Heart Failure Due to Reduced Ejection Fraction: Medical Management

 

Am Fam Physician. 2017 Jan 1;95(1):13-20.

  Patient information: See related handout on heart failure.

Author disclosure: No relevant financial affiliations.

Heart failure is an increasingly common condition resulting in high rates of morbidity and mortality. For patients who have heart failure and reduced ejection fraction, randomized clinical trials demonstrate consistent mortality benefit from angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, direct-acting vasodilators, beta blockers, and aldosterone antagonists. Additionally, some data show benefits from two new classes of drugs: angiotensin receptor blocker/neprilysin inhibitor and sinus node modulator. Diuretics and digoxin can be used as needed for symptom control. Statins are not recommended solely for treatment of heart failure. Implantable cardioverter-defibrillators and biventricular pacemakers improve mortality and function in selected patients. For patients who have been hospitalized for heart failure, disease management programs and telemonitoring can reduce hospitalizations and mortality.

American adults 40 years and older have about a 20% lifetime risk of developing heart failure.1 The diagnosis is associated with significant morbidity and mortality. Over the past three decades, the prevalence of heart failure in the United States has continued to increase, largely because the population is aging, and older individuals are at higher risk of developing the disease.2

WHAT IS NEW ON THIS TOPIC: HEART FAILURE

Based on limited high-quality evidence, American College of Cardiology/American Heart Association/Heart Failure Society of America guidelines recommend ARB/neprilysin inhibitor therapy as a first-line alternative to ACE inhibitors for those with symptomatic heart failure who are not hypotensive or intolerant of angiotensin system antagonists.

Disease management programs and telemonitoring can reduce hospitalizations and mortality, especially for patients who have previously been hospitalized for heart failure.


ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker.

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SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence ratingReferences

The combination of sacubitril/valsartan (Entresto) may be an alternative to angiotensin-converting enzyme inhibitors in patients with heart failure.

B

13

Aldosterone antagonists and beta blockers decrease mortality in patients with symptomatic heart failure.

A

510

The sinus modulator ivabradine (Corlanor) decreases the risk of cardiovascular death or hospitalization in patients with sinus rhythm, with a heart rate of more than 70 beats per minute, and who are taking the tolerated or target dosage of a beta blocker.

B

14

Consider referral for device therapy (implantable cardioverter-defibrillators and cardiac resynchronization therapy) in patients with reduced ejection fraction and symptomatic heart failure or ischemic cardiomyopathy whose life expectancy is more than one year.

A

2224, 42


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence ratingReferences

The combination of sacubitril/valsartan (Entresto) may be an alternative to angiotensin-converting enzyme inhibitors in patients with heart failure.

B

13

Aldosterone antagonists and beta blockers decrease mortality in patients with symptomatic heart failure.

A

510

The sinus modulator ivabradine (Corlanor) decreases the risk of cardiovascular death or hospitalization in patients with sinus rhythm, with a heart rate of more than 70 beats per minute, and who are taking the tolerated or target dosage of a beta blocker.

B

14

Consider referral for device therapy (implantable cardioverter-defibrillators and cardiac resynchronization therapy) in patients with reduced ejection fraction and symptomatic heart failure or ischemic cardiomyopathy whose life expectancy is more than one year.

A

2224, 42


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.

Clinical trials of patients with left ventricular systolic dysfunction, also called heart failure with reduced ejection fraction, have demonstrated that angiotensin-converting enzyme (ACE) inhibitors,3 angiotensin receptor blockers (ARBs),4 beta blockers,57 aldosterone antagonists,810 and in selected populations isosorbide dinitrate/hydralazine (Bidil)11,12 reduce all-cause mortality and hospitalizations for heart failure. More recent clinical trials have demonstrated benefit from an ARB/neprilysin inhibitor and from a sinus node modulator.13,14

Overall adjusted hospitalization rates for Medicare patients with heart failure dropped almost 30% between 1998 and 2008, partly because of application of these effective therapies.15 Also, risk-adjusted one-year mortality declined from 31.7% to 29.6%. These benefits occurred even though an analysis of 137 cardiology practices found only 80% of eligible patients were on ACE inhibitors or ARBs, 86% were on beta blockers, and 34% were on aldosterone antagonists.16

This article provides a symptom-based strategy for the treatment of heart failure with reduced ejection fraction. Symptoms of heart failure, often classified by the New York Heart Association (NYHA) system and occasionally by the American College of Cardiology/American Heart Association (ACC/AHA) system, are summarized in Table 1.17 Patients with symptoms and a history of hospitalization for heart failure are at significantly higher risk of subsequent mortality and recurrent hospitalization for heart failure. American Family Physician has published articles on the prevention and diagnosis of heart failure and the management of heart failure due to preserved ejection fraction.18,19  Electrophysiologic devices (defibrillators and biventricular pacing for resynchronization) and advanced heart failure therapies (mechanical assist devices, cardiac transplantation) are beyond the scope of this article. Table 2 summarizes heart failure symptom progression and suggested management. 3,514,2027

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Table 1.

Functional Classification Systems for Heart Failure

New York Heart Association classification

I: Asymptomatic

II: Minor symptoms, symptoms with modest exertion

III: Moderate symptoms, symptoms with minor exertion

IV: Symptoms at rest

American College of Cardiology/American Heart Association classification

A: At risk of heart failure but without structural disease

B: Structural heart failure but without symptoms

C: Structural heart failure with current or prior symptoms

D: Symptoms at rest


Information from reference 17.

Table 1.

Functional Classification Systems for Heart Failure

New York Heart Association classification

I: Asymptomatic

II: Minor symptoms, symptoms with modest exertion

III: Moderate symptoms, symptoms with minor exertion

IV: Symptoms at rest

American College of Cardiology/American Heart Association classification

A: At risk of heart failure but without structural disease

B: Structural heart failure but without symptoms

C: Structural heart failure with current or prior symptoms

D: Symptoms at rest


Information from reference 17.

