Ivabradine (Monograph)
Brand name: Corlanor
Drug class: Cardiotonic Agents
Introduction
A sinoatrial modulator; a hyperpolarization activated cyclic nucleotide-gated (HCN) channel (funny-channel [f-channel]) blocking agent.1 7 37 700
Uses for Ivabradine
Heart Failure
Used to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic, mild to severe chronic heart failure (NYHA class II–IV) with reduced ejection fraction (LVEF ≤35%), who are in sinus rhythm with a resting heart rate ≥70 bpm and are either on maximally tolerated dosages of a β-adrenergic blocking agent (β-blocker) or have a contraindication to β-blocker use.1 5 700 701
Current heart failure guidelines generally recommend clinical trial-proven β-blockers (e.g., carvedilol, bisoprolol, extended-release metoprolol succinate) in conjunction with neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs]) to inhibit the renin-angiotensin-aldosterone (RAA) system in patients with heart failure and reduced LVEF due to favorable effects of these drugs on survival and disease progression.524 700 If patients cannot tolerate therapy with a β-blocker or if increasing the β-blocker dosage is ineffective, consider ivabradine in symptomatic patients as an alternative or additional treatment option to reduce heart failure-related hospitalizations.5 8 700 701
Initiate and titrate the dosage of β-blockers upwards to optimal level for prevention of cardiovascular mortality, as tolerated, before assessing resting heart rate for consideration of ivabradine therapy.700
No reduction in cardiovascular mortality demonstrated with ivabradine in patients with chronic heart failure.1 2 8 15 20
Not established whether ivabradine can improve cardiovascular outcomes when added to optimally managed heart failure therapies.17
Angina
Adjunct to or substitute for β-blocker therapy for treatment of chronic stable angina pectoris† [off-label] in patients with inadequately controlled symptoms or a contraindication or intolerance to β-blockers. 11 13 14 24
Reduces heart rate, improves exercise capacity, and decreases the number of anginal attacks.21 23 30 31 34
No benefit with ivabradine in terms of cardiovascular outcomes (e.g., MI, cardiovascular death) in patients with stable coronary artery disease with or without stable heart failure who are receiving guideline-based therapy for angina (e.g., aspirin, statins, ACE inhibitors, β-blockers).1 26
Some clinical trial data suggest ivabradine use was associated with possible increase in the risk of death from cardiovascular causes or nonfatal MI in patients with more severe forms of angina and no clinical heart failure; further study and experience needed.26 29 42
Ivabradine Dosage and Administration
General
-
Individualize dosage according to patient's heart rate response and tolerance (target resting heart rate 50–60 bpm).1
Administration
Oral Administration
Administer twice daily with meals.1
If a dose is missed, take next dose at the regularly scheduled time; do not double the dose.1 (See Advice to Patients.)
Dosage
Available as ivabradine hydrochloride; dosage expressed in terms of ivabradine.1
Adults
Heart Failure
Oral
Initially, 5 mg twice daily.1
Initiate dosage of 2.5 mg twice daily in patients with history of conduction defects, or patients in whom bradycardia could lead to hemodynamic compromise.1
Allow 2 weeks to assess response to initial dosage.1 After initial adjustment period, adjust dosage as needed based on resting heart rate and tolerability to achieve resting heart rate of 50–60 beats/minute.1
If heart rate is >60 beats/minute, increase dosage by 2.5 mg (given twice daily) up to maximum of 7.5 mg twice daily.1
If heart rate is <50 beats/minute or patient is experiencing signs and symptoms of bradycardia, decrease dosage by 2.5 mg (given twice daily).1
Discontinue therapy if patient is receiving ivabradine 2.5 mg twice daily and heart rate is <50 beats/minute or patient is experiencing signs and symptoms of bradycardia.1
Angina† [off-label]
Oral
Dosages of 2.5–10 mg twice daily have been used.21 23 25 26 31 In clinical trials, ivabradine initiated at dosages of 5 or 7.5 mg twice daily and titrated after 2–4 weeks to a target heart rate of 50–60 beats/minute.25 26
In clinical trials, dosage was titrated downward in patients with resting heart rate <50 beats/minute or if signs or symptoms of bradycardia were present.25
Special Populations
Hepatic Impairment
No dosage adjustment required in patients with mild or moderate hepatic impairment.1 40
Contraindicated in patients with severe hepatic impairment (Child-Pugh class C); safety and efficacy not established in this population but increase in systemic exposure expected.1 40 (See Contraindications under Cautions.)
