.

PHARMACOLOGICAL MANAGEMENT

• Pharmacological management for patients with systolic dysfunction heart failure (HF) is a poly-pharmacy approach.
• Medications that have the effect on the natural history of the disease, especially the neurohormonal antagonist (ACE inhibitors, beta blockers, aldosterone antagonist) should be part of the treatment strategy.
• Prescribe only the medications that have proven benefit and use the appropriate dose from major clinical trials.
• Start each medication at appropriate level of NYHA class.
• Be aware of medications adverse reactions and how to manage them.
• Avoid prescribing medications that potentially have deleterious effects in heart failure such as most of the calcium channel blockers, antiarrhythmic class 1A, 1C, NSAIDs, Cox 2 inhibitors and Glitazones (in heart failure with fluid retention).
• Encourage prescribing aspirin, beta blockers, ACE inhibitors and statin drugs in post MI patients.

  NEUROHORMONAL ANTAGONISTS

  • ACE Inhibitor (ACEI)
  • Beta Blocker
  • Aldosterone Antagonist
  • Angiotensin Receptor Blocker (ARB)

  NEUROHORMONE

  • BNP (Diagnosis, prognosis, treatment)

NON NEUROHORMONAL ANTAGONISTS

• Hydralazine+ISDN
• Diuretic
• Digitalis
• Antiarrhythmic Agent
• Anticoagulation
• Antiplatelets
• Calcium Channel Blocker
• Medicines not recommend
• IV Inotropic

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

Print Heart Failure classification tables

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

.	I	II	III		IV
IV Inotropic	.				.
Digitalis	.	.			1
Diuretic	.	.
Aldosterone antagonist	.			2
Beta blocker	3	4
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)

Print these tables

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.
.	.	.	.	.	.	.
e.g.. Patients with: - Hypertension, coronary artery disease, diabetes mellitus, using cardiotoxins, FH of CM.	.	e.g.. Patients with: - previous MI, Left ventricular systolic dysfunction, asymptomatic valvular disease.	.	e.g.., Patients with: - known structural heart disease, shortness of breath and fatigue, reduced exercise tolerance.	.	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.	.	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.

Print Heart Failure classification tables

Back to top

NEUROHORMONAL ANTAGONISTS

• ACE Inhibitor (ACEI)
• Beta Blocker
• Aldosterone Antagonist
• Angiotensin Receptor Blocker (ARB)

NEUROHORMONE

• BNP (Diagnosis, prognosis, treatment)

NON NEUROHORMONAL ANTAGONISTS

• Hydralazine+ISDN
• Diuretic
• Digitalis
• Antiarrhythmic Agent
• Anticoagulation
• Antiplatelets
• Calcium Channel Blocker
• Medicines not recommend
• IV Inotropic

To view medicine tablets / capsules

ACE INHIBITOR

Use in Clinical Practice

• Should prescribe to all patients with decreased left ventricular systolic function, whether they are symptomatic or not (NYHA I - IV), unless drug intolerance or contraindication exists. Left ventricular ejection fraction in the trials were <35-45%.
• The "Class Effect" of ACEI allows us to have more choices for individual patient dose schedules and expense. Currently there are 7 FDA approved ACEIs for use in heart failure (HF) treatment. Should prescribe those that have proven benefit from the major trials.
• There has been no direct comparison trial of tissue and non tissue ACEI.
• Please review the "Comparison or ACEI" table below, for a list of ACEI that are FDA approved for HF treatment, initial dosing (low dose), target dosing (average maintenance dose used in the major clinical trials), and other characteristics.
• Start with low dose, about 1/4 of the target dose, then titrate upward to target dose in 3-4 steps, usually 1 week apart or less. This titration scheme may vary depending on the stability of the patient. Monitor BP, renal function and potassium in 1-2 weeks and other side effect symptoms, during dose upward titration.
• Hypotension and renal side effects from ACEI will increase if the patient has low intravascular volume or hyponatremia. Be prepared to lower or optimize the diuretic dose when starting and during dose upward titration of ACEI.
• Symptomatic improvement may be delayed for several weeks or months. Even if there is no apparent symptomatic improvement, ACEI may reduce the risk of disease progression.
• Try hard to prescribe ACEI. The benefit is worth more to live with minor side effects if the patient can tolerate. Early side effects should not prevent long term use later. Lower dose of ACEI is better than not at all (ATLAS Trial for Lisinopril).

