Staging and Management of Heart Failure

Release Date: February 1, 2016

Expiration Date: February 28, 2018


Dusty Lisi, MS, PharmD
Assistant Professor
School of Pharmacy, Philadelphia College of
Osteopathic Medicine—Georgia Campus
Suwannee, Georgia

Valerie Tapia, PharmD Candidate
Pharmacy Intern, Walgreens Company
School of Pharmacy, Philadelphia College of
Osteopathic Medicine—Georgia Campus
Suwannee, Georgia


Dr. Lisi and Ms. Tapia have no actual or potential conflict of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.


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Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge


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Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.


To educate the pharmacist on the epidemiology, pathophysiology, staging, and treatment of heart failure (HF). The pharmacist will learn how to stage and classify HF based on the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) and New York Heart Association (NYHA) criteria, as well as which medications are appropriate based upon these criteria.


After completing this activity, the participant should be able to:

  1. Understand the epidemiology and pathophysiology of HF.
  2. Recognize disease states that should be controlled and medically managed to prevent the development or further progression of HF.
  3. Identify ACCF/AHA staging and NYHA classification of HF based on symptoms and structural remodeling.
  4. Recommend treatment options for HF based on ACCF/AHA stage and NYHA class.

ABSTRACT: Heart failure (HF) is a progressive clinical syndrome that involves functional and structural alterations of the heart and can result in impaired ventricular filling or ejection of blood. The heart is unable to maintain cardiac output in order to adequately perfuse the body. There is no single diagnostic test for HF; diagnosis is largely based on medical history, physical examination, and symptom presentation. Medication regimens are selected based on the American College of Cardiology/American Heart Association Foundation staging and the New York Heart Association classification of HF. Lifestyle modifications in conjunction with medication adherence are essential to managing HF and delaying disease progression.

Heart failure (HF) occurs in over 5.8 million people in the United States and affects more men than women aged <65 years.1 Prevalence of HF increases with advancing age, and the incidence in both genders is almost equal beyond the age of 65 years.2 The most common etiologies include ischemic heart disease, hypertension, and diabetes. Other etiologies include inappropriate drug use, diet, and other comorbidities. Most causes of HF are preventable; therefore, controlling comorbidities, medication adherence, diet, and exercise are essential in preventing or delaying progression of HF.3


HF is characterized by decreased cardiac output (CO) and eventual reduction in perfusion to the rest of the body. Hallmark symptoms of HF include fatigue, dyspnea, and fluid retention leading to manifestations within the pulmonary or hepatic system and/or the periphery.4 Although HF can develop as a result of various abnormalities within the tissue and structure of the heart, most symptomatic HF patients have underlying impaired left-ventricular function. There is no single diagnostic test for identification of HF. Diagnosis is based on the presence of hallmark HF symptoms, signs of HF (pulmonary congestion, peripheral edema, and jugular venous distention), presence of comorbidities, and various laboratory analyses, including brain natriuretic peptide, that are altered in the setting of HF. Evaluation with echocardiogram provides definitive information about the structure and function of the heart, which confirms the diagnosis of HF.4

HF is a progressive disorder that may be initiated by a chronic underlying disease or an acute event that affects the structure or function of the heart. There are compensatory mechanisms stimulating biochemical and physiological changes that provide benefits in early HF stages, but eventually result in the progression of HF. These compensatory responses include the Frank-Starling mechanism, stimulation of the sympathetic nervous system, neurohormonal activation, and structural remodeling.5,6

In the early stages of HF, the Frank-Starling mechanism plays an important role. The stretching of the heart muscle caused by an increase in blood volume returned to the heart (preload) results in an increase in the CO, which is defined as the amount or volume of blood that is pumped out of the heart during the contraction of the ventricle. It is measured as a volume per unit of time (liters per minute) and is the product of heart rate (HR) and stroke volume (SV). However, the ability of the heart to increase the CO is limited. As the patient’s HF worsens and the preload continues to increase, the ability of the heart muscle to recoil is impaired. At this stage, the CO is decreased and fluid begins to accumulate in the periphery, as well as in the lungs.5-7

