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Contemporary Strategies in the Diagnosis and Management of Heart Failure

      Abstract

      Heart failure (HF) is an important public health problem, and strategies are needed to improve outcomes and decrease health care resource utilization and costs. Its prevalence has increased as the population ages, and HF continues to be associated with a high mortality rate and frequent need for hospitalization. The total cost of care for patients with HF was $30.7 billion in 2012, and it is estimated to more than double to $69.8 billion by 2030. Given this reality, there has been recent investigation into ways of identifying and preventing HF in patients at risk (stage A HF) and those with cardiac structural and functional abnormalities but no clinical HF symptoms (stage B). For patients who have symptoms of HF (stage C), there has been important research into the most effective ways to decongest patients hospitalized with acute decompensated HF and prevent future hospital readmissions. Successful strategies to treat patients with HF and preserved ejection fraction, which has increased in prevalence, continue to be sought. We are in the midst of a rapid evolution in our ability to care for patients with end-stage HF (stage D) because of the introduction of and improvements in mechanical circulatory support. Left ventricular assist devices used as destination therapy offer an important therapeutic option to patients who do not qualify for heart transplant because of advanced age or excessive comorbidity. This review provides a thorough update on contemporary strategies in the diagnosis and management of HF by stage (A to D) that have emerged during the past several years.

      Abbreviations and Acronyms:

      ACCF (American College of Cardiology Foundation), ACE-I (angiotensin-converting enzyme inhibitor), AHA (American Heart Association), ADHF (acute decompensated HF), CRT (cardiac resynchronization therapy), DAD-HF (Dopamine in Acute Decompensated Heart Failure), DCM (dilated cardiomyopathy), ED (emergency department), EF (ejection fraction), HF (heart failure), HFpEF (HF with preserved EF), HFrEF (HF with reduced EF), LVAD (left ventricular assist device), MCS (mechanical circulatory support), NYHA (New York Heart Association)
      Article Highlights
      • Heart failure (HF) is becoming more common and is associated with increasing costs of care.
      • Treatment of patients at risk for HF (stage A) should be aimed at controlling modifiable risk factors.
      • Stage B HF (structural heart abnormalities but no clinical symptoms of HF) is 3 to 4 times more common than stages C and D (clinical diagnosis of HF).
      • Referral to an HF specialist should be considered whenever questions arise in the diagnosis and management of patients with HF but particularly when symptom management is difficult, when a patient is unable to tolerate HF-related medications such as β-blockers, when complicated or recurrent HF hospitalizations occur, or when mechanical circulatory support and cardiac transplant may be an option.
      An estimated 5.8 million adults in the United States are currently living with heart failure (HF), and its prevalence is projected to increase to 25% by 2030.
      • Heidenreich P.A.
      • Albert N.M.
      • Allen L.A.
      • et al.
      American Heart Association Advocacy Coordinating Committee; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; Council on Clinical Cardiology; Council on Epidemiology and Prevention; Stroke Council
      Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association.
      Heart failure is primarily a disease of the elderly, with prevalence increasing from 0.9% in patients aged 55 to 64 years to 17.4% in those 85 years and older.
      • Bleumink G.S.
      • Knetsch A.M.
      • Sturkenboom M.C.
      • et al.
      Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk and prognosis of heart failure; the Rotterdam Study.
      The increasing prevalence of HF is attributed to aging of the population and improved survival from HF and other cardiovascular diseases. Given the increased prevalence and epidemic of hospitalizations in patients with HF, total costs are projected to increase from $30.7 billion in 2012 to $69.8 billion in 2030.
      • Heidenreich P.A.
      • Albert N.M.
      • Allen L.A.
      • et al.
      American Heart Association Advocacy Coordinating Committee; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; Council on Clinical Cardiology; Council on Epidemiology and Prevention; Stroke Council
      Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association.
      Although most of the focus in HF is aimed at treatment of affected patients, in 2001, the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) revised the HF classification to also include patients who are at high risk for the disease (stage A; Figure 1) but do not yet have structural cardiac abnormalities or clinical evidence of HF.
      • Hunt S.A.
      • Baker D.W.
      • Chin M.H.
      • et al.
      ACC/AHA Guidelines for the Chronic Management of Heart Failure in the Adult: Executive Summary.
      In 2010, Ramani et al
      • Ramani G.V.
      • Uber P.A.
      • Mehra M.R.
      Chronic heart failure: contemporary diagnosis and management.
      reviewed the contemporary diagnosis and management of HF in Mayo Clinic Proceedings, including a review of guideline-based management for patients with HF. Since then, there has been an expansion of indications for drug and device therapy, important progress made with mechanical circulatory support (MCS), and new clinical trials aimed toward enhancing the care of patients with HF. This complementary review will provide a thorough update on contemporary strategies in the diagnosis and management of HF by stage (A to D) that have emerged in the past several years, with a focus on new guidelines and research results that may affect clinical practice.
      Figure thumbnail gr1
      Figure 1Stages in the development of heart failure (HF). ACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CAD = coronary artery disease; CRT = cardiac resynchronization therapy; EF = ejection fraction; EP = electrophysiology; ICD = implantable cardioverter-defibrillator; MCS = mechanical circulatory support.
      Adapted from J Am Coll Cardiol,
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines
      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.
      with permission.

      Stage A HF: Patients at Risk

      Stage A HF includes patients who do not yet have HF or cardiac structural abnormalities but are at risk because of coronary artery disease, diabetes, hypertension, or other conditions. Because many of these predisposing conditions are highly prevalent, stage A HF is common. In one community study, it was estimated that 56% of the population aged 45 years or older had stage A or B HF.
      • Ammar K.A.
      • Jacobsen S.J.
      • Mahoney D.W.
      • et al.
      Prevalence and prognostic significance of heart failure stages: application of the American College of Cardiology/American Heart Association heart failure staging criteria in the community.