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Table 2.

Management of Heart Failure Due to Reduced Ejection Fraction

ACC/AHABCD
NYHA classificationIII to IIIIV

AsymptomaticSymptoms, current or priorRecurrent or ongoing rest dyspnea
Never hospitalizedHistory of hospitalization

Pharmacologic management

ACE inhibitor, ARB, or ARB/neprilysin inhibitor (sacubitril/valsartan [Entresto])3,13

ACE inhibitor

ACE inhibitor, ARB, or ARB/neprilysin inhibitor*

ACE inhibitor, ARB, or ARB/neprilysin inhibitor*

ACE inhibitor, ARB, or ARB/neprilysin inhibitor*

Beta blocker 57

Yes†

Yes

Yes

Yes‡

Aldosterone antagonist810

Yes

Yes

Yes

Isosorbide dinitrate/hydralazine (Bidil)11,12

Selected patients§

Selected patients§

Selected patients§

Diuretic

As needed for congestion

As needed for congestion

Yes

Digoxin20

As needed||

As needed||

As needed||

Ivabradine (Corlanor)14

Selected patients¶

Selected patients¶

Nonpharmacologic management

Refer for possible automatic implantable cardioverter-defibrillator or pacemaker2124

Selected patients**

Yes

Yes

Yes

Heart failure disease management25,26

Yes

Yes

Referral to an advanced heart failure program25,26

Yes

Yes††


note: See Table 1 for definitions of ACC/AHA and NYHA classifications of heart failure. Yellow shading = recommended; white shading = should be considered.

ACC = American College of Cardiology; ACE = angiotensin-converting enzyme; AHA = American Heart Association; ARB = angiotensin receptor blocker; NYHA = New York Heart Association.

*—One trial has demonstrated superiority of sacubitril/valsartan over enalapril (Vasotec) in symptomatic patients.13 Given the lack of real-world experience, either option is reasonable. Sacubitril/valsartan should not be used in conjunction with an ACE inhibitor or ARB. An ARB should be considered in those intolerant to ACE inhibitors because of cough. If intolerant to ACE inhibitors because of angioedema, the combination of isosorbide dinitrate/hydralazine may be used. An ARB may also be considered, but some cross-reactivity with ACE inhibitors exists.

†—There is no explicit evidence that beta blockers are beneficial in asymptomatic patients, although many of these patients have other indications for beta blockers, such as coronary artery disease.

‡—Beta blockers may be continued safely in patients with dyspnea at rest, except in those with signs of congestion or hemodynamic instability.

§—In one trial, isosorbide dinitrate/hydralazine benefited black patients.12 This combination may be added for black patients who remain symptomatic despite therapy with ACE inhibitors and beta blockers, and as tolerated without reducing the doses of the ACE inhibitor or beta blocker to subtarget dosages.

||—Digoxin may provide symptomatic benefit. If there is no benefit, the drug may be withdrawn; however, withdrawal may lead to clinical deterioration and should be done with caution.

¶—Ivabradine is indicated in patients who are in sinus rhythm and have a heart rate of more than 70 beats per minute; the beta blocker should first be titrated to the target dosage if tolerated.

**—If the patient is asymptomatic, only indicated with ischemic cardiomyopathy.

††—Refer for shared medical decision making regarding use of a left ventricular assist device, transplantation, or palliative care.

Adapted with permission from Chavey WE, et al. University of Michigan Health System. Guidelines for clinical care. Heart failure – systolic dysfunction. August 2013. http://www.med.umich.edu/1info/FHP/practiceguides/heart/HF.pdf. Accessed August 22, 2016; with additional information from references 3, 5 through 14, and 20 through 26.

Table 2.

Management of Heart Failure Due to Reduced Ejection Fraction

ACC/AHABCD
NYHA classificationIII to IIIIV

AsymptomaticSymptoms, current or priorRecurrent or ongoing rest dyspnea
Never hospitalizedHistory of hospitalization

Pharmacologic management

ACE inhibitor, ARB, or ARB/neprilysin inhibitor (sacubitril/valsartan [Entresto])3,13

ACE inhibitor

ACE inhibitor, ARB, or ARB/neprilysin inhibitor*

ACE inhibitor, ARB, or ARB/neprilysin inhibitor*

ACE inhibitor, ARB, or ARB/neprilysin inhibitor*

Beta blocker 57

Yes†

Yes

Yes

Yes‡

Aldosterone antagonist810

Yes

Yes

Yes

Isosorbide dinitrate/hydralazine (Bidil)11,12

Selected patients§

Selected patients§

Selected patients§

Diuretic

As needed for congestion

As needed for congestion

Yes

Digoxin20

As needed||

As needed||

As needed||

Ivabradine (Corlanor)14

Selected patients¶

Selected patients¶

Nonpharmacologic management

Refer for possible automatic implantable cardioverter-defibrillator or pacemaker2124

Selected patients**

Yes

Yes

Yes

Heart failure disease management25,26

Yes

Yes

Referral to an advanced heart failure program25,26

Yes

Yes††


note: See Table 1 for definitions of ACC/AHA and NYHA classifications of heart failure. Yellow shading = recommended; white shading = should be considered.

ACC = American College of Cardiology; ACE = angiotensin-converting enzyme; AHA = American Heart Association; ARB = angiotensin receptor blocker; NYHA = New York Heart Association.

*—One trial has demonstrated superiority of sacubitril/valsartan over enalapril (Vasotec) in symptomatic patients.13 Given the lack of real-world experience, either option is reasonable. Sacubitril/valsartan should not be used in conjunction with an ACE inhibitor or ARB. An ARB should be considered in those intolerant to ACE inhibitors because of cough. If intolerant to ACE inhibitors because of angioedema, the combination of isosorbide dinitrate/hydralazine may be used. An ARB may also be considered, but some cross-reactivity with ACE inhibitors exists.