Renal Impairment
No dosage adjustment required for patients with Clcr 15–60 mL/minute.1
Data lacking on use in patients with Clcr <15 mL/minute.1 7 16
Cautions for Ivabradine
Contraindications
-
Acute decompensated heart failure.1
-
BP <90/50 mm Hg.1
-
Resting heart rate <60 bpm prior to treatment.1
-
Severe hepatic impairment.1 40 (See Hepatic Impairment under Cautions.)
-
Pacemaker dependence (heart rate maintained exclusively by pacemaker).1
-
Concomitant use of potent CYP3A4 inhibitors.1 40 (See Drugs and Foods Affecting Hepatic Microsomal Enzymes under Interactions.)
-
Sick sinus syndrome, SA block, or third degree AV block, unless a functioning demand pacemaker is present.1
Warnings/Precautions
Fetal Toxicity
May cause fetal toxicity and teratogenicity when administered to pregnant women based on findings in animals.1
Embryofetal toxicity and cardiac teratogenic effects (abnormal shape of the heart, interventricular septal defect, complex anomalies of primary arteries) observed in fetuses of pregnant rats treated with ivabradine during organogenesis at exposures 1–3 times the human exposures at the maximum recommended human dose.1
Reduced fetal and placental weights and teratogenic effects (ectrodactylia) observed in pregnant rabbits treated with ivabradine during organogenesis at exposures 15 times the human exposure at the maximum recommended human dose.1
Advise women of childbearing potential to use effective contraception while taking ivabradine.1 (See Advice to Patients.)
Atrial Fibrillation
Increases risk of atrial fibrillation.1 2 41
In pivotal clinical trial, rate of atrial fibrillation was 5% per patient-year with ivabradine and 3.9% per patient-year with placebo.1
Regularly monitor cardiac rhythm and discontinue ivabradine if atrial fibrillation occurs.1 (See Advice to Patients.)
Bradycardia and Conduction Disturbances
Bradycardia, sinus arrest, and heart block reported with ivabradine use.1 2 Risk factors for bradycardia include sinus node dysfunction, conduction defects (e.g., first or second degree AV block, bundle branch block), ventricular dyssynchrony, and the use of other negative chronotropes (e.g., digoxin, diltiazem, verapamil, amiodarone).1 Avoid concurrent use of verapamil and diltiazem; increases ivabradine exposure and contributes to heart rate lowering.1 42 (See Calcium-channel Blocking Agents under Interactions.)
Avoid in patients with second degree AV block, unless a functioning demand pacemaker is present.1 (See Contraindications under Cautions.)
Patients with demand pacemakers set to a rate ≥60 bpm cannot achieve target heart rate <60 bpm and were excluded from clinical trials.1 43 Not recommended in patients with demand pacemakers set to rates ≥60 bpm.1
Sensitivity Reactions
Hypersensitivity reactions (e.g., angioedema, erythema, rash, pruritus, urticaria) reported during postmarketing experience.1 (See Contraindications under Cautions.)
Specific Populations
Pregnancy
May cause fetal harm.1 (See Fetal Toxicity under Cautions.)
Monitor pregnant women taking ivabradine, especially during the first trimester, for destabilization of heart failure that could result from heart rate slowing.1
Monitor pregnant women with chronic heart failure in their third trimester for preterm birth.1
Lactation
Distributed into milk in rats; not known whether ivabradine is distributed into human milk.1 Breast-feeding is not recommended.1
Pediatric Use
Safety and efficacy not established in patients <18 years of age.1
Geriatric Use
No pharmacokinetic differences observed in patients ≥65 years of age compared with the overall population.1 Ivabradine studied in only a limited number of patients ≥75 years of age.1
Renal Impairment
Renal impairment (Clcr 15–60 mL/minute) has minimal effect on pharmacokinetics of ivabradine.1
Data lacking on use in patients with Clcr <15 mL/minute.1
Hepatic Impairment
Pharmacokinetics of ivabradine similar in patients with mild and moderate hepatic impairment compared with that in patients with normal hepatic function.1 7
Contraindicated in patients with severe hepatic impairment (Child Pugh class C); increased systemic exposure expected.1 (See Contraindications under Cautions.)