      Predicting Risk for the Development of HF

      Although only patients with stage C and D disease would meet criteria for HF, this focus on identifying patients at risk for HF (stage A) has prompted the development of several incident HF risk scores. The Health ABC (Health, Aging, and Body Composition) study included 3075 community-dwelling elderly patients (aged 70-79 years) who were followed up for 7 years for clinical events, including the onset of HF, which developed in 258 participants.
      • Butler J.
      • Kalogeropoulos A.
      • Georgiopoulou V.
      • et al.
      Incident heart failure prediction in the elderly: the Health ABC heart failure score.
      A simple point score based on independent predictors of HF was developed (Figure 2). Although the risk score is easy to calculate, the ability to discriminate is only acceptable (C statistic, 0.72). Similarly, a model to predict incident HF validated in the ARIC (Atherosclerosis Risk in Communities) cohort
      • Agarwal S.K.
      • Chambless L.E.
      • Ballantyne C.M.
      • et al.
      Prediction of incident heart failure in general practice: the Atherosclerosis Risk in Communities (ARIC) Study.
      included many of the same variables (age, coronary artery disease, blood pressure, smoking, heart rate), as well as race, sex, diabetes, and body mass index. The investigators reported predictive ability similar to that of the Health ABC score and found that both models performed better with the addition of N-terminal pro-B-type natriuretic peptide. Either risk model would be acceptable to use in clinical practice to help identify patients who may be at higher risk for the development of HF.
      Figure thumbnail gr2
      Figure 2The Health, Aging, and Body Composition (Health ABC) study risk score for predicting risk of heart failure (HF). BP = blood pressure; bpm = beats/min; LV = left ventricular.
      From Circ Heart Fail,
      • Butler J.
      • Kalogeropoulos A.
      • Georgiopoulou V.
      • et al.
      Incident heart failure prediction in the elderly: the Health ABC heart failure score.
      with permission.

      Genetic Testing in Patients With Suspected Familial Cardiomyopathy

      A high proportion (20%-35%) of patients with dilated cardiomyopathy (DCM) may have familial cardiomyopathy (defined as 2 or more closely related family members with DCM).
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines
      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.
      A thorough family history should be obtained in patients with newly diagnosed DCM. If familial cardiomyopathy is suggested on the basis of history, genetic testing and referral to a genetic counselor should be considered. However, because pathogenic mutations are identified in only 30% to 35% of familial cases,
      • Hershberger R.E.
      • Siegfried J.D.
      Update 2011: clinical and genetic issues in familial dilated cardiomyopathy.
      negative results on a genetic screen do not eliminate the possibility of an inherited DCM. Unaffected first-degree relatives of patients with familial DCM should undergo screening with echocardiography at least every 3 to 5 years.
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines
      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.
      Hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia can also be inherited, and genetic screening, counseling, and testing in these conditions are thoroughly covered in a recent review.
      • Hershberger R.E.
      • Cowan J.
      • Morales A.
      • Siegfried J.D.
      Progress with genetic cardiomyopathies: screening, counseling, and testing in dilated, hypertrophic, and arrhythmogenic right ventricular dysplasia/cardiomyopathy.

      Treatment Aimed at Controlling Modifiable Risk Factors

      Treatment of patients identified to be at high risk for the development of HF should be aimed at reducing their risk by treatment of modifiable risk factors, including aggressive treatment of hypertension, diabetes, hyperlipidemia, and obesity. In particular, long-term hypertension control may reduce the risk of incident HF by more than 50%.
      • Beckett N.S.
      • Peters R.
      • Fletcher A.E.
      • et al.
      HYVET Study Group
      Treatment of hypertension in patients 80 years of age or older.
      • Sciarretta S.
      • Palano F.
      • Tocci G.
      • Baldini R.
      • Volpe M.
      Antihypertensive treatment and development of heart failure in hypertension: a Bayesian network meta-analysis of studies in patients with hypertension and high cardiovascular risk.
      The choice of antihypertensive therapy should be based on published guidelines,
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines
      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.
      • Chobanian A.V.
      • Bakris G.L.
      • Black H.R.
      • et al.
      National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee
      The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.
      although a meta-analysis suggested that diuretics, angiotensin-converting enzyme inhibitors (ACE-Is), and angiotensin receptor blockers are the most effective classes of drugs for reducing HF risk.
      • Sciarretta S.
      • Palano F.
      • Tocci G.
      • Baldini R.
      • Volpe M.
      Antihypertensive treatment and development of heart failure in hypertension: a Bayesian network meta-analysis of studies in patients with hypertension and high cardiovascular risk.

      Stage B HF: Structural Heart Abnormalities but No Clinical HF Symptoms

      Stage B HF includes patients with prior myocardial infarction, left ventricular remodeling including left ventricular hypertrophy and reduced ejection fraction (EF), and asymptomatic valvular heart disease who have never had active HF symptoms. The number of patients who have stage B HF is estimated to be 3 to 4 times the number of patients with stage C and D combined.
      • Ramani G.V.
      • Uber P.A.
      • Mehra M.R.
      Chronic heart failure: contemporary diagnosis and management.
      • Frigerio M.
      • Oliva F.
      • Turazza F.M.
      • Bonow R.O.
      Prevention and management of chronic heart failure in management of asymptomatic patients.
      The prevalence of asymptomatic reduced EF is estimated at 3% to 6%
      • Wang T.J.
      • Levy D.
      • Benjamin E.J.
      • Vasan R.S.
      The epidemiology of “asymptomatic” left ventricular systolic dysfunction: implications for screening.
      and increases with age. Asymptomatic diastolic dysfunction is more common, with an estimated prevalence as high as 27%.
      • Kuznetsova T.
      • Herbots L.
      • López B.
      • et al.
      Prevalence of left ventricular diastolic dysfunction in a general population.
      Patients with stage B HF are at high risk for the development of symptomatic (stage C) HF, but strategies exist to reduce that risk. In general, all of the therapies for stage A HF, including aggressive treatment of risk factors, should be used in patients with stage B. Additional therapies recommended for patients with stage B HF are shown in Figure 1.
      Chemotherapy may cause cardiotoxicity. The anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin) and the anthraquinone mitoxantrone are the most frequently implicated chemotherapeutic agents associated with the development of cardiotoxicity, with an incidence as high as 26%.
      • Belham M.
      • Kruger A.
      • Mepham S.
      • Faganello G.
      • Pritchard C.
      Monitoring left ventricular function in adults receiving anthracycline-containing chemotherapy.
      A meta-analysis suggested that the risk of both clinical cardiotoxicity (odds ratio, 5.43; 95% CI, 2.34-12.62) and subclinical cardiotoxicity (odds ratio, 2.88; 95% CI, 1.29-6.44) were higher in patients with cancer who were treated with anthracycline vs nonanthracycline-based compounds.
      • Smith L.A.
      • Cornelius V.R.
      • Plummer C.J.
      • et al.
      Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials.
      The risk of cardiotoxicity increases with higher cumulative dose and older age. Use of bolus vs continuous infusions, liposomal vs nonliposomal doxorubicin, concomitant use of iron-chelating agents, and use of epirubicin or mitoxantrone (lower-risk agents for cardiotoxicity) vs doxorubicin may help to mitigate the risk.
      • Belham M.
      • Kruger A.
      • Mepham S.
      • Faganello G.
      • Pritchard C.
      Monitoring left ventricular function in adults receiving anthracycline-containing chemotherapy.
      Patients treated with these agents should generally have an assessment of their EF at baseline and periodically thereafter based on cumulative dose and risk factors, with discontinuation of chemotherapy if the EF declines by 10%, resulting in an EF of less than 50%.
      • Jiji R.S.
      • Kramer C.M.
      • Salerno M.
      Non-invasive imaging and monitoring cardiotoxicity of cancer therapeutic drugs.
      All patients who experience a decline in EF should have therapy with ACE-Is and β-blockers, similar to other patients with stage B HF, although patients with chemotherapy-induced cardiotoxicity are frequently undertreated.
      • Yoon G.J.
      • Telli M.L.
      • Kao D.P.
      • Matsuda K.Y.
      • Carlson R.W.
      • Witteles R.M.
      Left ventricular dysfunction in patients receiving cardiotoxic cancer therapies: are clinicians responding optimally?.
      Ongoing studies are assessing whether patients being treated with anthracyclines should be concomitantly treated with ACE-Is to prevent the development of cardiotoxicity.
      • Cardinale D.
      • Colombo A.
      • Sandri M.T.
      • et al.
      Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition.
      Ways of detecting subclinical signs of left ventricular dysfunction, including changes in longitudinal strain on echocardiography and elevation in cardiac troponin I, are being investigated.
      • Sawaya H.
      • Sebag I.A.
      • Plana J.C.
      • et al.
      Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.
      Additional chemotherapeutic agents that can cause HF include cyclophosphamide, ifosfamide, trastuzumab, and other monoclonal antibody–based tyrosine kinase inhibitors.
      • Bovelli D.
      • Plataniotis G.
      • Roila F.
      ESMO Guidelines Working Group
      Cardiotoxicity of chemotherapeutic agents and radiotherapy-related heart disease: ESMO Clinical Practice Guidelines.