†—There is no explicit evidence that beta blockers are beneficial in asymptomatic patients, although many of these patients have other indications for beta blockers, such as coronary artery disease.

‡—Beta blockers may be continued safely in patients with dyspnea at rest, except in those with signs of congestion or hemodynamic instability.

§—In one trial, isosorbide dinitrate/hydralazine benefited black patients.12 This combination may be added for black patients who remain symptomatic despite therapy with ACE inhibitors and beta blockers, and as tolerated without reducing the doses of the ACE inhibitor or beta blocker to subtarget dosages.

||—Digoxin may provide symptomatic benefit. If there is no benefit, the drug may be withdrawn; however, withdrawal may lead to clinical deterioration and should be done with caution.

¶—Ivabradine is indicated in patients who are in sinus rhythm and have a heart rate of more than 70 beats per minute; the beta blocker should first be titrated to the target dosage if tolerated.

**—If the patient is asymptomatic, only indicated with ischemic cardiomyopathy.

††—Refer for shared medical decision making regarding use of a left ventricular assist device, transplantation, or palliative care.

Adapted with permission from Chavey WE, et al. University of Michigan Health System. Guidelines for clinical care. Heart failure – systolic dysfunction. August 2013. http://www.med.umich.edu/1info/FHP/practiceguides/heart/HF.pdf. Accessed August 22, 2016; with additional information from references 3, 5 through 14, and 20 through 26.

Pharmacologic Treatment Options

Recommended dosages for heart failure medications are presented in Table 3.27

Table 4 describes clinical nuances of administering the various treatment options.27

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Table 3.

Pharmacologic Therapy for Heart Failure

TherapyStarting dosageTarget/common dosageCost*

Drugs shown to decrease mortality and/or improve symptoms†

Aldosterone antagonists†

Eplerenone (Inspra)

25 mg once per day

50 mg once per day

$65 ($275)

Spironolactone (Aldactone)

12.5 mg once per day

25 mg once per day

$10 ($70)

Angiotensin-converting enzyme inhibitors†

Captopril

6.25 mg (one-half tablet) three times per day

12.5 to 50 mg three times per day

$35 to $150

Enalapril (Vasotec)

2.5 mg twice per day

10 mg twice per day

$25 ($920)

Fosinopril

5 to 10 mg once per day

40 mg once per day

$20

Lisinopril (Prinivil)

5 mg once per day

10 to 20 mg once per day

$9 ($60)

Perindopril (Aceon)

2 mg once per day

8 to 16 mg once per day

$40 to $125 ($100 to $200)

Quinapril (Accupril)

5 mg once per day

10 to 20 mg twice per day

$20 ($250)

Ramipril (Altace)

1.25 mg twice per day

5 mg twice per day

$13 ($300)

Trandolapril (Mavik)

1 mg once per day

4 mg once per day

$16 ($75)

Angiotensin receptor blockers†

Candesartan (Atacand)

4 mg once per day

32 mg once per day

$65 ($145)

Valsartan (Diovan)

40 mg twice per day

160 mg twice per day

$30 ($420)

Beta blockers†

Bisoprolol (Zebeta)

1.25 mg (one-fourth tablet§) once per day

10 mg once per day

$20 ($175)

Carvedilol (Coreg)

3.125 mg twice per day

25 mg twice per day

$10 ($266)

Metoprolol succinate (Toprol XL)

12.5 mg (one-half tablet) once per day

200 mg once per day

$35 ($100)

Angiotensin receptor blocker/neprilysin inhibitor

Sacubitril/valsartan (Entresto)

49 mg/51 mg twice per day

97 mg/103 mg twice per day

Not available ($425)

Sinus node modulator

Ivabradine (Corlanor)

5 mg twice per day

7.5 mg twice per day

Not available ($407)

Vasodilators†

Hydralazine

37.5 mg three times per day

75 mg three times per day

$35

Isosorbide dinitrate (Isordil)

20 mg three times per day

40 mg three times per day

$180 ($245)

Isosorbide dinitrate/hydralazine (Bidil)

20 mg/37.5 mg three times per day

40 mg/75 mg three times per day

Not available ($590)

Drugs for symptomatic therapy†

Diuretics (loop)‡§

Bumetanide

1 mg once per day

1 to 10 mg per dose (maximum 10 mg per day)

$165 for maximum

Ethacrynic acid (Edecrin)

25 mg once per day

25 to 200 mg per dose (maximum 400 mg per day)

$8,000 ($11,850)

Furosemide (Lasix)

40 mg once per day

20 to 160 mg per dose (maximum 600 mg per day)

$40 ($420) for maximum

Torsemide (Demadex)

20 mg once per day

20 to 100 mg per dose (maximum 200 mg per day)

$35 ($980) for maximum

Diuretics (thiazide)‡§

Hydrochlorothiazide

25 mg once per day

25 to 100 mg once per day

$8

Metolazone

2.5 mg once per day

2.5 to 10 mg once per day

$30

Inotrope†

Digoxin (Lanoxin)

0.125 mg once per day

0.125 to 0.375 mg per day

$15 ($230) to $35 ($650)


*—Estimated retail price of one month's treatment based on information obtained at http://www.goodrx.com (accessed October 19, 2016). Generic price listed first; brand price listed in parentheses.

†—Although other drugs are available in these classes, they have not been demonstrated to decrease mortality or improve symptoms in patients with heart failure.

‡—Common doses.

§—Diuretics have not been separately studied for target dosage. They should be titrated as needed for symptom relief.

Adapted with permission from Chavey WE, et al. University of Michigan Health System. Guidelines for clinical care. Heart failure – systolic dysfunction. August 2013. http://www.med.umich.edu/1info/FHP/practiceguides/heart/HF.pdf. Accessed August 22, 2016.

Table 3.