The neurohormonal activation mechanism involves the mean arterial pressure (MAP) and total peripheral resistance (TPR). The MAP is the product of CO and TPR. Reduced cardiac output results in a decrease in MAP. Activation of the neuro-hormonal system increases TPR by stimulation of the sympathetic nervous system (SNS), release of catecholamines (norepinephinephrine and epinephrine), and activation of the renin-angiotensin-aldosterone system (RAAS). Stimulation of the SNS and release of catecholamines results in increased heart rate and contractility, as well as vasoconstriction. RAAS activation also augments the MAP by causing vasoconstriction, sodium reabsorption, and vasopressin release (fluid retention). Activation of the neurohormonal system over time leads to progressive vasoconstriction as well as sodium and water retention, which, overall, causes undesirable elevation of preload and afterload and further worsening of HF.5,6,8-10

Structural remodeling is a process the heart undergoes in an attempt to increase CO. The maladaptive changes may begin following myocardial damage that occurs with exposure to cardiotoxins, coronary events, genetic abnormalities, and prolonged elevation in TPR. The heart enlarges and hypertrophies or dilates, which leads to impaired contractility. Patients may also have reduced ejection fraction (EF).5,11


EF is a measurement of the volume of blood that is leaving the left ventricle of the heart each time it contracts. The normal ejection fraction ranges from 50% to 70%. HF can be associated with a range of structural and functional features, including normal size of the left ventricle and preserved EF to severe dilation of the ventricle or tissue hypertrophy with or without reduced EF. Most patients have a combination of abnormalities affecting the filling and pumping of the heart (systolic and diastolic dysfunction), regardless of the EF. Most clinical trials evaluating efficacy of pharmacotherapy in HF patients have selected and evaluated patients based on EF values. Therefore, EF is essential in the classification of HF patients.

HF With Reduced Ejection Fraction

Patients with a clinical diagnosis of HF who have an EF ≤40% are defined as having reduced EF, or HFrEF. Randomized clinical trials demonstrating efficacious therapies in HF have primarily evaluated patients with an EF ≤35% or ≤40%. HFrEF can be caused by volume or pressure overload (e.g., valvular abnormalities), impaired contractility related to cardiotoxin exposure, or, most often, loss of functional myocardium due to ischemic heart disease or myocardial infarction (MI).4,6

HF With Preserved Ejection Fraction

Diagnosis and recognition of patients with preserved EF, or HFpEF, is more difficult, and it requires exclusion of other underlying noncardiac etiologies. Criteria proposed to identify patients with HFpEF include presence of clinical HF signs or symptoms, documented preserved or normal EF (≥50%), and abnormal left-ventricular diastolic function. Patients with HFpEF usually have chronic hypertension and are older women. Management of patients with EF in the intermediate range of 40% to 50% targets underlying comorbidities or HF risk factors and utilizes pharmacotherapy similar to what is recommended for patients with HFrEF.2,4,12


There are two systems used for staging and classification of HF, the American Heart Association (ACCF/ AHA) stages of HF and the New York Heart Association (NYHA) classification. The ACCF/AHA stages are determined by the development of structural changes within the heart and progression of HF, whereas the NYHA classes describe the capacity patients with HF have for completing exercise and functional activities.4,6,13

ACCF/AHA Staging

The ACCF/AHA staging system is based on structural impairment of the heart and patient presentation. It also identifies risk factors that are involved in the evolution and progression of HF. There are four stages of HF (A, B, C, and D). Stage A identifies patients who do not have structural alterations of the heart but have a high risk for developing HF due to underlying diseases. Stage B classifies patients who have underlying structural heart changes but do not have symptoms of HF. Patients with stage C have experienced symptoms of HF and also have underlying structural heart changes. Stage D comprises patients who have end-stage HF and require advanced interventions and pharmacotherapy including inotropes and mechanical circulatory support (MCS). The last two stages represent the classic diagnosis of HF.13