      Stage C HF: Structural Heart Abnormalities and Symptoms of HF

      Once a patient has clinical signs and symptoms of HF, they are categorized as having stage C disease, even if they later become asymptomatic. Important clinical pearls in the general management of patients with stage C HF were included in the review by Ramani et al,
      • Ramani G.V.
      • Uber P.A.
      • Mehra M.R.
      Chronic heart failure: contemporary diagnosis and management.
      and comprehensive guidelines for the management of patients with HF have been published by the ACCF/AHA.
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines
      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.
      This section will focus on important areas of recent research in stage C HF.

      Biomarkers for Estimating Prognosis in Patients with HF

      Although biomarkers are most widely used to diagnose HF, they can also help to provide an estimate of prognosis in patients with stage C and D HF. The natriuretic peptides, namely B-type natriuretic peptide or its amino-terminal fragment (N-terminal pro-B-type natriuretic peptide), which are released in response to myocardial stretch, and troponins, released in response to myocyte injury, are the most widely reported and used biomarkers for prognosis in HF. Higher natriuretic peptide levels have consistently been shown to predict mortality but have been less useful in predicting hospital readmissions. One emerging biomarker, ST2, a member of the interleukin 1 receptor family, is predictive of mortality in HF,
      • Ky B.
      • French B.
      • McCloskey K.
      • et al.
      High-sensitivity ST2 for prediction of adverse outcomes in chronic heart failure.
      may help in identifying patients with HF who would benefit from β-blocker titration,
      • Gaggin H.K.
      • Motiwala S.
      • Bhardwaj A.
      • Parks K.A.
      • Januzzi Jr., J.L.
      Soluble concentrations of the interleukin receptor family member ST2 and β-blocker therapy in chronic heart failure.
      and may become more widely used in the coming years. Cystatin C is a marker of acute kidney injury during an HF hospitalization, and an increase of more than 0.3 mg/L in the first 48 hours of HF hospitalization is associated with longer duration of stay and a 4-fold higher in-hospital mortality.
      • Lassus J.P.
      • Nieminen M.S.
      • Peuhkurinen K.
      • et al.
      FINN-AKVA study group
      Markers of renal function and acute kidney injury in acute heart failure: definitions and impact on outcomes of the cardiorenal syndrome.
      The clinical value of serial biomarker-guided management of HF remains controversial. Although individual trials have often failed to find any reduction in mortality or HF hospitalizations with a natriuretic peptide–guided strategy,
      • Eurlings L.W.
      • van Pol P.E.
      • Kok W.E.
      • et al.
      Management of chronic heart failure guided by individual N-terminal pro-B-type natriuretic peptide targets: results of the PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) study.
      • Shah M.R.
      • Califf R.M.
      • Nohria A.
      • et al.
      The STARBRITE trial: a randomized, pilot study of B-type natriuretic peptide-guided therapy in patients with advanced heart failure [published correction appears in J Card Fail. 2011;17(9):788].
      meta-analyses have suggested there may be some mortality benefit to this approach.
      • Felker G.M.
      • Hasselblad V.
      • Hernandez A.F.
      • O'Connor C.M.
      Biomarker-guided therapy in chronic heart failure: a meta-analysis of randomized controlled trials.
      • Porapakkham P.
      • Porapakkham P.
      • Zimmet H.
      • Billah B.
      • Krum H.
      B-type natriuretic peptide–guided heart failure therapy: a meta-analysis.
      The ongoing GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment) trial may shed some light on this topic as it investigates the efficacy of a strategy of biomarker-guided therapy compared with usual care in high-risk patients with left ventricular systolic dysfunction.