Pharmacologic Therapy for Heart Failure

TherapyStarting dosageTarget/common dosageCost*

Drugs shown to decrease mortality and/or improve symptoms†

Aldosterone antagonists†

Eplerenone (Inspra)

25 mg once per day

50 mg once per day

$65 ($275)

Spironolactone (Aldactone)

12.5 mg once per day

25 mg once per day

$10 ($70)

Angiotensin-converting enzyme inhibitors†

Captopril

6.25 mg (one-half tablet) three times per day

12.5 to 50 mg three times per day

$35 to $150

Enalapril (Vasotec)

2.5 mg twice per day

10 mg twice per day

$25 ($920)

Fosinopril

5 to 10 mg once per day

40 mg once per day

$20

Lisinopril (Prinivil)

5 mg once per day

10 to 20 mg once per day

$9 ($60)

Perindopril (Aceon)

2 mg once per day

8 to 16 mg once per day

$40 to $125 ($100 to $200)

Quinapril (Accupril)

5 mg once per day

10 to 20 mg twice per day

$20 ($250)

Ramipril (Altace)

1.25 mg twice per day

5 mg twice per day

$13 ($300)

Trandolapril (Mavik)

1 mg once per day

4 mg once per day

$16 ($75)

Angiotensin receptor blockers†

Candesartan (Atacand)

4 mg once per day

32 mg once per day

$65 ($145)

Valsartan (Diovan)

40 mg twice per day

160 mg twice per day

$30 ($420)

Beta blockers†

Bisoprolol (Zebeta)

1.25 mg (one-fourth tablet§) once per day

10 mg once per day

$20 ($175)

Carvedilol (Coreg)

3.125 mg twice per day

25 mg twice per day

$10 ($266)

Metoprolol succinate (Toprol XL)

12.5 mg (one-half tablet) once per day

200 mg once per day

$35 ($100)

Angiotensin receptor blocker/neprilysin inhibitor

Sacubitril/valsartan (Entresto)

49 mg/51 mg twice per day

97 mg/103 mg twice per day

Not available ($425)

Sinus node modulator

Ivabradine (Corlanor)

5 mg twice per day

7.5 mg twice per day

Not available ($407)

Vasodilators†

Hydralazine

37.5 mg three times per day

75 mg three times per day

$35

Isosorbide dinitrate (Isordil)

20 mg three times per day

40 mg three times per day

$180 ($245)

Isosorbide dinitrate/hydralazine (Bidil)

20 mg/37.5 mg three times per day

40 mg/75 mg three times per day

Not available ($590)

Drugs for symptomatic therapy†

Diuretics (loop)‡§

Bumetanide

1 mg once per day

1 to 10 mg per dose (maximum 10 mg per day)

$165 for maximum

Ethacrynic acid (Edecrin)

25 mg once per day

25 to 200 mg per dose (maximum 400 mg per day)

$8,000 ($11,850)

Furosemide (Lasix)

40 mg once per day

20 to 160 mg per dose (maximum 600 mg per day)

$40 ($420) for maximum

Torsemide (Demadex)

20 mg once per day

20 to 100 mg per dose (maximum 200 mg per day)

$35 ($980) for maximum

Diuretics (thiazide)‡§

Hydrochlorothiazide

25 mg once per day

25 to 100 mg once per day

$8

Metolazone

2.5 mg once per day

2.5 to 10 mg once per day

$30

Inotrope†

Digoxin (Lanoxin)

0.125 mg once per day

0.125 to 0.375 mg per day

$15 ($230) to $35 ($650)


*—Estimated retail price of one month's treatment based on information obtained at http://www.goodrx.com (accessed October 19, 2016). Generic price listed first; brand price listed in parentheses.

†—Although other drugs are available in these classes, they have not been demonstrated to decrease mortality or improve symptoms in patients with heart failure.

‡—Common doses.

§—Diuretics have not been separately studied for target dosage. They should be titrated as needed for symptom relief.

Adapted with permission from Chavey WE, et al. University of Michigan Health System. Guidelines for clinical care. Heart failure – systolic dysfunction. August 2013. http://www.med.umich.edu/1info/FHP/practiceguides/heart/HF.pdf. Accessed August 22, 2016.

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Table 4.

“Clinical Pearls” in the Pharmacologic Treatment of Heart Failure

Drug categoryClinical pearls

ACE inhibitors/ARBs

Class effect. ACE inhibitors appear to exhibit a class effect. All members of this class may be equally effective.

Contraindications. ACE inhibitors and ARBs may cause hyperkalemia in the presence of renal failure and should be avoided or used with caution in patients with a creatinine level of more than 2.5 mg per dL (221 μmol per L), a glomerular filtration rate of less than 30 mL per minute per 1.73 m2, or a potassium level of more than 5 mEq per L (5 mmol per L). Both drug classes are contraindicated in pregnant women and in patients with bilateral renal artery stenosis, unilateral renal artery stenosis and a solitary kidney, or allergies. Angioedema occurs rarely with either drug class.

ARB/neprilysin inhibitor

Contraindications. An ARB/neprilysin inhibitor should not be used concomitantly with ACE inhibitors or ARBs. It may cause hypotension or rarely angioedema. Precautions appropriate for ARBs related to concerns for hyperkalemia and renal failure also apply to the ARB/neprilysin inhibitor.

Beta blockers

Add when stable. Beta blockers may be used in patients with heart failure due to systolic dysfunction who do not have contraindications. They should be added when patients are stable to stop the progression of the disease. They are not used as rescue therapy for patients who are decompensating.

Dosing. Start at a low dose, and double the dose every two to four weeks as tolerated until the target dosage is reached (see Table 3 for dosing). Stop titration if the patient is intolerant of higher doses.

Absolute contraindications are heart block, bradycardia, and severe reversible airway disease.

Relative contraindications are dyspnea at rest with signs of congestion or hemodynamic instability. Once these issues have resolved, beta blockers may be added to the chronic regimen.