Common Adverse Effects
Bradycardia, hypertension, atrial fibrillation, luminous visual phenomena (phosphenes).1 2
Drug Interactions
Metabolized principally by CYP3A4; does not modify CYP3A4 substrate metabolism or plasma concentrations.1 7 16 38 40
Drugs and Foods Affecting Hepatic Microsomal Enzymes
CYP3A4 inhibitors: Increase plasma ivabradine concentrations; may exacerbate bradycardia and conduction disturbances.1 16 Concomitant use of potent CY3A4 inhibitors (e.g., azole antifungal agents, macrolide antibiotics, HIV protease inhibitors, nefazodone) contraindicated.1 16 40 (See Contraindications under Cautions.) Avoid use of moderate CYP3A4 inhibitors.1
CYP3A4 inducers: Decrease plasma ivabradine concentrations; avoid concomitant use.1
Specific Drugs and Foods
Drug or Food |
Interaction |
Comments |
---|---|---|
β-Adrenergic blocking agents (β-blockers) |
Increases risk of bradycardia1 |
Monitor heart rate with concomitant use1 |
Amiodarone |
Increases risk of bradycardia1 |
Monitor heart rate with concomitant use1 |
Antifungals, azoles (e.g., itraconazole, ketoconazole) |
Increases plasma ivabradine concentrations; may exacerbate bradycardia and conduction disturbances1 7 16 |
|
Barbiturates |
||
Calcium-channel blocking agents, nondihydropyridine (e.g., diltiazem, verapamil) |
Increases plasma ivabradine concentrations, and may exacerbate bradycardia and conduction disturbances; increases risk of bradycardia1 7 16 42 |
|
Digoxin |
Increases risk of bradycardia; digoxin exposure unchanged1 |
Monitor heart rate with concomitant use1 |
Grapefruit juice |
Increases plasma ivabradine concentrations; may exacerbate bradycardia and conduction disturbances1 7 |
|
HIV protease inhibitors (e.g., nelfinavir) |
Increases plasma ivabradine concentrations; may exacerbate bradycardia and conduction disturbances1 16 |
|
Macrolides (e.g., clarithromycin, telithromycin) |
Increases plasma ivabradine concentrations; may exacerbate bradycardia and conduction disturbances1 16 |
|
Metformin |
No effects on the pharmacokinetics of metformin1 |
No dosage adjustment necessary1 |
Nefazodone |
Increases plasma ivabradine concentrations; may exacerbate bradycardia and conduction disturbances1 16 |
|
Phenytoin |
||
Proton-pump inhibitors (e.g., lansoprazole, omeprazole) |
||
Rifampin |
||
Sildenafil |
||
Simvastatin |
No effects on the pharmacokinetics of ivabradine1 |
No dosage adjustment necessary1 |
St. John's wort (Hypericum perforatum) |
||
Warfarin |
Ivabradine Pharmacokinetics
Absorption
Bioavailability
Absolute bioavailability approximately 40%.1 7 16 38 40
Following oral administration, peak plasma concentrations occur within 1 hour under fasting conditions.1 7 16 38 40
Food
Food delays absorption by approximately 1 hour and increases plasma exposure by 20–40%.1 7 16 38 40
Distribution
Extent
Distributed into milk in rats; not known whether distributed into human milk.1 7
Plasma Protein Binding
Approximately 70%.1 7 16 38 40
Elimination
Metabolism
Undergoes first-pass metabolism in gut and liver via CYP3A4-mediated oxidation.1 7 16 38 40 Major metabolite is N-desmethylated derivative (S 18982), which is equipotent to ivabradine and circulates at concentrations approximately 40% that of ivabradine; also metabolized by CYP3A4.1 7 16 38
Elimination Route
Equally excreted in feces and urine as metabolites;1 approximately 4% of an oral dose eliminated in urine as unchanged drug.1 16 38 40
Half-life
Distribution half-life of 2 hours and effective half-life of approximately 6 hours.1
Special Populations
Increased systemic exposure anticipated in severe hepatic impairment (Child-Pugh class C).1
Stability
Storage
Oral
Tablets
25°C (may be exposed to 15–30°C).1
Actions
-
Inhibits the funny-current (I f) by blocking the funny-channel (f-channel) in the cardiac SA node, which is a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel.1 7 36 37 These f-channels, unlike other voltage-gated ion channels, open with hyperpolarization rather than depolarization and have a mixed permeability to sodium and potassium ions.37 38 39 40
-
Enters cardiac pacemaker cells and blocks the f-channel from the cytoplasmic side of the membrane preferentially when the channel is in an open state (state-dependent) and is more efficient at depolarized than hyperpolarized voltages.7 37 40
-
Interaction between ivabradine and the f-channel binding is dependent upon the rate of opening and closing of the channels in response to repolarization and depolarization (i.e., related to heart rate); this use-dependent property makes ivabradine's heart rate reduction effect more pronounced at elevated heart rates.6 7 10 40
-
Ivabradine is drawn to and dissociates from the binding domain of the f-channel by the electrostatic forces generated by depolarization and repolarization (current-dependent). 6 37
-
Blockade of the f-channels by ivabradine inhibits the I f, leading to a reduction in the slow diastolic depolarization phase of the SA node action potential and thereby a reduction in heart rate.7 34 40
-
Adverse effects on vision (e.g., phosphenes) caused by interaction of ivabradine with retinal ion channels (I h), which closely resemble the I f channels in the SA node.7 38 40 (See Common Adverse Effects under Cautions.)