      Updates on the Long-term Management of Patients With Stage C HF

      HF With Preserved EF

      Half of patients with HF have preserved EF (HFpEF), which is variably defined across studies but usually refers to an EF of more than 40% to 50%. Studies have suggested that the prevalence of HFpEF is increasing over time,
      • Owan T.E.
      • Hodge D.O.
      • Herges R.M.
      • Jacobsen S.J.
      • Roger V.L.
      • Redfield M.M.
      Trends in prevalence and outcome of heart failure with preserved ejection fraction.
      and it is most common in older women. Additional comorbidities including anemia, hypertension, and atrial fibrillation are more common in patients with HFpEF than in those who have HF with reduced EF (HFrEF).
      • Lee D.S.
      • Gona P.
      • Vasan R.S.
      • et al.
      Relation of disease pathogenesis and risk factors to heart failure with preserved or reduced ejection fraction: insights from the Framingham Heart Study of the National Heart, Lung, and Blood Institute.
      Similar to patients with HFrEF, patients with HFpEF are at increased risk for death, with 5-year mortality estimated at 50% in both groups.
      • Bursi F.
      • Weston S.A.
      • Redfield M.M.
      • et al.
      Systolic and diastolic heart failure in the community.
      Compared with patients who have HFrEF, patients with HFpEF are more likely to experience a noncardiovascular cause of death.
      • Henkel D.M.
      • Redfield M.M.
      • Weston S.A.
      • Gerber Y.
      • Roger V.L.
      Death in heart failure: a community perspective.
      Despite its increasing prevalence, there are still no known efficacious pharmacological therapies for HFpEF. Whether renin-angiotensin system antagonists improve outcomes in HFpEF has been highly debated, and a recent analysis of patients enrolled in the Swedish HF registry suggested that there may be mortality reduction associated with renin-angiotensin system inhibition in HFpEF.
      • Lund L.H.
      • Benson L.
      • Dahlström U.
      • Edner M.
      Association between use of renin-angiotensin system antagonists and mortality in patients with heart failure and preserved ejection fraction.
      However, randomized controlled trials have consistently failed to document any improvement in mortality in patients with HFpEF treated with ACE-Is
      • Kitzman D.W.
      • Hundley W.G.
      • Brubaker P.H.
      • et al.
      A randomized double-blind trial of enalapril in older patients with heart failure and preserved ejection fraction: effects on exercise tolerance and arterial distensibility.
      or angiotensin receptor blockers
      • Massie B.M.
      • Carson P.E.
      • McMurray J.J.
      • et al.
      I-PRESERVE Investigators
      Irbesartan in patients with heart failure and preserved ejection fraction.
      • Yusuf S.
      • Pfeffer M.A.
      • Swedberg K.
      • et al.
      CHARM Investigators and Committees
      Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial.
      compared with placebo. There has been recent interest in using phosphodiesterase 5 inhibitors, a therapy for patients with pulmonary hypertension, to treat patients with HFpEF. However, the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) multicenter randomized controlled trial found no change in exercise capacity or clinical status after 24 weeks of sildenafil therapy compared with placebo.
      • Redfield M.M.
      • Chen H.H.
      • Borlaug B.A.
      • et al.
      RELAX Trial
      Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial.
      Although aldosterone antagonism with eplerenone did not improve exercise capacity in the recent RAAM-PEF (Randomized Aldosterone Antagonism in Heart Failure with Preserved Ejection Fraction) trial, it had favorable effects on diastolic function.
      • Deswal A.
      • Richardson P.
      • Bozkurt B.
      • Mann D.L.
      Results of the Randomized Aldosterone Antagonism in Heart Failure with Preserved Ejection Fraction trial (RAAM-PEF).
      The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial results, which were presented at the AHA Scientific Sessions in November 2013, found no reduction in the combined risk of cardiovascular mortality, aborted cardiac arrest, or HF hospitalization in patients with HFpEF treated with spironolactone compared with placebo, although a reduction in the secondary end point of HF hospitalizations was observed. Currently, there is insufficient evidence to recommend routine treatment with aldosterone antagonists in patients with HFpEF, although they could be a reasonable choice for patients with another indication for these therapies such as hypertension.
      • Pfeffer M.A.
      • McKinlay S.
      • Pitt B.
      • et al.
      Treatment of preserved cardiac function heart failure with an aldosterone Antagonist (TOPCAT).
      Increasing evidence suggests that activation of the sympathetic nervous system plays a prominent role in the pathophysiology of HFpEF.
      • Verloop W.L.
      • Beeftink M.M.
      • Nap A.
      • et al.
      Renal denervation in heart failure with normal left ventricular ejection fraction: rationale and design of the DIASTOLE (DenervatIon of the renAl Sympathetic nerves in hearT failure with nOrmal Lv Ejection fraction) trial.
      Renal denervation is a transcutaneous catheter-based procedure used to disrupt renal sympathetic nerves. Early studies in hypertensive patients have found it to be safe and effective.
      Symplicity HTN-1 Investigators
      Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months.
      • Krum H.
      • Schlaich M.
      • Whitbourn R.
      • et al.
      Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study.
      There is interest in determining whether renal denervation would be an efficacious therapeutic option in patients with HFpEF, which will be tested in the upcoming DIASTOLE (Denervation of the Renal Sympathetic Nerves in Heart Failure With Normal LV Ejection Fraction) trial.
      • Verloop W.L.
      • Beeftink M.M.
      • Nap A.
      • et al.
      Renal denervation in heart failure with normal left ventricular ejection fraction: rationale and design of the DIASTOLE (DenervatIon of the renAl Sympathetic nerves in hearT failure with nOrmal Lv Ejection fraction) trial.
      Therapy in patients with HFpEF should continue to focus on aggressive management of hypertension, optimizing fluid status with diuretics, and treatment of concomitant comorbidities such as sleep-disordered breathing. Although patients with HFpEF often have dyspnea with exertion, exercise training is safe and improves exercise capacity.
      • Kitzman D.W.
      • Brubaker P.H.
      • Morgan T.M.
      • Stewart K.P.
      • Little W.C.
      Exercise training in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial.

      Monitoring for Hyperkalemia

      Close monitoring for hyperkalemia is necessary for patients treated with aldosterone antagonists. In randomized controlled trials, eplerenone
      • Zannad F.
      • McMurray J.J.
      • Krum H.
      • et al.
      EMPHASIS-HF Study Group
      Eplerenone in patients with systolic heart failure and mild symptoms.
      and spironolactone
      • Pitt B.
      • Zannad F.
      • Remme W.J.
      • et al.
      The effect of spironolactone on morbidity and mortality in patients with severe heart failure: Randomized Aldactone Evaluation Study Investigators.
      markedly reduced death and readmissions in patients with HFrEF. As a result, aldosterone antagonists have received a class I recommendation in the ACCF/AHA guidelines.
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines
      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.
      However, they have not been adopted as readily as other guideline-based therapies, in part due to concern about the risk of hyperkalemia, particularly in high-risk patients such as those treated with renin-angiotensin system antagonists or those with chronic kidney disease. To address the efficacy and safety of these agents in real-world populations, Hernandez et al
      • Hernandez A.F.
      • Mi X.
      • Hammill B.G.
      • et al.
      Associations between aldosterone antagonist therapy and risks of mortality and readmission among patients with heart failure and reduced ejection fraction.
      conducted an analysis of 5887 patients enrolled in the Get With the Guidelines-Heart Failure registry, reporting no difference in mortality or all-cause rehospitalization in the 18.2% of patients treated with these medications. Although patients treated with aldosterone antagonists did have a lower risk of HF-related rehospitalization, they also had a 2.5-fold increased risk of hospitalization for hyperkalemia within 30 days of initiation of therapy. The implications of these data taken in conjunction with those from randomized trials are that aldosterone antagonists can be efficacious therapies but should be used with caution in patients with a history of hyperkalemia or renal insufficiency (estimated glomerular filtration rate <60 mL/min). Potassium levels and renal function should be monitored at 1 week, 4 weeks, and 3 months after treatment initiation in all patients.