Aldosterone antagonists

Hyperkalemia. The risk of hyperkalemia may be significant. These risks can be minimized by avoiding use in patients with a glomerular filtration rate of less than 30 mL per minute per 1.73 m2 or a creatinine level of more than 2.5 mg per dL, and by ensuring appropriate patient selection before initiating therapy (Table 2). Electrolytes must be monitored closely, as was done in clinical trials: monitor electrolytes when medication changes are made five to seven days after a dose change, and again after 30 days. A potassium elevation of more than 5 mEq per L should prompt a dose reduction or drug discontinuation.

Isosorbide dinitrate and hydralazine

Dosing. These medications are available as a fixed-dose combination (Bidil) or as individual generic components. Clinical trials were performed using isosorbide dinitrate. Isosorbide mononitrate is dosed daily and is more convenient. Evidence of clinical equivalence of the mononitrate form is based on expert opinion.

Contraindications. These medications cannot be used concomitantly with phosphodiesterase inhibitors, such as sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra).

Ivabradine (Corlanor)

Initiation. It is used in patients with persistent symptoms and a heart rate of more than 70 beats per minute despite maximally tolerated or target dosage of beta-blocker therapy.

Contraindication. It should not be used in patients with atrial fibrillation.

Diuretics

Background therapy. Although not specifically tested in clinical trials, diuretics should be used as needed for volume overload. Diuretics were consistently part of background therapy in all published placebo-controlled mortality trials of symptomatic patients in which ACE inhibitors, beta blockers, and aldosterone antagonists were tested.

Combining drugs

Starting other drugs. The therapy described in Table 2 is the desired end point for patients with the indicated symptoms and history. No data are available to indicate how best to introduce these medications. All of the major trials added beta blockers or spironolactone to background therapy of ACE inhibitors, diuretics, and sometimes digoxin.

Electrolytes and renal function. Many of the medications appropriate for heart failure (ACE inhibitors, ARBs, aldosterone antagonists, digoxin) can affect potassium levels or can be affected by potassium levels and renal function. Vigilant monitoring is required.

Discontinuation. ACE inhibitors, beta blockers, spironolactone, and ARBs should not be discontinued if symptoms improve because they slow disease progression and decrease mortality.

Referral

Consider referral for diagnostic procedures, ventricular arrhythmias, revascularization procedures, valvular heart disease, worsening or refractory heart failure, or consideration for transplantation.


ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker.

Adapted with permission from Chavey WE, et al. University of Michigan Health System. Guidelines for clinical care. Heart failure – systolic dysfunction. August 2013. http://www.med.umich.edu/1info/FHP/practiceguides/heart/HF.pdf. Accessed August 22, 2016.

Table 4.

“Clinical Pearls” in the Pharmacologic Treatment of Heart Failure

Drug categoryClinical pearls

ACE inhibitors/ARBs

Class effect. ACE inhibitors appear to exhibit a class effect. All members of this class may be equally effective.

Contraindications. ACE inhibitors and ARBs may cause hyperkalemia in the presence of renal failure and should be avoided or used with caution in patients with a creatinine level of more than 2.5 mg per dL (221 μmol per L), a glomerular filtration rate of less than 30 mL per minute per 1.73 m2, or a potassium level of more than 5 mEq per L (5 mmol per L). Both drug classes are contraindicated in pregnant women and in patients with bilateral renal artery stenosis, unilateral renal artery stenosis and a solitary kidney, or allergies. Angioedema occurs rarely with either drug class.

ARB/neprilysin inhibitor

Contraindications. An ARB/neprilysin inhibitor should not be used concomitantly with ACE inhibitors or ARBs. It may cause hypotension or rarely angioedema. Precautions appropriate for ARBs related to concerns for hyperkalemia and renal failure also apply to the ARB/neprilysin inhibitor.

Beta blockers

Add when stable. Beta blockers may be used in patients with heart failure due to systolic dysfunction who do not have contraindications. They should be added when patients are stable to stop the progression of the disease. They are not used as rescue therapy for patients who are decompensating.

Dosing. Start at a low dose, and double the dose every two to four weeks as tolerated until the target dosage is reached (see Table 3 for dosing). Stop titration if the patient is intolerant of higher doses.

Absolute contraindications are heart block, bradycardia, and severe reversible airway disease.

Relative contraindications are dyspnea at rest with signs of congestion or hemodynamic instability. Once these issues have resolved, beta blockers may be added to the chronic regimen.

Aldosterone antagonists

Hyperkalemia. The risk of hyperkalemia may be significant. These risks can be minimized by avoiding use in patients with a glomerular filtration rate of less than 30 mL per minute per 1.73 m2 or a creatinine level of more than 2.5 mg per dL, and by ensuring appropriate patient selection before initiating therapy (Table 2). Electrolytes must be monitored closely, as was done in clinical trials: monitor electrolytes when medication changes are made five to seven days after a dose change, and again after 30 days. A potassium elevation of more than 5 mEq per L should prompt a dose reduction or drug discontinuation.

Isosorbide dinitrate and hydralazine

Dosing. These medications are available as a fixed-dose combination (Bidil) or as individual generic components. Clinical trials were performed using isosorbide dinitrate. Isosorbide mononitrate is dosed daily and is more convenient. Evidence of clinical equivalence of the mononitrate form is based on expert opinion.

Contraindications. These medications cannot be used concomitantly with phosphodiesterase inhibitors, such as sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra).

Ivabradine (Corlanor)

Initiation. It is used in patients with persistent symptoms and a heart rate of more than 70 beats per minute despite maximally tolerated or target dosage of beta-blocker therapy.

Contraindication. It should not be used in patients with atrial fibrillation.

Diuretics

Background therapy. Although not specifically tested in clinical trials, diuretics should be used as needed for volume overload. Diuretics were consistently part of background therapy in all published placebo-controlled mortality trials of symptomatic patients in which ACE inhibitors, beta blockers, and aldosterone antagonists were tested.