Advice to Patients
-
Importance of advising patients to read the manufacturer's patient labeling (medication guide).1
-
Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.1 Importance of clinician advising females of reproductive potential to use effective contraception and to notify their healthcare provider about a known or suspected pregnancy.1 Importance of informing pregnant women about the potential risks to the fetus.1
-
Importance of advising patients to report substantial decreases in heart rate or symptoms such as dizziness, fatigue, or hypotension.1
-
Importance of advising patients to report symptoms of atrial fibrillation, such as heart palpitations or racing pulse, chest pressure, or worsened shortness of breath.1 Importance of patients receiving regular cardiac rhythm monitoring.1
-
Importance of advising patients about the possible occurrence of luminous phenomena (phosphenes).1 Importance of advising patients to use caution if they are driving or using machines in situations where sudden changes in light intensity may occur, especially when driving at night.1 Importance of informing patients that phosphenes may subside spontaneously during continued treatment with ivabradine.1
-
Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 Importance of advising patients to avoid ingestion of grapefruit juice or St. John's wort.1
-
Importance of advising patients to take ivabradine twice daily with meals.1 If a dose is missed, the next dose should be taken at the usual time; the missed dose should not be doubled.1
-
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Tablets (film-coated) |
5 mg (of ivabradine) |
Corlanor |
Amgen |
7.5 mg (of ivabradine) |
Corlanor |
Amgen |
AHFS DI Essentials™. © Copyright 2024, Selected Revisions April 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.
References
1. Amgen Inc. Corlanor (ivabradine) tablets prescribing information. Thousand Oaks, CA; 2015 Apr.
2. Swedberg K, Komajda M, Böhm M et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010; 376:875-85. http://www.ncbi.nlm.nih.gov/pubmed/20801500?dopt=AbstractPlus
5. Urbanek I, Kaczmarek K, Cygankiewicz I et al. Risk-benefit assessment of ivabradine in the treatment of chronic heart failure. Drug Healthc Patient Saf. 2014; 6:47-54. http://www.ncbi.nlm.nih.gov/pubmed/24855390?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4010635&blobtype=pdf
6. Scicchitano P, Cortese F, Ricci G et al. Ivabradine, coronary artery disease, and heart failure: beyond rhythm control. Drug Des Devel Ther. 2014; 8:689-700. http://www.ncbi.nlm.nih.gov/pubmed/24940047?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4051626&blobtype=pdf
7. Parakh N, Bhargava B. Rate control with ivabradine: angina pectoris and beyond. Am J Cardiovasc Drugs. 2011; 11:1-12. http://www.ncbi.nlm.nih.gov/pubmed/21090826?dopt=AbstractPlus
8. Di Franco A, Sarullo FM, Salerno Y et al. Beta-blockers and ivabradine in chronic heart failure: from clinical trials to clinical practice. Am J Cardiovasc Drugs. 2014; 14:101-10. http://www.ncbi.nlm.nih.gov/pubmed/24327100?dopt=AbstractPlus
9. Fox K, Borer JS, Camm AJ et al. Resting heart rate in cardiovascular disease. J Am Coll Cardiol. 2007; 50:823-30. http://www.ncbi.nlm.nih.gov/pubmed/17719466?dopt=AbstractPlus
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16. Perry CM. Ivabradine: in adults with chronic heart failure with reduced left ventricular ejection fraction. Am J Cardiovasc Drugs. 2012; 12:415-26. http://www.ncbi.nlm.nih.gov/pubmed/23181944?dopt=AbstractPlus
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19. Böhm M, Borer J, Ford I et al. Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study. Clin Res Cardiol. 2013; 102:11-22. http://www.ncbi.nlm.nih.gov/pubmed/22575988?dopt=AbstractPlus
20. Borer JS, Böhm M, Ford I et al. Effect of ivabradine on recurrent hospitalization for worsening heart failure in patients with chronic systolic heart failure: the SHIFT Study. Eur Heart J. 2012; 33:2813-20. http://www.ncbi.nlm.nih.gov/pubmed/22927555?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3498004&blobtype=pdf
