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Improving heart failure patient outcomes utilizing guideline-directed therapy

Davidson, Beth Towery DNP, ACNP-BC, CHFN, CCRN; Allison, Terri Lynn DNP, ACNP-BC, FAANP

doi: 10.1097/01.NPR.0000520610.88962.03
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Heart failure (HF) prevalence continues to rise and remains a significant burden to patients, caregivers, providers, and the healthcare system. Guideline-directed medical therapy with standard neurohormonal blockade has been the cornerstone of medical management for many years. Despite aggressive utilization of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists, HF hospitalizations and readmissions are common and residual mortality remains high. With the development of two novel medical therapies (sacubitril/valsartan and ivabradine), the American College of Cardiology, American Heart Association, and Heart Failure Society of America released a pharmacologic update to provide guidelines for incorporation of these agents into clinical practice. Although effective via different mechanisms of action, both agents now have a prominent role in risk reduction. HF medical regimens often become quite complex, especially when associated with comorbid conditions, and require frequent follow-up. Providers must be proficient in patient monitoring, medication dose titration, and therapy optimization. Individualized patient care strategies such as guideline-directed therapy can promote long-term adherence and quality of life.

Beth Towery Davidson is the director of the Heart Failure Disease Management Program at TriStar Centennial Medical Center, Nashville, Tenn.

Terri Lynn Allison is the director of the DNP program and associate professor of nursing in the Vanderbilt University School of Nursing, Nashville, Tenn.

Heart failure (HF) is a complex clinical syndrome caused by structural or functional abnormalities of the myocardium that result in impaired ventricular filling or ejection of blood, typically because of diminished left ventricular (LV) function.1,2 HF is the most rapidly growing cardiovascular disorder worldwide, and prevalence doubles for each decade of life.3 The incidence of HF is highest among those over age 65, and over half of hospital admissions for HF occur in older adults over age 75.2-4

HF risk factors are numerous and variable among world regions; however, the predominant risk factors include hypertension, rheumatic fever or other valvular disease, cardiopulmonary disease, and cardiomyopathy.5 Ischemic heart disease is the major risk factor for development of HF in high-income Western countries, whereas hypertension is a prevalent HF risk factor around the world.5 Besides hypertension, common comorbid conditions associated with development of HF in the U.S. population include diabetes mellitus (DM), metabolic syndrome, and atherosclerotic disease. Seventy-five percent of individuals with HF have antecedent hypertension, and control can reduce the risk of HF by 50%.2,6 Obesity, insulin resistance, metabolic syndrome, and DM elevate HF risk, and DM has an adverse effect on patients with known HF. Treatment of comorbid risk factors is essential to reduce the likelihood an individual will progress toward HF.2 The risk of HF increases with age and is highest among individuals over age 65, an age 20% of Americans are expected to reach by 2050.2 Black Americans have the greatest risk for HF and a higher 5-year mortality compared with White Americans.6 Hispanic, White, and Chinese Americans follow Black Americans in relation to degree of risk for development of HF; the discrepancy is primarily related to differences in the occurrence of hypertension and DM, and lower socioeconomic status.6

Management of HF is costly and can result in frequent hospitalizations and readmissions.2,6 In 2012, the total U.S. cost of HF was approximately $31 billion, and projections estimate that the cost to care for patients with HF will increase to almost $70 billion by 2030.6 The number of hospital discharges for a diagnosis of HF is essentially unchanged over the past 2 decades, and the highest HF mortality occurs among individuals who experience a previous HF admission.6 The current U.S. 30-day HF readmission rate is 21.9%.7 Hospitals exceeding the national HF readmission rate are financially penalized; therefore, provider efficacy of HF management and organizational transitions of care processes for HF is essential.8

HF has significant impact on health-related quality of life (HRQOL) and patients' functional status.2 Individuals with HF, caregivers, and family members experience a significant burden living with a chronic disease requiring substantial lifestyle and behavior modification, polypharmacy, frequent healthcare follow-up, and frequent interactions with providers. Achievement of optimal HF patient outcomes occurs via utilization of guideline-directed medical therapy (GDMT) designed to mediate the pathophysiologic responses to myocardial dysfunction while maintaining the patient's functional status and quality of life.2