Combining drugs

Starting other drugs. The therapy described in Table 2 is the desired end point for patients with the indicated symptoms and history. No data are available to indicate how best to introduce these medications. All of the major trials added beta blockers or spironolactone to background therapy of ACE inhibitors, diuretics, and sometimes digoxin.

Electrolytes and renal function. Many of the medications appropriate for heart failure (ACE inhibitors, ARBs, aldosterone antagonists, digoxin) can affect potassium levels or can be affected by potassium levels and renal function. Vigilant monitoring is required.

Discontinuation. ACE inhibitors, beta blockers, spironolactone, and ARBs should not be discontinued if symptoms improve because they slow disease progression and decrease mortality.

Referral

Consider referral for diagnostic procedures, ventricular arrhythmias, revascularization procedures, valvular heart disease, worsening or refractory heart failure, or consideration for transplantation.


ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker.

Adapted with permission from Chavey WE, et al. University of Michigan Health System. Guidelines for clinical care. Heart failure – systolic dysfunction. August 2013. http://www.med.umich.edu/1info/FHP/practiceguides/heart/HF.pdf. Accessed August 22, 2016.

ACE INHIBITORS

Since the 1980s, ACE inhibitors have been the cornerstone of therapy for heart failure in patients without contraindications or intolerance. With the exception of isosorbide dinitrate/hydralazine11 and ARBs,4 which demonstrated benefit among those who cannot tolerate ACE inhibitors, all other heart failure therapies have been studied in patients who were already on ACE inhibitors. All ACE inhibitors that have been tested in clinical trials have shown benefit, and thus exhibit a class effect.

ARB/NEPRILYSIN INHIBITOR

The inhibition of neutral endopeptidase (neprilysin), a protease, leads to increasing concentrations of natriuretic and vasoactive peptides.28 Targeted neprilysin inhibition can produce beneficial and deleterious effects.29 The PARADIGM-HF study aimed to assess the impact of the neprilysin inhibitor sacubitril combined with the ARB valsartan (Entresto) among patients with heart failure and reduced ejection fraction.13 This drug company–sponsored trial included 8,842 patients with symptomatic heart failure who received sacubitril/valsartan or the ACE inhibitor enalapril (Vasotec) at a dosage of 10 mg twice daily. The primary outcome was a composite of death from cardiovascular causes or a first hospitalization from heart failure. The trial was stopped early at 27 months (the planned duration was 34 months) because of demonstrated benefit. The primary outcome was reached in 26.5% of patients taking enalapril vs. 21.8% of those taking sacubitril/valsartan (hazard ratio [HR] = 0.80; P < .001; number needed to treat [NNT] = 22). Although it was not the primary outcome, death from cardiovascular causes was reduced (16.5% vs. 13.3%; HR = 0.80; P < .001; NNT = 31), as was the overall death rate (19.8% vs. 17.0%; HR = 0.84; P < .001; NNT = 36). The sacubitril/valsartan combination, the only product of its kind, is now being referred to as an ARB/neprilysin inhibitor.

The estimated yearly cost for sacubitril/valsartan is $4,600.30 The associated cost-effectiveness ratio of $51,000 per quality-adjusted life-year is at the upper range of what is generally considered cost-effective.30 Another U.S. analysis found an incremental cost-effectiveness ratio of $45,000 per quality-adjusted life-year compared with enalapril.31 A theoretical concern is that inhibition of neprilysin might increase β-amyloid peptides associated with Alzheimer disease, but this effect has not yet been shown to be clinically relevant.32

In July 2015, the U.S. Food and Drug Administration approved the use of sacubitril/valsartan in patients with chronic heart failure and reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure.33 However, it has been tested in only one study and there has been limited postmarketing surveillance for potential deleterious effects. Based on limited high-quality evidence, ACC/AHA/Heart Failure Society of America (HFSA) guidelines recommend ARB/neprilysin inhibitor therapy as a first-line alternative to ACE inhibitors in patients with symptomatic heart failure who are not hypotensive or intolerant of angiotensin system antagonists.34 The American Academy of Family Physicians did not endorse this guideline because of concerns about its methodology and insufficient evaluation of harms.

BETA BLOCKER

Beta blockers, such as bisoprolol (Zebeta), carvedilol (Coreg), and metoprolol succinate (Toprol XL), are effective at reducing mortality in patients with symptomatic heart failure when combined with ACE inhibitors.57 Beta blockers have not been tested in those with NYHA class I (asymptomatic) heart failure. However, because heart failure with reduced ejection fraction is often caused by ischemic heart disease, many patients with NYHA class I heart failure might also benefit from beta blockers. Beta blockers work by blunting the noradrenergic hormonal influences and have long-term benefits. They are not rescue agents, and are best started when patients are stable and have no symptoms at rest. Dosing is important when using beta blockers for heart failure; dosages below the target do not appear to have the same impact.

ALDOSTERONE ANTAGONIST

Eplerenone (Inspra) and spironolactone have been proven beneficial in patients with heart failure when added to ACE inhibitor and beta-blocker therapy.810 Eplerenone or spironolactone is indicated in all symptomatic patients with heart failure due to reduced ejection fraction, and three to 14 days post–myocardial infarction in patients with reduced ejection fraction and symptomatic heart failure or concomitant diabetes mellitus.

ARB

ARBs have shown benefit as a substitute in those who cannot take ACE inhibitors.4 They should not be used in patients taking ACE inhibitors.