In this staging system, HF can only worsen. For example, once a patient has progressed to stage C, regression to stage B is not possible. This staging system also recognizes that treatment implemented for earlier stages can reduce HF morbidity and mortality.13 The updated 2013 HF guidelines refer to medications that are specifically recommended for use in HF as guideline-directed medication therapy (GDMT), which include the following drug classes: ACE inhibitors, angiotensin II receptor blockers (ARBs), beta-blockers, loop diuretics, the hydralazine and isosorbide dinitrate combination, and aldosterone antagonists.4,14-24 As patients progress in ACCF/AHA stage or NYHA class (see NYHA Classification, below), medications are added to the patient’s regimen sequentially in accordance with the GDMT. Refer to TABLE 1 for patient characteristics and management recommendations based upon the ACCF/AHA stage, and refer to TABLE 2 for initial and target dosing of GDMT medications.4

Stage A patients are at high risk for HF but do not exhibit any structural remodeling or functional abnormalities of the heart. These patients also do not have any signs or symptoms specific to HF. High-risk patients may have multiple comorbidities, a history of exposure to cardiotoxic medications, or a family history of cardiomyopathy, or have behavioral exposures that may lead to HF (e.g., cigarette smoking, alcohol intake, or illicit drug use).4,13 High-risk comorbidities for HF include hypertension, coronary artery disease (CAD), arteriosclerotic vascular disease (ASCVD), diabetes, obesity, and a personal history of rheumatic fever.4,13 Elevated blood pressure is a precursor for development of both HFpEF and HFrEF. Cardiotoxic medications include anthracyclines (e.g., doxorubicin and daunorubicin), mitoxantrone, cyclophosphamide, and trastuzumab.4 There is no specific HF treatment for stage A patients. However, hypertension, dyslipidemia, obesity, and diabetes mellitus should be managed in accordance with respective guidelines, and other factors that may contribute to HF—such as cardiotoxins and tobacco—should be avoided.4,5,13

Stage B patients have structural remodeling of the heart, but do not exhibit any HF symptoms. Structural remodeling can be defined as left ventricular hypertrophy or fibrosis, cardiomyopathy, or asymptomatic valvular heart disease. Stage B patients can be those with previous MI or acute coronary syndromes (ACS) who do not have characteristic HF symptoms, including dyspnea, exercise intolerance, or edema. An echocardiogram should be performed on individuals with high risk for decreased left ventricular ejection fraction (LVEF); for example, those patients with a family history of heart disease or HF, uncontrolled hypertension, or previous MI, or those receiving cardiotoxic medications (most notably chemotherapy regimens including doxorubicin and/or trastuzumab). The recommendations for patients in stage A also apply to those patients in stage B HF; initial therapy should include managing uncontrolled hypertension, diabetes, CAD, ASCVD, or any other comorbidities and avoiding known cardiotoxic agents.4 ACE inhibitors and evidence-based beta-blockers should be used in all patients with a reduced EF (≤40%) to prevent symptomatic HF.4,14-20 ACE inhibitors, evidence-based beta-blockers, and statins are recommended in all patients with a history of MI or ACS with reduced EF. ARBs are considered an appropriate alternative when patients have an intolerance to ACE inhibitors.4 Any ACE inhibitor can be used, as the mortality benefit is seen as a class effect.14,15 The ARBs shown to have mortality benefits in HF include candesartan, losartan, and valsartan.16,17 Evidence-based beta-blockers shown to prevent symptomatic HF and provide mortality benefits include bisoprolol, carvedilol, and metoprolol succinate.13,18-20

