fact this treatment has been associated with shortened survival.

Goal: To improve quality of life.

Patients: Those who are compliant and receiving maximal medical therapy (ACEI or ARB, beta blocker, diuretic, aldosterone antagonist, digitalis, at adequate dose) but remain in NYHA high level class III or class IV with significant DOE, orthopnea, PND, persistent edema, fatigue and cannot carry on any minor activity.

Contraindication:

Aortic stenosis, mitral stenosis, unstable angina or recent MI, ventricular arrhythmia, hypertrophic cardiomyopathy, diastolic dysfunction heart failure,

Duration of treatment:

(1). Long duration infusion: This treatment has been used in hospitalized very severe heart failure patient waiting for cardiac transplantation - a bridging therapy.

(2). 2 -3 day infusion, likely intermittently: To improve symptoms and promote diureses (with diuretics).

Note: The intermittent intravenous inotropic treatment is not generally recommended by the major guidelines. However several centers and clinics continue to utilized this treatment. Home infusion has been performed in some places to improve severe symptoms. The mortality is likely increased with this treatment.

Drugs selection:

A. Patients with symptomatic hypotension prior infusion treatment.

Dobutamine (beta agonist)

  • 250 mg of Dobutamine in 250 cc D5W.
  • 2.5 microgram/kg/min for the first hour.
  • 5.0 microgram/kg/min ( or higher dose) for 48-72 hour
  • 2.5 microgram/kg/min for one hour before discontinue the infusion.
Monotor: BP and heart rate q 15 min x 2, q 30 min x 1, then hourly during infusion. Watch heart rate and tachyarrthymia, palpitation, angina. headache, nausea.

Check: BP, heart rate, weight, electrolytes before treatment, weight after treatment.

B. Patients with tachycardia prior infusion treatment.

Milrinone (Phosphodiesterase inhibitor)

  • 20 mg of Milrinone in 100 cc D5W.
  • Loading dose of 25 - 50 microgram/kg infuse over 15 minutes. No loading dose in patients with siginificantly low BP or with renal insufficiency.
  • Maintenance dose of 0.375 - 0.5 microgram/kg/min for 48-72 hours.

Monitor: BP, heart rate, q 15 min x 2, q 30 min x 1, then hourly during infusion. Watch hypotension, headache, angina, thrombocytopenia.

Check: BP, heart rate, weight electrolytes before treatment, weight after treatment.

C. Patients receiving beta blockers.

Use Milrinone. (If use Dobutamine, will need higher dose).

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