DIRECT-ACTING VASODILATORS

The direct-acting vasodilator isosorbide dinitrate/hydralazine is an option for those intolerant of ACE inhibitors and ARBs because of renal disease, and is indicated as adjunctive therapy in black patients who remain symptomatic despite treatment with ACE inhibitors. The African-American Heart Failure Trial showed that isosorbide dinitrate/hydralazine added to ACE inhibitor therapy provides incremental mortality benefit in black patients.12 Retrospective evaluations of prior trials suggest that nonblack patients have greater benefit from ACE inhibitors, but black patients have greater benefit from isosorbide dinitrate/hydralazine.35,36 A substudy of the African-American Heart Failure Trial showed that a genetic polymorphism that is more common among blacks is responsible for the difference in outcomes.37 Isosorbide dinitrate/hydralazine is taken three times daily, making compliance a challenge.

DIGOXIN

Digoxin should be considered for those who remain symptomatic despite therapy with all other disease-modifying agents. It works as a positive inotrope but can also be arrhythmogenic. In the only large controlled trial of digoxin in patients with heart failure, digoxin had no impact on mortality but decreased hospitalization rates.20

SINUS NODE MODULATOR

The SHIFT trial was a double-blind randomized controlled trial of ivabradine (Corlanor) vs. placebo that included patients with reduced ejection fraction who had been admitted to the hospital for heart failure within the 12 months before enrollment; were in sinus rhythm; and were taking some combination of an ACE inhibitor (79%), ARB (14%), beta blocker (90%), diuretic (84%), aldosterone antagonist (60%), and glycoside (digoxin, digitoxin [no longer available in the United States]; 22%). In the study, 6,558 patients were followed for a median of 22.9 months, and ivabradine was titrated to a maximum dosage of 7.5 mg twice daily.14 The primary end point was cardiovascular death or hospitalization for decompensated heart failure. Patients in the treatment arm had an 18% lower risk of reaching the primary end point compared with those in the placebo arm (24% vs. 29%; HR = 0.82; P < .0001; NNT = 26), primarily because of a reduction in admissions for heart failure. Further analysis demonstrated that the improved clinical outcomes occurred only in patients with a heart rate of more than 70 beats per minute. Ivabradine provided no benefit in patients with a lower heart rate. The U.S. Food and Drug Administration approved ivabradine for heart failure management in 2015.38

In contrast to the SHIFT study, ivabradine was not effective in a previous trial of patients with reduced ejection fraction and ischemic heart disease, not all of whom had a prior hospitalization for heart failure.39 According to ACC/AHA/HFSA guidelines, ivabradine may be considered in appropriate patients, but the beta blocker should first be titrated to the target dosage if tolerated.34

DIURETICS

Diuretic therapy (loop and thiazide) is essential when needed to manage volume status in patients with heart failure. Diuretics do not provide mortality benefit, so they should be used only when needed to treat congestion.

STATINS

The role of statins in the management of patients with heart failure is unproven. Two large trials failed to demonstrate any benefit from statins among patients with heart failure and reduced ejection fraction, even if the heart failure was due to ischemic heart disease.40,41 The 2013 ACC/AHA guidelines do not recommend statin therapy solely for the treatment of heart failure.21

Device Therapy

Implantable cardioverter-defibrillators improve mortality, and cardiac resynchronization therapy (biventricular pacemakers with or without an automatic implantable cardioverter-defibrillator) can improve symptoms among patients with heart failure.2224,42 The determination of patient eligibility for device therapy can be complicated and is driven in part by Medicare coverage criteria. Any patient with reduced ejection fraction and symptomatic heart failure or ischemic cardiomyopathy whose life expectancy is more than one year may be referred to electrophysiology for possible device therapy. 2224,42

Disease Management

Disease management programs and telemonitoring can reduce hospitalizations and mortality, especially in patients who were previously hospitalized for heart failure.25,26 Key components include heart failure education emphasizing self-care and adherence to medications, face-to-face contact after hospital discharge, mechanisms for postdischarge medication adjustment, and patient hotlines or other ways of quickly reaching clinicians.43

Data Sources: A literature review was generated from Essential Evidence Plus, which included relevant POEMs, Cochrane reviews, diagnostic test data, and a PubMed search for the best available evidence. Search date: August 12, 2015.

The authors thank Ellen Patrick for her assistance with the preparation of the manuscript.

The Authors

show all author info

WILLIAM E. CHAVEY, MD, MS, is an associate professor and service chief in the Department of Family Medicine at the University of Michigan in Ann Arbor....

ROBERT V. HOGIKYAN, MD, MPH, is an associate professor in the Department of Internal Medicine at the University of Michigan. He is also section chief of geriatric medicine, director of the Advanced Fellowship in Geriatrics, and medical director of the Healthcare System Community Living Center at the Veterans Affairs Hospital in Ann Arbor.

R. VAN HARRISON, PhD, is a professor emeritus at the University of Michigan Health System in Ann Arbor.

JOHN M. NICKLAS, MD, is an associate professor in the Department of Internal Medicine, Division of Cardiology, at the University of Michigan Health System.

Address correspondence to William E. Chavey, MD, MS, 1150 W. Medical Center Dr., M7300 Med Sci I – SPC5625, Ann Arbor, MI 48109-5625 (e-mail: wchavey@umich.edu). Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.

REFERENCES

show all references

1. Lloyd-Jones DM, Larson MG, Leip EP, et al.; Framingham Heart Study. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation. 2002;106(24):3068–3072....

2. Curtis LH, Whellan DJ, Hammill BG, et al. Incidence and prevalence of heart failure in elderly persons, 1994–2003. Arch Intern Med. 2008;168(4):418–424.

3. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991;325(5):303–310.

4. Pfeffer MA, Swedberg K, Granger CB, et al.; CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme [published correction appears in Lancet. 2009;(9703):1744]. Lancet. 2003;362(9386):759–766.

5. Packer M, Bristow MR, Cohn JN, et al.; U.S. Carvedilol Heart Failure Study Group. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med. 1996;334(21):1349–1355.

6. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353(9169):2001–2007.

7. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353(9146):9–13.

8. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341(10):709–717.

9. Pitt B, White H, Nicolau J, et al.; EPHESUS Investigators. Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure. J Am Coll Cardiol. 2005;46(3):425–431.