Stage C patients have structural abnormalities of the heart as well as symptoms of HF, including edema, dyspnea, and reduced exercise tolerance. Patients should be evaluated and educated regarding adherence to the medication regimen, sodium-restricted diet (1.5-2 g per day), and daily weight checks.4 Regular exercise or exercise training is recommended to improve functional status. In addition to the stage A and B therapies, stage C HF patients are initiated on medications for both additional symptom resolution and, if applicable, further mortality reduction. All patients with current or prior symptoms of HFrEF, unless contraindicated, should receive an ACE inhibitor or ARB and evidence-based beta-blockers. Loop diuretics are added, or doses of loop diuretics increased, for patients with new or worsening symptoms of fluid retention.4 The combination of hydralazine and isosorbide dinitrate should be initiated for further mortality reduction and symptom control in African American patients with NYHA class III or IV HFrEF who continue to experience severe symptoms despite receiving GDMT. Hydralazine and isosorbide dinitrate in combination can be used for patients who are unable to receive an ACE inhibitor or ARB owing to intolerance or renal insufficiency.4,21,22 Stage C patients with NYHA class II to IV who have LVEF of ≤35% are recommended to receive aldosterone-receptor antagonists to reduce morbidity and mortality. Aldosterone-receptor antagonists are also recommended for morbidity and mortality reduction in patients following an acute MI who have LVEF ≤40% and a history of diabetes, or in those who develop symptomatic HF.4,23 Digoxin can be added in patients with HFrEF. Digoxin was shown to reduce hospitalization for patients with HFrEF, but has no effect on mortality.4,24 Additional recommendations for stage C HF patients include calcium channel blockers (except amlodipine). Most antiarrhythmics (except amiodarone or dofetilide), thiazolidinediones, and nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided or discontinued. An implantable cardiac defibrillator (ICD) or chronic resynchronization therapy (CRT) may also be recommended for prevention of sudden cardiac death to reduce total mortality.4,13

Stage D patients have progressed from stage C and now have refractory HF. These patients exhibit severe HF symptoms despite optimizing the doses of GDMT. These symptoms include dyspnea and/or fatigue at rest, episodes of fluid retention, reduced coronary output at rest, and evidence of cardiac dysfunction. A nonpharmacologic recommendation for stage D patients includes a fluid-restricted diet, roughly about 2 L per day.4,13,25 Patients with cardiogenic shock should receive temporary inotropic support until resolution of the precipitating problem. It is reasonable to consider continuous inotropic support in patients who are awaiting MCS or a heart transplant.4,13,26,27 Refer to TABLE 3 for a description of inotropic medications used in HF. Long-term continuous IV administration of inotropic agents can be considered for symptom control in selected patients who are not eligible for MCS or heart transplantation.28 MCS may be beneficial in selected patients with stage D HFrEF in whom cardiac recovery is possible or a cardiac transplant is anticipated.28,29 Ultimately, for stage D HF, cardiac transplantation is the only definitive treatment if there is no acute cause or exacerbation that can be treated.30,31 Palliative care and hospice are recommended for those patients in whom recovery is not possible and who are unable to receive a cardiac transplant.4,13

NYHA Classification

The NYHA Classification is based upon the patient’s functional status. Regression is possible between the NYHA classes, which is not the case with ACCF/AHA staging.

Class I patients are those who do not exhibit symptoms of HF; for example, dyspnea upon exertion.

Class II patients are those who begin to exhibit HF symptoms and a slight limitation of physical activity that is relieved with rest.

Class III patients have marked limitations of physical activity that are relieved with rest.

Class IV patients are those who exhibit HF symptoms even at rest and are unable to perform any physical activity without experiencing these symptoms.

For those patients in ACCF/AHA stages of HF, the NYHA classification can aid in treatment selection. The ACCF/AHA stages do not directly correlate with the NYHA stages, meaning that NYHA class can be applied to different ACCF/AHA stages of HF. For example, ACCF/AHA stages B and C patients can be NYHA class I.4,13 ACCF/AHA stage C patients can be NYHA classes I to IV, depending on which symptoms the patient exhibits and the severity of those symptoms. Refer to TABLE 4 to identify patient characteristics associated with each NYHA Functional Classification, as well as the associated ACCF/AHA stages. For class I HF patients, an ACE inhibitor plus a beta-blocker or an ARB plus a beta-blocker should be initiated for mortality benefits.14-20 For patients in classes II to IV, it is recommended to initiate loop diuretics for those exhibiting fluid-overload symptoms like edema.4,13 For NYHA classes III and IV African American patients with persistent symptoms, it is recommended to initiate hydralazine-isosorbide dinitrate.21,22 For persistent symptoms in NYHA classes II to IV, it is recommended to initiate digoxin and aldosterone antagonists if it is not contraindicated.23,24

Case Study: A.B. is a 58-year-old woman who was diagnosed with HF with left ventricular hypertrophy last year. She arrives at the clinic for her routine checkup and states that she has been experiencing increasing shortness of breath over the last couple of days. She says that it even happens when she’s walking to the kitchen from the adjacent living room. She feels that sometimes she has to stop and sit down halfway before she can walk the rest of the distance. Her symptoms resolve when she sits down for a while to rest. She is not at optimal doses for GDMT. What ACCF/AHA stage and NYHA class is this patient?