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26. Fox K, Ford I, Steg PG et al. Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med. 2014; 371:1091-9. http://www.ncbi.nlm.nih.gov/pubmed/25176136?dopt=AbstractPlus
27. Fox K, Ford I, Steg PG et al. Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur Heart J. 2009; 30:2337-45. http://www.ncbi.nlm.nih.gov/pubmed/19720635?dopt=AbstractPlus
28. Heusch G. A BEAUTIFUL lesson--ivabradine protects from ischaemia, but not from heart failure: through heart rate reduction or more?. Eur Heart J. 2009; 30:2300-1. http://www.ncbi.nlm.nih.gov/pubmed/19720636?dopt=AbstractPlus
29. Ohman EM, Alexander KP. The challenges with chronic angina. N Engl J Med. 2014; 371:1152-3. http://www.ncbi.nlm.nih.gov/pubmed/25176137?dopt=AbstractPlus
30. Ruzyllo W, Tendera M, Ford I et al. Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: a 3-month randomised, double-blind, multicentre, noninferiority trial. Drugs. 2007; 67:393-405. http://www.ncbi.nlm.nih.gov/pubmed/17335297?dopt=AbstractPlus
31. Borer JS, Fox K, Jaillon P et al. Antianginal and antiischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation. 2003; 107:817-23. http://www.ncbi.nlm.nih.gov/pubmed/12591750?dopt=AbstractPlus
33. Jones DA, Timmis A, Wragg A. Novel drugs for treating angina. BMJ. 2013; 347:f4726. http://www.ncbi.nlm.nih.gov/pubmed/24018101?dopt=AbstractPlus
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35. Ruys TP, Cornette J, Roos-Hesselink JW. Pregnancy and delivery in cardiac disease. J Cardiol. 2013; 61:107-12. http://www.ncbi.nlm.nih.gov/pubmed/23290155?dopt=AbstractPlus
36. Thollon C, Vilaine JP. I(f) inhibition in cardiovascular diseases. Adv Pharmacol. 2010; 59:53-92. http://www.ncbi.nlm.nih.gov/pubmed/20933199?dopt=AbstractPlus
37. DiFrancesco D. Funny channels in the control of cardiac rhythm and mode of action of selective blockers. Pharmacol Res. 2006; 53:399-406. http://www.ncbi.nlm.nih.gov/pubmed/16638640?dopt=AbstractPlus
38. Rosa GM, Ferrero S, Ghione P et al. An evaluation of the pharmacokinetics and pharmacodynamics of ivabradine for the treatment of heart failure. Expert Opin Drug Metab Toxicol. 2014; 10:279-91. http://www.ncbi.nlm.nih.gov/pubmed/24377458?dopt=AbstractPlus
39. Murray KT. It's a funny thing…. J Cardiovasc Electrophysiol. 2013; 24:1401-2. http://www.ncbi.nlm.nih.gov/pubmed/24033556?dopt=AbstractPlus
40. Deedwania P. Selective and specific inhibition of If with ivabradine for the treatment of coronary artery disease or heart failure. Drugs. 2013; 73:1569-86. http://www.ncbi.nlm.nih.gov/pubmed/24065301?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3786091&blobtype=pdf
41. Martin RI, Pogoryelova O, Koref MS et al. Atrial fibrillation associated with ivabradine treatment: meta-analysis of randomised controlled trials. Heart. 2014; 100:1506-10. http://www.ncbi.nlm.nih.gov/pubmed/24951486?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4174120&blobtype=pdf
42. Beltrame JF. Ivabradine and the SIGNIFY conundrum. Eur Heart J. 2015; :. http://www.ncbi.nlm.nih.gov/pubmed/26264551?dopt=AbstractPlus
43. Swedberg K, Komajda M, Böhm M et al. Rationale and design of a randomized, double-blind, placebo-controlled outcome trial of ivabradine in chronic heart failure: the Systolic Heart Failure Treatment with the I(f) Inhibitor Ivabradine Trial (SHIFT). Eur J Heart Fail. 2010; 12:75-81. http://www.ncbi.nlm.nih.gov/pubmed/19892778?dopt=AbstractPlus
524. WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M 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:e240-327.
700. 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. Circulation. 2016; :.
701. Ponikowski P, Voors AA, Anker SD et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016; :. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4946749&blobtype=pdf
703. Ansara AJ, Kolanczyk DM, Koehler JM. Neprilysin inhibition with sacubitril/valsartan in the treatment of heart failure: mortality bang for your buck. J Clin Pharm Ther. 2016; 41:119-27. http://www.ncbi.nlm.nih.gov/pubmed/26992459?dopt=AbstractPlus
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