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

• History of angioedema.
• History of severe adverse reactions. For history of mild to moderate adverse reactions, it may be rechallenged again.
• History of allergy, i.e.. rash.
• Pregnancy.

Caution

• Serum creatinine >3.0 mg/dL.
• In practice, most physicians set their own creatinine level when not to use an ACEI. In major Clinical Guidelines, there is no limited level of creatinine as long as it is stable and patient is not hypovolemic or hyponatremic, before starting an ACEI. Follow up creatinine carefully in 1 week. Should allow creatinine to rise no more than 0.5 mg/dL.
• Renal insufficiency from ACEI is reversible when the medication is discontinued.
• Beware of conditions that increase creatinine level or potentiate ACEI renal side effect (mentioned earlier)
• Potassium > 5.5 mEq/L
• Bilateral renal artery stenosis.
• Hypotension (systolic BP <90 mmHg). Many patients comfortably tolerate blood pressures <90 or even <80 mmHg, however, too low of a BP may reduce renal perfusion resulting in azotemia.

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.

View the pills
Print ACEI, Beta Blocker, ARB and AA Tables
Print this table and formulary/price table

Back to list of medicines

.
BETA BLOCKER

Use in Clinical Practice

• Should prescribe to all mild to severe symptomatic heart failure (NYHA II - IV) patients with decreased left ventricular function, unless drug intolerance or contraindication exists. Left ventricular ejection in the trials were <35-45%. Recent recommendation is to use in NYHA I patients as well.
• Have not been proven to have class effect. Only 3 beta blockers have been proven benefit. FDA has approved 2 beta blockers for heart failure (HF) treatment.
• Patients are usually already on ACEI and some on diuretic.
• Beta blocker should only be started in stable patients.
• Start with lower dose, no more than 1/4 of target dose (average maintenance dose used in clinical trials), then titrate upward in 3-4 steps, 2 weeks apart. This titration scheme may vary depending on how stable the patients are. Monitor weight, blood pressure, heart rate and side effect symptoms.
• Try hard to prescribe beta blocker. The benefit is worth more to live with minor side effects if the patient can tolerate. Early side effects should not prevent long term use later. Lower dose of beta blocker is better than not at all (MOCHA Trial for Carvedilol dose as low as 6.25 mg bid. There is no data for other beta blockers low dose).
• Symptomatic improvement may be delayed for several weeks or months. Even if there is no apparent symptomatic improvement, beta blockers may reduce the risk of disease progression.
• Should always prescribe in post MI patients with or without heart failure. Beta blockers used in post MI trials are not the same as in heart failure trials.
• COMET trial (2003) showed that Carvedilol is superior to Metoprolol tartrate. It did not compare cavedilol to Metoprolol succinate which has similar heart failure benefit from separate trials.

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

• There are no proven benefit data for other Beta blockers.
• (a) = When prescribe low dose, only Carvedilol has proven benefit. Carvedilol is superior to Metoprolol Tartrate, although dosage may not be equivalent and there is no comparison to Metoprolol Succinate CR (COMET, 2003)
• (b) = There is no mortality benefit data for Metoprolol tartrate.
• (c)  = At target dose in clinical trials, these selective beta blocker may become non selective ones.

View the pills
Print ACEI, Beta Blocker, ARB and AA Tables
Print this table and formulary/price table

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

• Bronchospastic disease.
• Symptomatic bradycardia or advanced heart block (unless treated with a pacemaker).
• Unstable HF or hospitalized patient undergoing treatment for acute or deteriorating HF condition.

Caution

• Asymptomatic low BP.
• Asymptomatic bradycardia (<60 bpm).
• Reactive airway disease.

Drug Interaction (see appendix)

Back to list of medicines

.
ALDOSTERONE ANTAGONIST

Use In Clinical Practice

• When used as a neurohormonal antagonist for treatment of heart failure (HF) with systolic dysfunction:
  • RALES trial (1999) (for Spironolactone) only includes patients in NYHA class IV and if they are in class III, they were in class IV within 6 months.
  • EPHESUS (2003) trial (for Eplerenone) shows benefit when use early post MI with heart failure.
  • Initial and target dose of Spironolactone is12.5-25 mg/day.
  • Initial and target dose of Eplerenone are 25 and 50 mg/day.
  • At initiation, serum potassium should be <5.0 mEq/L and serum creatinine should be <2.5 mg/dL.
  • Monitor serum potassium in 1, 4, 8, 12 weeks, then 6, 9, 12 months, then 6 monthly thereafter if patient condition is stable.
  • Discontinue or readjust dose of potassium supplement as needed.