Answer: Owing to the left ventricular hypertrophy, ACCF/ AHA stage A can immediately be eliminated as a possible choice. The patient is also symptomatic, as demonstrated by her shortness of breath upon walking, which also eliminates ACCF/AHA stage B as a possible selection. Since her symptoms are resolved upon rest and she is not yet at optimal doses for her medication, ACCF/AHA stage D and NYHA class IV can also be eliminated as possibilities. It seems that the patient is also experiencing marked limitations, as she cannot make it the full distance between adjacent rooms without taking a break to sit down. The correct answer is ACCF/AHA stage C and NYHA class III.


Upon diagnosis of HF, patients should be educated about the disease. Lack of education can lead to increased noncompliance, rehospitalization, and worsening symptoms. Implementation of a healthy diet and routine exercise are vital to managing the symptoms and progression of HF. Patients should be advised to limit sodium intake to 1.5-2 g per day from any source. Patients should also be counseled on what constitutes a balanced and nutritious diet.34 For patients in stage D or class IV HF, it may also be necessary to initiate a fluid-restricted diet (~2 L/day), as excess fluid can exacerbate HF symptoms in these patients.24 Also, patients should be advised to engage in aerobic exercise for at least 40 minutes for three to four sessions during the week.34,35 It is essential that patients learn to recognize signs and symptoms of worsening HF or an exacerbation, so that they may seek the appropriate medical attention. Daily weight checks allow patients to monitor and detect initial stages of fluid retention.4,13,35 The physician should be contacted if there is a weight gain of 1 lb per day or 3 lb per week.35 In addition, patients must recognize and monitor for signs and symptoms of edema or abnormal swelling of the limbs. Education should emphasize that patients seek immediate medical attention if they begin to experience altered mental status or unrelieved chest pain. Patients should consult the physician or pharmacist before starting any new medications, especially OTC medications and supplements, as they may interact with the disease state or medication regimen.32,33


Pharmacists must work as part of an interdisciplinary team to aid in management of HF, formulate the medication regimen with optimized GDMT dosing, and reinforce compliance for each patient. Recognition of the ACCF/AHA stages and NYHA classes is required for appropriate staging and classification of patients and selection of optimal pharmacotherapy. It is important for pharmacists to stress compliance with both the medication regimen and lifestyle modifications. Patient compliance with the medication regimen can be enhanced through education about potential adverse effects and how to monitor and identify which medication may be causing specific side effects. For example, a pharmacist could counsel patients to monitor for cough while on an ACE inhibitor, as it may be a reason to change therapy to an ARB, or to monitor for occurrence of angio-edema while on an ACE inhibitor, as it is an emergency situation requiring immediate medical attention. Pharmacists can educate patients about the pertinent signs and symptoms of HF that indicate worsening HF or congestion, and when it is appropriate to call the physician or seek immediate medical attention. For example, patients should be monitoring their weight daily and should contact the physician when there is a rapid increase in body weight (3 lb per week) so as to prevent an acute HF exacerbation.35 Pharmacists can further assist HF patients by providing counseling for new prescriptions as well as education for OTC medications.


HF is a progressive disease that worsens over time and is characterized by decreased CO and decreased perfusion. Most causes of HF are preventable; for instance, by controlling comorbidities, making lifestyle modifications, and reconciling medications. Two major systems are used used to stage and classify HF: ACCF/AHA staging and NYHA classes. The ACCF/AHA staging is based on the structural impairment of the heart as well as the presence and severity of HF symptoms. The NYHA classifications are based on symptom presentation and exercise tolerance. GDMT, as well as education and lifestyle modifications, is essential in managing HF.