      Cardiac Resynchronization Therapy

      Cardiac resynchronization therapy (CRT) should be considered in patients with less severe symptoms. In previous versions of the ACCF/AHA guidelines, a class I indication for CRT was given only for patients with New York Heart Association (NYHA) functional class III symptoms, an EF of 35% or less, and a QRS duration of 120 milliseconds or more. In the 2012 ACCF/AHA/Heart Rhythm Society update, the class I indication was expanded to include patients with NYHA class II symptoms.
      • Tracy C.M.
      • Epstein A.E.
      • Darbar D.
      • et al.
      American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; Heart Rhythm Society
      2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society [published correction appears in Circulation. 2013;127(3):e357–e359].
      However, the class I recommendation was confined to patients with a left bundle branch block and QRS duration of 150 milliseconds or more (Table 1). These changes were made on the basis of results of trials including the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction),
      • Linde C.
      • Abraham W.T.
      • Gold M.R.
      • St John Sutton M.
      • Ghio S.
      • Daubert C.
      REVERSE (REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction) Study Group
      Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms.
      MADIT-CRT (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy),
      • Moss A.J.
      • Hall W.J.
      • Cannom D.S.
      • et al.
      MADIT-CRT Trial Investigators
      Cardiac-resynchronization therapy for the prevention of heart-failure events.
      and RAFT (Resynchronization-Defibrillation for Ambulatory Heart Failure Trial)
      • Tang A.S.
      • Wells G.A.
      • Talajic M.
      • et al.
      Resynchronization-Defibrillation for Ambulatory Heart Failure Trial Investigators
      Cardiac-resynchronization therapy for mild-to-moderate heart failure.
      studies.
      Table 1Indications for Cardiac Resynchronization Therapy
      EF = ejection fraction; LBBB = left bundle branch block; NA = not applicable; NYHA = New York Heart Association.
      ,
      All patients should be receiving goal-directed medical therapy before consideration of cardiac resynchonization therapy.
      Data from J Am Coll Cardiol.
      • Tracy C.M.
      • Epstein A.E.
      • Darbar D.
      • et al.
      American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; Heart Rhythm Society
      2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society [published correction appears in Circulation. 2013;127(3):e357–e359].
      NYHA functional classClassification of recommendation
      Class I: benefit substantially outweighs riskClass IIa: benefit outweighs riskClass IIb: benefit may outweigh riskClass III: no benefit
      INANAEF ≤30%

      QRS ≥150 ms

      LBBB

      Ischemia
      QRS <150 ms

      No LBBB
      IIEF ≤35%

      QRS ≥150 ms

      LBBB

      Sinus rhythm
      EF ≤35%

      QRS 120-149 ms

      LBBB

      Sinus rhythm
      EF ≤35%

      QRS ≥150 ms

      No LBBB

      Sinus rhythm
      QRS <150 ms

      No LBBB
      IIIEF ≤35%

      QRS ≥150 ms

      LBBB

      Sinus rhythm
      EF ≤35%

      Sinus rhythm

      LBBB + QRS 120-149 ms

      or

      No LBBB + QRS ≥150 ms
      EF ≤35%

      QRS 120-149 ms

      No LBBB

      Sinus rhythm
      NA
      IV, stage DNANANAIf limited, survival to <1 y
      Atrial fibrillationNAEF <35% and requires pacing or expected to pace frequentlyNANA
      a EF = ejection fraction; LBBB = left bundle branch block; NA = not applicable; NYHA = New York Heart Association.
      b All patients should be receiving goal-directed medical therapy before consideration of cardiac resynchonization therapy.

      Intravenous Iron Therapy

      Intravenous iron therapy improves exercise capacity in iron-deficient patients with HF. Anemia is associated with increased morbidity and mortality among patients with HF
      • Dunlay S.M.
      • Weston S.A.
      • Redfield M.M.
      • Killian J.M.
      • Roger V.L.
      Anemia and heart failure: a community study.
      • Groenveld H.F.
      • Januzzi J.L.
      • Damman K.
      • et al.
      Anemia and mortality in heart failure patients: a systematic review and meta-analysis.
      and is more common in women and patients with HFpEF. Given the prevalence of anemia in HF and associated adverse effects, there has been interest in using iron and erythropoietin therapy. Because iron is not well absorbed orally, its safety and efficacy when administered intravenously have been investigated in 3 randomized trials. Although no consistent improvements in hard clinical end points such as death and hospitalization were seen, intravenous iron therapy was safe and improved NYHA functional class and exercise capacity
      • Anker S.D.
      • Comin Colet J.
      • Filippatos G.
      • et al.
      FAIR-HF Trial Investigators
      Ferric carboxymaltose in patients with heart failure and iron deficiency.
      • Okonko D.O.
      • Grzeslo A.
      • Witkowski T.
      • et al.
      Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency: FERRIC-HF; a randomized, controlled, observer-blinded trial.
      • Toblli J.E.
      • Lombraña A.
      • Duarte P.
      • Di Gennaro F.
      Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency.
      in iron-deficient patients with HF with and without anemia. Thus, use of intravenous iron therapy should be considered in patients with HF and iron deficiency. Erythropoietin is produced by the kidneys, is often elevated in patients with HF, and is associated with adverse outcomes. In patients with advanced chronic kidney disease, erythropoietin is frequently used to treat anemia and thus was of interest for use in patients with HF and anemia. Despite promising results in smaller studies, the recently published RED-HF (Reduction of Events With Darbepoetin Alfa in Heart Failure) Trial, which randomized 1136 patients with hemoglobin levels of 9 to 12 g/dL (to convert to g/L, multiply by 10.0) to darbepoetin alfa or placebo, found no difference in clinical outcomes in patients treated with darbepoetin.
      • Swedberg K.
      • Young J.B.
      • Anand I.S.
      • et al.
      RED-HF Committees; RED-HF Investigators
      Treatment of anemia with darbepoetin alfa in systolic heart failure.
      At this time, there is insufficient data to support the routine use of erythropoietin agents in patients with HF and anemia.