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

• Prescribe to heart failure (HF) patients who cannot take ACEI.
• There are conflicting data when add ARB to ACEI or to ACEI and Beta Blocker.
  • Val-Heft Trial, 2001. Benefit when add to ACEI. Early report showed no benefit when add ARB to ACEI and Beta blocker, however the investigators felt that this finding was a by chance incident.
  • CHARM Trial, 2003. Benefit when add to ACEI and beta blocker (triple therapy).
  • VALIANT Trial, 2003. No benefit when add to ACEI in early post MI patient. Need further confirmation.
• Benefit in heart failure with preserved LV systolic function (CHARM 2003).
• Should prescribe at target dose as in the good benefit trials, since the lower target dose trials usually have less benefit.

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.

View the pills
Print ACEI, Beta Blocker, ARB and AA Tables
Print this table and formulary/price table

Contraindications and caution

• Better tolerability than ACEI.
• Much lower angioedema incident.
• Similar BP and renal effect as in ACEI.

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.

• Circulating BNP level increases in proportion to the severity of heart failure.
• Conditions that raise BNP level beside heart failure
  • Age, sex (female), left ventricular hypertrophy, acute coronary syndrome, acute myocardial infarction, cardiac inflammation, arrhythmogenic RV with decrease ejection, primary pulmonary hypertension, worsening of corpulmonale with increased RV pressure and volume, acute pulmonary emboli, Kawasaki disease, advanced renal failure, cirrhosis, hyperaldosteronism, Cushing syndrome, and decreased clearance.
• Heart failure conditions that may have low BNP
  • Flash pulmonary edema within 1 hour, acute chordal rupture, pulmonary congestion-edema from mitral stenosis, severe end stage heart failure, and heart failure in obese patients (BMI>30 kg/m2).

Potential usefulness are:

1. Diagnosis for HF

• Utilization of BNP level to help differentiate heart failure from other causes of dyspnea in ER or urgent care setting, using Point of Care measurement technique. BNP level over 100 pg/ml favors the diagnosis of heart failure. The range of BNP level in most heart failure patients is from a few hundreds to >1000 pg/ml. BNP should not be a stand alone test. Clinical judgment is always important, Elevated BNP are seen in other conditions (Table 1). Low BNP may be found in few acute heart failure conditions and in obese patients with heart failure.
  
  Table 1. Common causes of BNP elevation in routine clinical practice

Age. Female Renal failure (Cr >2) or on dialysis Myocardial infarction Acute coronary syndrome

Pulmonary disease with right-side failure Acute pulmonary embolism Sepsis Baseline left ventricular dysfunction

• Utilization of BNP level as a diagnostic tool for heart failure with preserved systolic function. A heart failure patient with normal echocardiographic LV systolic function, abnormal diastolic filling abnormalities and elevated BNP should favor this diagnosis.

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

• Nesiritide (Natrecor) is a human recombinant BNP.
• Dosage: Intravenous 2 microgram/kg bolus, followed by infusion of 0.01 microgram/kg/min.
• Duration: Up to 7 days (or more?).
• Action: Hemodynamic effect is observed in an hour or less. There is no tolerance for several days of infusion. Hemodynamic effect resolves by 2-4 hours after cessation of the infusion.
• Nesiritide promotes diuresis.
• Use appropriate dose of diuretic. Over diuresing may potentiate hypotension side effect.
• Side effects: Hypotension (more in cases taking ACEI), nausea, headache.
• Caution: Volume depletion, aortic stenosis, hypertrophic cardiomyopathy, cardiogenic shock.
• Usually does not require hemodynamic monitoring.
• Beware of drug incompatibility in the infusion process.
• May obtain proBNP but not BNP level during nesiritide infusion.
• In the responder cases, if the BNP level is checked 2 hours (or more) after stopping the infusion it should be lower than the preinfusion level.