  1. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation. 2011;123:e18-209.
  2. Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure. Nat Rev Cardiol. 2011;8(1):30-41.
  3. Bahrami H, Kronmal R, Bluemke DA, et al. Differences in the incidence of congestive heart failure by ethnicity: the multi-ethnic study of atherosclerosis. Arch Intern Med. 2008;168:2138-2145.
  4. 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;128:1-375.
  5. The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, MA: Little, Brown; 1994:253-256.
  6. Kemp CD, Conte JV. The pathophysiology of heart failure. Cardiovasc Pathol. 2012;21(5):365-371.
  7. Westerhof N, O’Rourke MF. Haemodynamic basis for the development of left ventricular failure in systolic hypertension and for its logical therapy. J Hypertens. 1995;13:943-952.
  8. Lee CS, Tkacs NC. Current concepts of neurohormonal activation in heart failure: mediators and mechanisms. AACN Adv Crit Care. 2008;19:364-385.
  9. Chaggar PS, Malkin CJ, Shaw SM, et al. Neuroendocrine effects on the heart and targets for therapeutic manipulation in heart failure. Cardiovasc Ther. 2009;27:187-193.
  10. Rea ME, Dunlap ME. Renal hemodynamics in heart failure: implications for treatment. Curr Opin Nephrol Hypertens. 2008;17:87-92.
  11. Curry CW, Nelson GS, Wyman BT, et al. Mechanical dyssynchrony in dilated cardiomyopathy with intraventricular conduction delay as depicted by 3D tagged magnetic resonance imaging. Circulation. 2000;101:E2.
  12. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J. 2011;32:670-679.
  13. 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). Circulation. 2001;104:2996-3007.
  14. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandina-vian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429-1435.
  15. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293-302.
  16. McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362:767-771.
  17. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667-1675.
  18. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353:9-13.
  19. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:1651-1658.
  20. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001-2007.
  21. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2005;351:2049-2057.
  22. 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;314:1547-1552.
  23. 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;341:709-717.
  24. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336:525-533.
  25. Travers B, O’Loughlin C, Murphy NF, et al. Fluid restriction in the management of decompensated heart failure: no impact on time to clinical stability. J Card Fail. 2007;13:128-132.
  26. Cuffe MS, Califf RM, Adams KF Jr, et al. Short-term intravenous milri-none for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 2002;287:1541-1547.
  27. Elkayam U, Tasissa G, Binanay C, et al. Use and impact of inotropes and vasodilator therapy in hospitalized patients with severe heart failure. Am Heart J. 2007;153:98-104.
  28. Pagani FD, Miller LW, Russell SD, et al. Extended mechanical circulatory support with a continuous-flow rotary left ventricular assist device. J Am Coll Cardiol. 2009;54:312-321.
  29. Elhenawy AM, Algarni KD, Rodger M, et al. Mechanical circulatory support as a bridge to transplant candidacy. J Card Surg. 2011;26:542–547.
  30. Grady KL, Jalowiec A, White-Williams C. Improvement in quality of life in patients with heart failure who undergo transplantation. J Heart Lung Transplant. 1996;15:749-757.
  31. Deng MC, De Meester JM, Smits JM, et al. Effect of receiving a heart transplant: analysis of a national cohort entered on to a waiting list, stratified by heart failure severity: Comparative Outcome and Clinical Profiles in Transplantation (COCPIT) Study Group. BMJ. 2000;321:540-545.
  32. Lexicomp. Hudson, OH: Wolters Kluwer Health, Inc. 1978-2015. http:// Accessed October, 2015.
  33. Micromedex. Greenwood Village, CO: Truven Health Analytics, Inc. Accessed October, 2015.
  34. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline of lifestyle management to reduce cardiovascular risk. Am Coll of Cardiol. 2014;63(25):2960-2984.
  35. van der Wal MH, van Veldhuisen DJ, Veeger NJ, et al. Compliance with non-pharmacological recommendations and outcome in heart failure patients. Eur Heart J. 2010;31:1486-1493.