      Pharmacogenetics

      Pharmacogenetics may help individualize treatment of patients with HF. Pharmacogenetics is the study of the role that inherited factors play in an individual's response to a drug. Advances in DNA sequencing and genotyping have made it possible to rapidly and accurately identify variation in DNA sequence and structure. As a result, we can now correlate genomic variation with drug response, which helps us to predict individual variation in responses to specific medications, to optimize medication selection and dose, and to avoid adverse medication effects. In HF, one early example of the potential importance of pharmacogenetics is with use of β-blockers. Although β-blockers are known to reduce morbidity and mortality in HF, the response is heterogeneous. It was hypothesized that this heterogeneity may be explained in part by genetic variation in the β1-adrenergic receptor. The HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) DNA study found that patients with a specific allelic variant of the β1-adrenergic receptor (Arg389) required larger doses of β-blockers to achieve similar effects compared with other patients.
      • Fiuzat M.
      • Neely M.L.
      • Starr A.Z.
      • et al.
      Association between adrenergic receptor genotypes and beta-blocker dose in heart failure patients: analysis from the HF-ACTION DNA substudy.
      There are important challenges to address regarding the implementation of pharmacogenetics in clinical practice, including availability of genotyping, insurance coverage of testing, and physician and patient acceptance.
      • Pereira N.L.
      • Weinshilboum R.M.
      The impact of pharmacogenomics on the management of cardiac disease.

      Updates on the Management of Patients With Acute Decompensated HF

      Emergency Department Observations Units

      Emergency department (ED) observation units may decrease the need for hospital admission of patients with acute decompensated HF (ADHF). Each year, nearly 800,000 patients with HF are admitted from the ED to the hospital. Only a small proportion of patients present in cardiogenic shock or require invasive diagnostic evaluations or intravenous inotrope infusions. However, only 10% to 20% of the patients who present to the ED with HF are discharged to home,
      • Weintraub N.L.
      • Collins S.P.
      • Pang P.S.
      • et al.
      American Heart Association Council on Clinical Cardiology and Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation
      Acute heart failure syndromes: emergency department presentation, treatment, and disposition: current approaches and future aims; a scientific statement from the American Heart Association.
      with the remainder admitted to the hospital. Because some of the patients admitted may only require decongestion and monitoring for a short time, there has been interest in understanding whether ED observation protocols can be developed to treat patients with HF who require further evaluation before deciding about disposition. A 2-level algorithm to identify low- and intermediate-risk candidates for observation has been proposed.
      • Collins S.P.
      • Pang P.S.
      • Fonarow G.C.
      • Yancy C.W.
      • Bonow R.O.
      • Gheorghiade M.
      Is hospital admission for heart failure really necessary? the role of the emergency department and observation unit in preventing hospitalization and rehospitalization.
      Patients exhibiting high-risk features such as hemodynamic instability, worsening renal function, and elevated troponin levels would be admitted to an inpatient unit. Those who quickly return to their baseline status after initiation of diuretic therapy and have no high-risk features could be discharged to home. The third group of low- and intermediate-risk patients would be candidates for a 24-hour observation unit where continued response to therapy could be monitored. Up to 50% of patients who are currently admitted with HF may qualify for observation units, and up to 75% of those may be able to be discharged home after observation without requiring hospitalization. However, a randomized controlled trial would be needed before deciding whether this option can reduce costs and resource use without affecting outcomes.

      Decongestion Strategies for Patients Hospitalized With HF

      There are multiple equivalent strategies to alleviate congestion in patients who are admitted to the hospital with HF. Approximately 90% of such patients are treated with loop diuretics, but there has been controversy as to whether bolus dosing or continuous infusion produces better results. Several small trials have been undertaken, but they were underpowered and reported disparate results.
      • Allen L.A.
      • Turer A.T.
      • Dewald T.
      • Stough W.G.
      • Cotter G.
      • O'Connor C.M.
      Continuous versus bolus dosing of furosemide for patients hospitalized for heart failure.
      • Thomson M.R.
      • Nappi J.M.
      • Dunn S.P.
      • Hollis I.B.
      • Rodgers J.E.
      • Van Bakel A.B.
      Continuous versus intermittent infusion of furosemide in acute decompensated heart failure.
      • Salvador D.R.
      • Rey N.R.
      • Ramos G.C.
      • Punzalan F.E.
      Continuous infusion versus bolus injection of loop diuretics in congestive heart failure.
      In 2011, the National Institutes of Health–sponsored DOSE-AHF (Diuretic Optimal Strategy Evaluation in Acute Heart Failure) Study reported no difference in patient-reported symptoms, change in renal function, or net fluid loss in patients treated with bolus vs continuous infusion of intravenous furosemide.
      • Felker G.M.
      • Lee K.L.
      • Bull D.A.
      • et al.
      NHLBI Heart Failure Clinical Research Network
      Diuretic strategies in patients with acute decompensated heart failure.
      A reasonable total daily intravenous furosemide starting dose on admission would be 2.5 times the patient's total daily outpatient oral diuretic dose in furosemide equivalents. Lower doses could be employed but may require longer duration of intravenous diuresis or a dose increase if a lack of response is observed.