10. Zannad F, McMurray JJ, Krum H, et al.; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11–21.

11. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med. 1986;314(24):1547–1552.

12. Taylor AL, Ziesche S, Yancy C, et al.; African-American Heart Failure Trial Investigators. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure [published correction appears in N Engl J Med. 2005;352(12):1276]. N Engl J Med. 2004;351(20):2049–2057.

13. McMurray JJ, Packer M, Desai AS, et al.; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993–1004.

14. Swedberg K, Komajda M, Böhm M, et al.; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study [published correction appears in Lancet. 2010; 376(9757):1988]. Lancet. 2010;376(9744):875–885.

15. Chen J, Normand SL, Wang Y, Krumholz HM. National and regional trends in heart failure hospitalization and mortality rates for Medicare beneficiaries, 1998–2008. JAMA. 2011;306(15):1669–1678.

16. Fonarow GC, Albert NM, Curtis AB, et al. Improving evidence-based care for heart failure in outpatient cardiology practices: primary results of the Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting (IMPROVE HF). Circulation. 2010;122(6):585–596.

17. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the International Society for Heart and Lung Transplantation; Endorsed by the Heart Failure Society of America. Circulation. 2001;104(24):2996–3007.

18. King M, Kingery J, Casey B. Diagnosis and evaluation of heart failure. Am Fam Physician. 2012;85(12):1161–1168.

19. Satpathy C, Mishra TK, Satpathy R, Satpathy HK, Barone E. Diagnosis and management of diastolic dysfunction and heart failure [published correction appears in Am Fam Physician. 2008;78(4):434]. Am Fam Physician. 2006;73(5):841–846.

20. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336(8):525–533.

21. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):e240–e327.

22. Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G; Multicenter Unsustained Tachycardia Trial Investigators. A randomized study of the prevention of sudden death in patients with coronary artery disease [published correction appears in N Engl J Med. 2000; 342(17):1300]. N Engl J Med. 1999;341(25):1882–1890.

23. Moss AJ, Zareba W, Hall WJ, et al.; Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346(12):877–883.

24. Bardy GH, Lee KL, Mark DB, et al.; Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure [published correction appears in N Engl J Med. 2005;352(20):2146]. N Engl J Med. 2005;352(3):225–237.

25. McAlister FA, Stewart S, Ferrua S, McMurray JJ. Multidisciplinary strategies for the management of heart failure patients at high risk for admission: a systematic review of randomized trials. J Am Coll Cardiol. 2004;44(4):810–819.

26. Inglis SC, Clark RA, McAlister FA, et al. Structured telephone support or telemonitoring programmes for patients with chronic heart failure. Cochrane Database Syst Rev. 2010;(8):CD007228.

27. Chavey WE, et al. University of Michigan Health System. Guidelines for clinical care. Heart failure – systolic dysfunction. August 2013. http://www.med.umich.edu/1info/FHP/practiceguides/heart/HF.pdf. Accessed August 22, 2016.

28. Sonnenberg JL, Sakane Y, Jeng AY, et al. Identification of protease 3.4.24.11 as the major atrial natriuretic factor degrading enzyme in the rat kidney. Peptides. 1988;9(1):173–180.

29. Mangiafico S, Costello-Boerrigter LC, Andersen IA, Cataliotti A, Burnett JC Jr. Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics. Eur Heart J. 2013;34(12):886–893c.

30. Institute for Clinical and Economic Review. ICER releases final report on CardioMEMS HF System and Entresto for management of congestive heart failure. https://icer-review.org/announcements/chf-final-report-released/. Accessed November 1, 2016.

31. Gaziano TA, Fonarow GC, Claggett B, et al. Cost-effectiveness analysis of sacubitril/valsartan vs enalapril in patients with heart failure and reduced ejection fraction. JAMA Cardiol. 2016;1(6):666–672.

32. Vodovar N, Paquet C, Mebazaa A, Launay JM, Hugon J, Cohen-Solal A. Neprilysin, cardiovascular, and Alzheimer's diseases: the therapeutic split? Eur Heart J. 2015;36(15):902–905.

33. U.S. Food and Drug Administration. FDA approves new drug to treat heart failure. July 7, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm453845.htm. Accessed November 1, 2016.

34. Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2016;68(13):1476–1488.

35. Carson P, Ziesche S, Johnson G, Cohn JN; Vasodilator-Heart Failure Trial Study Group. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. J Card Fail. 1999;5(3):178–187.

36. Exner DV, Dries DL, Domanski MJ, Cohn JN. Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction. N Engl J Med. 2001;344(18):1351–1357.

37. McNamara DM, Tam SW, Sabolinski ML, et al. Endothelial nitric oxide synthase (NOS3) polymorphisms in African Americans with heart failure: results from the A-HeFT trial. J Card Fail. 2009;15(3):191–198.

38. U.S. Food and Drug Administration. FDA approves Corlanor to treat heart failure. Updated July 6, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm442978.htm. Accessed November 1, 2016.

39. Fox K, Ford I, Steg PG, Tendera M, Ferrari R; BEAUTIFUL Investigators. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9641):807–816.

40. Tavazzi L, Maggioni AP, Marchioli R, et al.; Gissi-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9645):1231–1239.

41. Kjekshus J, Apetrei E, Barrios V, et al.; CORONA Group. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357(22):2248–2261.

42. Bristow MR, Saxon LA, Boehmer J, et al.; Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350(21):2140–2150.

43. Guirguis-Blake J. Transitional care interventions to prevent readmissions for patients with heart failure. Am Fam Physician. 2016;93(5):401–403.

44. Chavey WE, Bleske BE, Van Harrison R, Hogikyan RV, Kesterson SK, Nicklas JM. Pharmacologic management of heart failure caused by systolic dysfunction. Am Fam Physician. 2008;77(7):957–964.

 

 

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