HF is described a number of ways. HF with reduced ejection fraction (HFrEF), accompanied by LV hypertrophy (LVH) and enlargement, is typically associated with an ejection fraction (EF) of 40% or less (normal EF, 55% to 75%). HF with preserved EF (HFpEF), defined by an EF of 50% or greater, is characterized by restriction in LV function or LV diastolic dysfunction.2 About 50% of patients with HF have HFpEF.1,2

HF is further categorized according to stages determined by the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) as well as the New York Heart Association (NYHA) Functional Classification (see Stages of HF and NYHA Classifications).2 The ACCF/AHA HF staging focuses on progression of disease, whereas the NYHA classification emphasizes exercise tolerance in individuals with known HF.2 These categorizations of HF are instrumental in determining disease trajectory, guiding treatment decisions, and anticipating patient outcomes. For the purposes of this article, the emphasis is on management of patients with Stage C HF.

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Etiology of HF

Cardiomyopathy, by definition, is a disease of the heart muscle and is a term often used to describe the process provoking the HF clinical syndrome.9 However, HF can occur because of diseases of the pericardium, myocardium, endocardium, heart valves, coronary arteries, and/or certain metabolic disorders.2 Patients may develop HF because of structural or functional defects of the heart, primarily of the left ventricle. In the United States, ischemic cardiomyopathy, or coronary artery disease (CAD), accounts for HF in approximately 70% of patients, usually associated with myocardial infarction (MI).10 Structural disease of the myocardium or heart valves, metabolic or endocrine abnormalities, pregnancy, and the effects of toxic substances on the heart can precipitate myocardial changes resulting in HF (see Etiology of HF).2,10

Changes in the myocardium, called cardiac remodeling, occur in response to an insult that reduces cardiac function. HF is further characterized by the interaction between the underlying myocardial dysfunction and the pathophysiologic, neurohormonal mechanisms that change the shape and structure of the heart.11 Neurohormonal activation is a compensatory response to a decrease in cardiac output and includes stimulation of the sympathetic nervous system (SNS), renin-angiotensin-aldosterone system (RAAS), and release of natriuretic peptides. The SNS releases epinephrine in response to initial hypotension. Activation of the RAAS results in the vasoconstricting action of angiotensin II and the release of aldosterone, causing renal sodium and water retention. Stimulation of the SNS and RAAS causes vasoconstriction, tachycardia, enhanced myocardial contractility, and fluid retention, mechanisms that initially maintain cardiac output and systemic perfusion. However, SNS and RAAS effects increase myocardial workload and oxygen demand, becoming maladaptive in a failing heart. Natriuretic peptides, like brain natriuretic peptide (BNP), are secreted by the ventricles because of increased wall stretch from volume and pressure overload. The effect of BNP is vasodilation and increased natriuresis, or sodium excretion by the kidney, which reduces excess fluid volume. BNP is measured in the blood, and elevation is a marker of ventricular filling pressure that correlates with worsening HF and predicts mortality.1,11 The HF cycle depicts the cyclical nature of neurohormonal activation. The goal of GDMT is to improve myocardial function and modulate the neurohormonal responses of HF.

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Clinical presentation

Patients with HF may present initially with signs and symptoms that are vague and nonspecific. Dyspnea (at rest or with exertion) and fatigue are often primary complaints causing an individual to seek treatment, but may lead to misdiagnosis of HF in lieu of other disease processes. Additional hallmark symptoms include fluid retention manifesting as weight gain; edema of the lower extremities, vulva, scrotum, or abdomen; and orthopnea and paroxysmal nocturnal dyspnea. Patients may complain of abdominal pain and early satiety because of splanchnic and liver congestion.1,2 Characteristic exam findings often include tachycardia and irregular pulse, S3/S4 heart sounds, systolic murmur, elevated jugular venous pressure, pulmonary crackles, hepatomegaly, and edema (see Signs and symptoms of HF for a complete list).11