      Cardiorenal Syndrome

      Therapy for patients presenting with cardiorenal syndrome remains challenging. Strategies previously advocated have included use of ultrafiltration, low-dose dopamine, and nesiritide. However, recent results have suggested that none of these therapies is more efficacious than intravenous diuretics. The CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) trial found that ultrafiltration resulted in similar weight loss compared with diuretics plus inotropes but was associated with worsening renal function and increased adverse events.
      • Bart B.A.
      • Goldsmith S.R.
      • Lee K.L.
      • et al.
      Cardiorenal rescue study in acute decompensated heart failure: rationale and design of CARRESS-HF, for the Heart Failure Clinical Research Network.
      The efficacy of adding low-dose dopamine to diuretics was tested in the DAD-HF (Dopamine in Acute Decompensated Heart Failure) and ROSE-AHF (Renal Optimization Strategies Evaluation in Acute Heart Failure) trials. In the DAD-HF study, patients randomized to a low-dose furosemide infusion and 5 μg/kg per minute of dopamine had improved renal function compared with patients treated with very-high-dose furosemide infusion (20 mg/h).
      • Giamouzis G.
      • Butler J.
      • Starling R.C.
      • et al.
      Impact of dopamine infusion on renal function in hospitalized heart failure patients: results of the Dopamine in Acute Decompensated Heart Failure (DAD-HF) Trial.
      However, the ROSE-AHF trial found no difference in urine volume or renal function with addition of dopamine to intravenous diuretics in patients with ADHF and renal dysfunction.
      • Chen H.H.
      • Anstrom K.J.
      • Givertz M.M.
      • et al.
      NHLBI Heart Failure Clinical Research Network
      Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial.
      Finally, nesiritide, a recombinant B-type natriuretic peptide, was approved for use in the United States in 2001 for patients with ADHF because studies had found an improvement in dyspnea and reduction in pulmonary capillary wedge pressure after administration.
      • Colucci W.S.
      • Elkayam U.
      • Horton D.P.
      • et al.
      Nesiritide Study Group
      Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure [published corrections appear in N Engl J Med. 2000;343(20):1504; N Engl J Med. 2000;343(12):896].
      Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF)
      Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial [published correction appears in JAMA. 2002;288(5):577].
      However, subsequent meta-analyses raised concerns that nesiritide may be associated with worsening renal function and higher mortality.
      • Sackner-Bernstein J.D.
      • Skopicki H.A.
      • Aaronson K.D.
      Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure [published correction appears in Circulation. 2005;111(17):2274].
      Both the ASCEND (A Study of Cardiovascular Events in Diabetes)
      • O'Connor C.M.
      • Starling R.C.
      • Hernandez A.F.
      • et al.
      Effect of nesiritide in patients with acute decompensated heart failure [published correction appears in N Engl J Med. 2011;365(8):773].
      and ROSE-AHF
      • Chen H.H.
      • Anstrom K.J.
      • Givertz M.M.
      • et al.
      NHLBI Heart Failure Clinical Research Network
      Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial.
      randomized trials found no increase in the risk of death or worsening renal function in patients treated with nesiritide. Both studies found a greater risk of hypotension with nesiritide, and only the ASCEND study reported a small, nonsignificant improvement in dyspnea with nesiritide compared with placebo. There is no strong evidence to support the routine use of ultrafiltration, dopamine, or nesiritide in the management of ADHF and cardiorenal syndrome. A more prudent approach may be to treat patients with intravenous loop diuretics and to only consider additional therapies in patients refractory to initial management.

      HF Readmissions

      There is no easy solution to the HF readmissions problem. One in 4 patients discharged from the hospital following an admission for HF is readmitted within 30 days (median cost of $9923 per readmission
      • Eapen Z.J.
      • Reed S.D.
      • Curtis L.H.
      • Hernandez A.F.
      • Peterson E.D.
      Do heart failure disease management programs make financial sense under a bundled payment system?.
      ), and HF is the most frequent reason for readmission among Medicare beneficiaries.
      • Jencks S.F.
      • Williams M.V.
      • Coleman E.A.
      Rehospitalizations among patients in the Medicare fee-for-service program [published correction appears in N Engl J Med. 2011;364(16):1582].
      Given the economic and public health implications of readmissions, several health care–related institutes and payers have focused on this metric as an indicator of the quality of the care that is provided. On October 1, 2012, the Centers for Medicare and Medicaid Services began to financially penalize hospitals with higher than expected 30-day readmission rates for pneumonia, acute myocardial infarction, and HF. Thus, hospitals have begun scrambling to implement strategies to reduce readmissions and avoid the pay-for-performance penalties. Although a wide variety of strategies have been implemented, they can be been categorized into 3 groups: (1) quality improvement efforts and performance monitoring (eg, presence of a quality improvement team, partnering with community-based agencies to reduce readmission), (2) medication management (eg, medication reconciliation and patient teaching), and (3) discharge and follow-up procedures (eg, early outpatient follow-up, care transitions programs).
      • Bradley E.H.
      • Curry L.
      • Horwitz L.I.
      • et al.
      Contemporary evidence about hospital strategies for reducing 30-day readmissions: a national study.
      Most hospitals have implemented multiple practices in these domains.
      • Bradley E.H.
      • Curry L.
      • Horwitz L.I.
      • et al.
      Contemporary evidence about hospital strategies for reducing 30-day readmissions: a national study.
      Perhaps the most enlightening analysis of best practices is that by Bradley et al,
      • Bradley E.H.
      • Curry L.
      • Horwitz L.I.
      • et al.
      Hospital strategies associated with 30-day readmission rates for patients with heart failure.
      who recently described 6 strategies that were associated with a significant reduction in readmissions in a national hospital survey (Table 2). Although the magnitude of readmission reduction for each of these strategies was small, their combined effect may constitute a meaningful difference, and these strategies would be an appropriate place to focus readmission reduction efforts.
      Table 2Six Effective Strategies to Reduce Readmissions in HF
      Data from Circ Cardiovasc Qual Outcomes.
      • Bradley E.H.
      • Curry L.
      • Horwitz L.I.
      • et al.
      Hospital strategies associated with 30-day readmission rates for patients with heart failure.
      Strategy to reduce readmissionEstimated absolute reduction in risk-standardized 30-d readmission rates (%)
      1. Partnering with community physicians or physician groups0.33
      2. Partnering with local hospitals to reduce readmissions0.34
      3. Having nurses responsible for medication reconciliation0.18
      4. Arranging follow-up appointments before discharge0.18
      5. Having a process in place to send all discharge papers or electronic summaries directly to the patient's primary physician0.21
      6. Assigning staff to follow up on test results that return after the patient is discharged0.26