4. Potential outpatient intermittent treatment in severe heart failure

(Waiting for FUSION 2 trial)

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

.
HYDRALAZINE / ISDN

Use in Clinical Practice

• Prescribe in HF patients who truely cannot take ACEI and ARB.
• Hydralazine is an antioxidant. It blocks the development of nitrate tolerance. To achieve this effect, the dose should be high enough (see below).
• Nitrate should not be used alone.
• Beware of new information from A-HeFT trial (2004. There is benefit in African American patients)

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

Back to list of medicines

.
DIURETIC

Use in Clinical Practice

• Should prescribe to patients with heart failure (HF) who are symptomatic with fluid retention or who have a history of recurrent fluid retention. A stable patient without fluid retention may not need diuretics.
• Diuretic should be used in combination with low sodium diet (<3 gm/day) and daily weight monitoring.
• Diuretic dose should not be fixed. It should vary with (fluid) weight.
• There are 3 types of diuretics: (1) Loop: (2) Thiazide and thiazide-related; (3) Potassium sparing (see tables below).
• Symptomatic fluid retention HF patients generally require loop diuretics.
• Over diuresing may lead to volume contraction, hyponatremia and azotemia. These conditions will potentiate ACEI side effects of hypotension and worsening renal function.
• Under diuresing may blunt ACEI effect and increase beta blocker side effect with more HF symptoms.

.	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.

Print this table and formulary table

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.

Print Diuretics tables

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

.	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

Print Diuretics tables

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)

Back to list of medicines

.
DIGITALIS

Use In Clinical Practice

• Digitalis is beneficial in symptomatic heart failure (HF) patients who are already have been on ACEI, beta blocker, and diuretics.
• Not indicated in acute decompensate HF (unless the patient has rapid atrial fibrillation, although there are other treatment as well, ie.. cardioversion with or without precardioversion transesophageal echocardiogram depending on the duration of the atrial fibrillation; may temporary use intravenous Diltiazem for rapid rate control in acute case. Most calcium channel blockers should not be used chronically in HF patients).
• It has been traditionally thought to be ideal for rate control of atrial fibrillation in HF patients. Currently beta blockers or amiodarone would be a better choice for chronic use.
• Only digoxin brand should be prescribed, Usual dose is 0.125-0.25 mg/day. Adjust for renal function and drug interaction. No need for loading dose.
• Obtain blood level if: (1) Significant change in renal function; (2) Possible drug interaction; (3) Possible digoxin toxicity. (Blood level should be drawn more than 6 hours after dosing.)

Adverse Reaction

• Usually at >2 ng/ml

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

• Significant sinus node disease or atrioventricular block unless treated with pacemaker.

Caution

• In patients taking medicines that depress the sinus and AV node, medicines that interact with digoxin, and in patients with fluctuation renal function.

Drug Interaction (see appendix)

.
ANTIARRHYTHMIC AGENT

• Avoid prescribing other antiarrhythmic agents in heart failure patients except amiodarone, beta blockers (not all) and dofetilide.

.
ANTICOAGULATION

Use in Clinical Practice

• Warfarin should be used in HF patients with atrial fibrillation or with history of thromboembolic events.
• There is no conclusive data to recommend routine warfarin use in HF patients with EF <30% for now.

Drug Interaction (see appendix)

.
ANTIPLATLETS

Aspirin (ASA)

• The issue of ASA-ACE Inhibitors (ACEIs) interaction through prostaglandin synthesis has not been resolved.
• Lower ASA dose (<100 mg/day) may have less or no interaction with ACEI and continue to be effective for vascular protection. Fortunately current recommended chronic ASA dose for ichemic heart disease is 81 mg/day.
• Current recommendation is to continue the use of ASA and ACEI for their own indications as usual, until there is more data.

ADP Antagonists (Ticlopidine, Clopidogrel)

• Has no effect on prostaglandin synthesis.

.
CALCIUM CHANNEL BLOCKER

• They have deleterious effect on left ventricular systolic function and worsening of heart failure except for amlodipine (norvasc) and felodipine (plendil).
• May use amlodipine or felodipine if there are indications other than heart failure.
• Do not chronically use calcium channel blocker, ie. diltiazem or verapamil for antiarrhythmia.

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).

Back to list of medicines

.