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HF management strategies

The 2013 ACCF/AHA practice guidelines are intended to assist clinical decision-making by describing generally acceptable approaches to HF management.2 Specific treatment recommendations can be categorized by the ACCF/AHA HF staging system.2 The cornerstone of medical management remains neurohormonal blockade to limit disease progression and decrease mortality, including angiotensin-converting enzyme inhibitors (ACEIs); angiotensin II receptor blockers (ARBs); aldosterone antagonists (AAs), also known as mineralocorticoid receptor antagonists (MRAs); and beta-blockers (BBs). Diuretics are utilized to control symptoms of congestion. Alternate vasodilator therapy (hydralazine and nitrates) may be used for patients with contraindications or intolerance to ACEI/ARB therapy, and in special populations, such as Black Americans. Digoxin may be prescribed to improve symptoms and reduce HF hospitalization rates. Of available medications, ACEIs, ARBs, AAs, and BBs have mortality benefit in patients with HF.2 Stages, phenotypes, and treatment of HF outlines specific goals and treatment strategies for management of each HF stage.

Approval of two novel medications for the treatment of HFrEF prompted the release of the 2016 Focused Update on New Pharmacological Therapy for Heart Failure developed in collaboration with the ACCF, AHA, and the Heart Failure Society of America (HFSA).12 This update to the 2013 ACCF/AHA Guideline for the Management of Heart Failure includes the addition of an angiotensin II receptor blocker-neprilysin inhibitor (ARNI) (valsartan/sacubitril) and a sinoatrial node modulator (ivabradine) to the list of treatment options for Stage C HFrEF. Although effective via different mechanisms of action, both agents now have a prominent role in the HF armamentarium.

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Novel therapeutic options

Sacubitril/valsartan (Entresto). Upregulation of neurohormonal pathways, including the SNS and RAAS, contributes to the clinical progression of HF.2 The benefits of ACEIs, ARBs, BBs, and AAs are well established.13 Despite GDMT, patients continue to experience HF exacerbations and progression of the disease. More recently, the inadequate compensatory response of the natriuretic peptides was linked to the chronic neurohormonal imbalance in HF, prompting the search for new therapies. Neprilysin is the key enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive agents, such as angiotensin II.14 Neprilysin inhibition allows for the plasma levels of the endogenous natriuretic peptides to rise, thus promoting the beneficial effects of BNP: natriuresis and vasodilation. Concurrent RAAS modulation is indicated as neprilysin inhibition also increases circulating angiotensin II levels.15,16 Sacubitril/valsartan combines neprilysin inhibition with an ARB, allowing for parallel modulation of the neurohormonal system.17 In the largest randomized controlled trial to date in patients with HFrEF, PARADIGM HF, sacubitril/valsartan was superior to enalapril in reducing the risk of cardiovascular death, HF hospitalization, and all-cause mortality.18

Sacubitril/valsartan is the first, and only, ARNI commercially approved in the United States. The adverse reaction profile is very similar to that of other RAAS-modulating therapies, including hypotension, cough, dizziness, impaired renal function, and angioedema. When initiating sacubitril/valsartan, ACEIs or ARBs must be discontinued. To reduce the risk of angioedema, ACEIs must be stopped for 36 hours before initiating sacubitril/valsartan.19 As BNP is a substrate for neprilysin, BNP levels will rise and reflect the action of the drug; therefore, BNP levels measured in the blood will not be a reliable biomarker of congestion.17 In patients taking sacubitril/valsartan, providers should use N-terminal proBNP (NTproBNP) as the assay to monitor therapy response.17

Sacubitril/valsartan is available in three strengths (24/26 mg, 49/51 mg, and 97/103 mg) and administered twice daily. The valsartan formulation in Entresto has greater bioavailability than the traditional commercial formulation of valsartan alone; therefore, the dosage is different for valsartan used in combination with sacubitril.19

Ivabradine (Corlanor). Heart rate reduction with a rate less than 70 beats per minute (BPM) is a therapeutic target in patients with HFrEF, because an elevated heart rate is associated with worsening cardiovascular outcomes.20,21 Despite the use of BBs and other GDMT, data from large HF trials show that baseline heart rates in patients with HFrEF typically remain over 70 BPM.18,21-23 Ivabradine, via a first-in-class mechanism of action, is a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker that works at the level of the sinoatrial node to lower heart rate without compromising BP. Blocking the HCN channel causes a delay in depolarization, resulting in heart rate reduction.24

The Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT) was the first prospective study to specifically examine the effect of heart rate reduction on HF.21 Ivabradine or placebo was added to standard of care therapy, including maximally tolerated beta blockade. Compared with placebo, patients in the ivabradine group had an 18% relative risk reduction in cardiovascular death or hospitalization for worsening HF. This composite endpoint reflected only a reduction in risk of hospitalization for worsening HF with no favorable effect on cardiovascular death; thus, ivabradine does not have a mortality indication.21

On average, after initiation of ivabradine, heart rate reduction was 10 BPM from baseline at rest and with activity, with the size of effect greatest in patients with higher baseline heart rates.21 Reported adverse reactions included bradycardia, hypertension, atrial fibrillation (AF), and transient enhanced brightness in the visual field or a luminous phenomenon called phosphenes. Patient reports of phosphenes are not an indication to discontinue the drug.

Ivabradine is taken twice daily with meals and available in two strengths, 5 mg and 7.5 mg tablets. The dose should be titrated between 2.5 mg and 7.5 mg twice daily to maintain a resting heart rate between 50 and 60 BPM.

Ivabradine is primarily metabolized by the CYP3A4 pathway. Concomitant use of CYP3A4 inhibitors or inducers such as grapefruit juice, macrolide antibiotics, protease inhibitors, and non-dihydropyridine calcium channel blockers can affect plasma concentrations and should be avoided.24 (See Highlights of prescribing information.)

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Integrating new therapies into clinical practice

Treatment goals are based on clinical trials, guideline recommendations, and best practices individualized to the patient. Guideline recommendations serve to provide direction regarding choice of therapy. Mortality and HF hospitalization rates remain key targets for improved outcomes and quality of life. Even for stable HF patients, a change in medication regimen to add sacubitril/valsartan and/or ivabradine may be indicated.

Per the 2016 Focused Update, RAAS modulation with a therapeutic regimen of an ACEI, ARB, or ARNI along with a BB and an AA is the recommended therapy for patients with chronic symptomatic HFrEF.12 Per the guideline recommendation, patients with NYHA II/III HFrEF who can tolerate standard ACEI/ARB therapy should be switched to an ARNI to further reduce morbidity and mortality.12 However, ARNIs should not be used concurrently with other RAAS agents, and are contraindicated in pregnancy and patients with a history of angioedema.

Ivabradine may be beneficial to reduce heart rate and HF hospitalizations in patients with symptomatic, stable, chronic HFrEF who are receiving GDMT and are in sinus rhythm with a baseline heart rate greater than 70 BPM.12 Before adding ivabradine to the regimen, providers should ensure that patients are receiving maximal beta blockade unless intolerant or contraindicated. GDMT for HFrEF Stage C, NYHA I-IV depicts GDMT for HFrEF Stage C, NYHA I-IV, including newer therapies.

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Optimization of HF therapy

Medical management remains the cornerstone of HF treatment. Therapeutic targets to prevent disease progression, control symptoms, and avoid HF hospitalization are outlined in Therapy targets and agents.

In addition to medical therapy, nonpharmacologic interventions include individualized patient education, a low-sodium diet, treatment of sleep disorders, weight loss, physical activity, and fluid restriction as indicated.2

HF medical regimens often become complex, especially when associated with comorbid conditions, and require frequent follow-up. The provider must be proficient in patient monitoring, medication dose titration, and therapy optimization. Individualized patient care strategies can promote long-term adherence and quality of life.

Practical strategies to promote adherence and regimen optimization include:2,25,26

* Minimize diuretics to the lowest possible dose to maintain euvolemia.

* Avoid up-titration of neurohormonal blockade if volume is depleted or the patient is in acute decompensated HF (ADHF).

* Space medication dosing to avoid excessive fluctuations in BP or hypotension.

* Simplify the dosing regimen when possible (daily dosing is preferable to multiple daily doses).

* Initiate at low doses and up-titrate slowly (“start low, go slow”).

* Monitor serial labs to assess renal function and electrolytes.

* Trend biomarkers (BNP, NTproBNP, troponin) to assist with clinical decision-making and determine response to therapy.

* Confirm affordability of and access to prescribed medication regimen.

* Reconcile medications at every visit; discuss potential adverse reactions and reinforce benefits.

* Use “teach back” to assess recall and understanding; include caregivers in patient education.

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Adjunct therapies and treatment

A subset of patients with chronic HF will be candidates for adjunct therapies and treatment. The use of device therapy is well established in this population. Two types of devices are currently approved for patients with HFrEF and should only be considered in patients receiving optimal GDMT: implantable cardioverter defibrillators (ICDs) and cardiac resynchronization therapy (CRT).

ICDs protect HF patients from sudden cardiac death because of cardiac dysrhythmias and are highly effective; however, frequent shocks may decrease quality of life and result in significant stress and anxiety.2 The use of antiarrhythmic medications, catheter ablation of arrythmogenic myocardium, and refined ICD and CRT programming can decrease the frequency of dysrhythmias requiring shocks to restore normal sinus rhythm. Wearable external defibrillators are available for patients at risk for sudden cardiac death who do not qualify for an ICD implant.

In approximately one third of patients, HF progression is associated with a prolongation of the QRS interval and asynchronous contraction between the right and left ventricle, resulting in decreased efficiency in cardiac performance. CRT can improve ventricular function, decrease mitral regurgitation, reverse ventricular remodeling, and improve EF.2 Recommendations for device therapy for management of Stage C HF are detailed in the 2013 guideline document.2

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Advanced therapies for end-stage HF

Despite GDMT and ICD/CRT implantation, some patients will ultimately develop advanced HF (ACCF/AHA Stage D). Complex treatment plans for this population may include inotropic therapy, mechanical circulatory support, transplantation, palliative care, and hospice.

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Inotropic agents

The primary mechanism of action of inotropic agents is to support myocardial contractility.27 These agents are reserved for patients who demonstrate a low cardiac output or are “cold” and hypoperfused. The three inotropic agents used for advanced HF management in the United States are dopamine and dobutamine (both catecholamines), and milrinone (a phosphodiesterase inhibitor).28 While these inotropes enhance contractility and improve quality of life, none improves quantity of life and may increase mortality from arrhythmogenic adverse reactions.

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Mechanical circulatory support

The use of ventricular assist devices (VADs) has rapidly increased throughout the United States. As technology continues to evolve, these devices have improved durability and are now a viable option for refractory, chronic HFrEF. Long-term strategies for mechanical circulatory support include: 1) bridge to transplant, 2) bridge to decision/candidacy for transplant, and 3) destination therapy.2 VAD implantation is a costly and complex surgical procedure. Patients require meticulous anticoagulation, close clinical follow-up, and monitoring for complications including infection, pump failure, thrombosis, and stroke. See VADs for examples.

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Cardiac transplantation

Cardiac transplantation remains the gold standard for refractory, end-stage HF in patients who meet the selection criteria. With advances in immunosuppressive therapy to prevent organ rejection, post-transplant survival exceeds the 50% 5-year survival rates expected in the typical HF population. Five-year survival following heart transplantation is approximately 79%.29

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Palliative care and hospice

Despite advances in GDMT and implementation of device strategies, HF is a progressive disease that can negatively affect quality of life and mortality. Frequent exacerbations and worsening symptoms lead to additional psychosocial distress for patients and families. Palliative care and hospice can assist the patient and caregiver with advanced care planning, aggressive symptom control, and end-of-life discussions and management.30

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HF management

HF disease management programs utilize an interprofessional team approach where physicians, advanced practice nurses, nurses, pharmacists, social workers, and nutritionists provide collaborative care to patients with HF. Disease management programs have the greatest opportunity to impact hospital readmissions and patient quality of life by providing a comprehensive range of services, including education, early access to providers, and ensuring the use of guideline-directed medical and device therapy.31

Candidates for referral to HF disease management programs include patients with:32

* recent HF hospitalization

* comorbid conditions (renal insufficiency, DM, chronic obstructive pulmonary disease)

* persistent NYHA Class III or IV symptoms

* frequent hospitalizations (all-cause)

* depression and/or cognitive dysfunction

* poor socioeconomic status

* nonadherence.

If HF disease management programs are not available, close follow-up with the cardiology team and the primary care provider is critical to assure continuity of care and optimal patient outcomes.31

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Case presentation

R.B. is a 46-year-old Black American male with chronic HF who presents with worsening dyspnea, fatigue, and abdominal bloating following recent hospitalization for ADHF. Current medications include aspirin (81 mg daily), carvedilol (3.125 mg twice daily), digoxin (0.125 mg daily), furosemide (80 mg twice daily), and lisinopril (10 mg daily). His vital signs are BP, 98/56 mm Hg; heart rate, 90 BPM; and respirations, 20 breaths/minute. His jugular venous pressure is 10 to 12 cm (normal, less than 8 cm) with hepatojugular reflux and 1+ lower extremity edema.

His labs show NTproBNP levels of 1300 pg/mL (over 450 pg/mL is consistent with HF) and creatinine 1.2 mg/dL. His medical history includes dilated cardiomyopathy, HFrEF with EF 25%; NYHA III, ACCF/AHA Stage C; hypertension; and a previous ICD/CRT implant.

His social history includes remote tobacco use and prior cocaine abuse, and his urine drug screen is positive for cannabis.

Based on this information, R.B.'s provider decides to discontinue lisinopril, wait 36 hours for his ACEI to washout, and start him on sacubitril/valsartan (24/26 mg twice daily). The provider ensures that R.B. is evaluated every 1 to 2 weeks in the facility's HF disease management clinic. Follow-up at 3 months shows a creatinine increase to 1.4 mg/dL and a NTproBNP decrease to 800 pg/mL, so no change in therapy is ordered.

At his 6-month follow-up, R.B.'s BP is 108/78 mm Hg and his heart rate is 91. On exam, he is euvolemic and he reports feeling “great.” His NTproBNP 300 pg/mL, but he is unable to tolerate up-titration of carvedilol because he has erectile dysfunction. His urine drug screens remain negative.

With frequent follow-up and titration of his medical therapy, R.B. is symptomatically improved and now NYHA II. Other potential interventions to promote his long-term optimal outcomes include:

* Ongoing, individualized patient education

– Discontinue cannabis use

– Restrict fluids to 2 L per day

– Weigh daily; report gain of 2 lb or more per day; 5 lb or more per week

– Restrict dietary sodium to 2 g per day

– Increase physical activity; begin by walking 20 minutes three times weekly

– Report signs and symptoms of adverse reactions (angioedema, symptomatic hypotension)

– Obtain lab tests to evaluate kidney function and electrolytes in 1 week

– Return to clinic in 2 weeks.

* Addiction counseling with random urine drug screening

* Ivabradine for heart rate reduction

* Advanced therapies such as heart transplantation or VAD.

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HF is the most rapidly growing cardiovascular condition and remains a significant burden to patients, caregivers, providers, and the healthcare system. Changing demographics and an aging population result in a rapidly increasing number of patients with HF. Primary prevention is the most effective strategy to limit overall healthcare burden and includes aggressive control of hypertension, tobacco cessation, and risk factor reduction.3,5

Adherence to GDMT will improve the overall management of HF. Ongoing research and development is needed to target novel therapies, especially for patients with HFpEF. Adequate transitions of care and improved healthcare systems are needed to manage chronic disease, improve outcomes, and control costs.3 Providers must be proficient in patient monitoring, medication dose titration, therapy optimization, and individualized patient care strategies to promote long-term patient adherence to therapy and improved quality of life.

At time this article was written, the 2017 ACC/AHA/HFSA Heart Failure Focused Update was simultaneously published online in the Journal of the American College of Cardiology and was available April 28, 2017. This 2017 focused update reflects the most recent pharmacological therapies presented in Improving Heart Failure Patient Outcomes Utilizing Guideline-Directed Therapy.

Yancy, Clyde W., et al. “2017 ACC/AHA/HFSA Focused 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.” Journal of the American College of Cardiology (2017).

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heart failure; guideline-directed therapy; ivabradine; pharmacology; sacubitril/valsartan

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