      Stage D HF: Refractory End-Stage HF

      Stage D encompasses patients with HF that is refractory despite usual medical therapy and often includes patients with recurrent hospitalizations. These patients experience daily life-limiting symptoms and are unlikely to have stable disease with continuation of stage C HF therapies. It is estimated that approximately 5% of patients with HF have stage D disease.
      • Costanzo M.R.
      • Mills R.M.
      • Wynne J.
      Characteristics of “Stage D” heart failure: insights from the Acute Decompensated Heart Failure National Registry Longitudinal Module (ADHERE LM).
      Although the risk of death in stage D HF may vary according to the specific clinical characteristics of the individual patient, the estimated 1- and 5-year mortality in all patients with stage D HF is 28%
      • Costanzo M.R.
      • Mills R.M.
      • Wynne J.
      Characteristics of “Stage D” heart failure: insights from the Acute Decompensated Heart Failure National Registry Longitudinal Module (ADHERE LM).
      and 80%,
      • Ramani G.V.
      • Uber P.A.
      • Mehra M.R.
      Chronic heart failure: contemporary diagnosis and management.
      respectively. In recent years, therapeutic options for patients with stage D HF have increased. However, not all options are medically appropriate for all patients, and some therapies may not be in alignment with an individual's goals and preferences. Therefore, there has been a recognized need to promote shared decision making and improved patient-physician communication around potential options in patients with stage D HF.
      • Allen L.A.
      • Stevenson L.W.
      • Grady K.L.
      • et al.
      American Heart Association; Council on Quality of Care and Outcomes Research; Council on Cardiovascular Nursing; Council on Clinical Cardiology; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Surgery and Anesthesia
      Decision making in advanced heart failure: a scientific statement from the American Heart Association.
      Referral to an HF specialist should be considered any time questions arise in the management of patients with HF but particularly when a patient's HF symptoms are difficult to manage, when a patient is unable to tolerate HF-related medications such as β-blockers, when complicated or recurrent HF hospitalizations occur, or when a physician believes that MCS and cardiac transplant should be considered (Table 3).
      Table 3When to Consider Cardiac Transplant or LVAD as Destination Therapy
      EF = ejection fraction; LVAD = left ventricular assist device; RV = right ventricular; V˙o2 = oxygen consumption per unit time.
      IndicationsContraindications
      Heart transplant
      • Refractory cardiogenic shock

      • Severe persistent angina and coronary arteries not amenable to revascularization

      • Markedly reduced exercise capacity (peak V˙o2 <10-14 mL/kg/min)

      • Recurrent refractory ventricular arrhythmias
      • High pulmonary vascular resistance

      • Active malignancy or infection

      • Active substance abuse

      • Inadequate social support

      • Age (>70 y, heart alone; >65 y, dual organ transplant)
      Indicates a relative contraindication.


      • Excessive comorbidity (eg, uncontrolled diabetes, psychiatric disease, morbid obesity)
      Indicates a relative contraindication.
      LVAD as destination therapy
      An LVAD may be used as a bridge to transplant in any patient awaiting heart transplant who may benefit. The LVAD is removed at the time of heart transplant. A total artificial heart may be considered in a patient awaiting heart transplant who needs mechanical circulatory support but has very poor RV function.
      • Has indications for heart transplant but ineligible due to age, high pulmonary vascular resistance, comorbidities

      • Medicare requires EF <25%
      • Active malignancy or infection

      • Cirrhosis

      • Severe RV dysfunction

      • Inadequate social support

      • Active substance abuse
      Indicates a relative contraindication.


      • Hemodialysis
      Indicates a relative contraindication.


      • Inability to tolerate long-term anticoagulation
      a EF = ejection fraction; LVAD = left ventricular assist device; RV = right ventricular; V˙o2 = oxygen consumption per unit time.
      b Indicates a relative contraindication.
      c An LVAD may be used as a bridge to transplant in any patient awaiting heart transplant who may benefit. The LVAD is removed at the time of heart transplant. A total artificial heart may be considered in a patient awaiting heart transplant who needs mechanical circulatory support but has very poor RV function.

      Mechanical Circulatory Support

      Mechanical circulatory support is an efficacious therapy for selected patients with stage D HF. We are in the midst of a rapid evolution in our ability to care for patients with advanced HF due to the introduction and improvements in MCS. Until recently, cardiac replacement therapy was limited to orthotopic heart transplant. Although heart transplant is an efficacious therapy, organ supply is limited, having remained around 2200 heart transplants per year in the United States with most organs allocated to younger patients with limited comorbidities. In the past 2 decades, MCS devices have become smaller and the rate of complications has decreased. The left ventricular assist devices (LVADs) used most frequently now provide continuous flow from the left ventricle through the pump and into the aorta. They are quite durable and have enabled patients who are not candidates for cardiac transplant to be implanted with an LVAD that can remain in situ until death (destination therapy). In addition, they have also allowed patients who are awaiting heart transplant to reap the benefits of improvement in HF symptoms and quality of life until suitable organs become available (bridge to transplant).
      As with any therapy, there are risks and benefits with MCS. Although survival and quality of life are both improved in patients with advanced HF treated with MCS compared with medical therapy (1-year survival, 68% vs 25%, respectively
      • Rose E.A.
      • Gelijns A.C.
      • Moskowitz A.J.
      • et al.
      Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group
      Long-term use of a left ventricular assist device for end-stage heart failure.
      • Slaughter M.S.
      • Rogers J.G.
      • Milano C.A.
      • et al.
      HeartMate II Investigators
      Advanced heart failure treated with continuous-flow left ventricular assist device.
      ), complications are common. In patients with an LVAD implanted as destination therapy, both device-related infection (incidence of 8.01 per 100 patient-months) and stroke (incidence of 0.13 per patient-year) are still very common.
      • Slaughter M.S.
      • Rogers J.G.
      • Milano C.A.
      • et al.
      HeartMate II Investigators
      Advanced heart failure treated with continuous-flow left ventricular assist device.
      The most common reason for readmission after LVAD implantation is gastrointestinal bleeding,
      • Hasin T.
      • Marmor Y.
      • Kremers W.
      • et al.
      Readmissions after implantation of axial flow left ventricular assist device.
      and a growing body of evidence has implicated acquired von Willebrand factor deficiency with a loss of large von Willebrand multimers.
      • Crow S.
      • Chen D.
      • Milano C.
      • et al.
      Acquired von Willebrand syndrome in continuous-flow ventricular assist device recipients.
      • Uriel N.
      • Pak S.W.
      • Jorde U.P.
      • et al.
      Acquired von Willebrand syndrome after continuous-flow mechanical device support contributes to a high prevalence of bleeding during long-term support and at the time of transplantation.
      Severe device malfunction requiring pump exchange is rare (incidence of 0.06 per patient-year).
      • Slaughter M.S.
      • Rogers J.G.
      • Milano C.A.
      • et al.
      HeartMate II Investigators
      Advanced heart failure treated with continuous-flow left ventricular assist device.
      It is estimated that only 30% of patients receiving MCS are free from any adverse event (infection, bleeding, device malfunction, stroke, or death) within the first year of implantation.
      • Kirklin J.K.
      • Naftel D.C.
      • Kormos R.L.
      • et al.
      Fifth INTERMACS annual report: risk factor analysis from more than 6,000 mechanical circulatory support patients.
      Furthermore, nearly all patients require one or more readmissions early after implantation, with an average of 2 readmissions in the first 6 months.
      • Hasin T.
      • Marmor Y.
      • Kremers W.
      • et al.
      Readmissions after implantation of axial flow left ventricular assist device.
      • Forest S.J.
      • Bello R.
      • Friedmann P.
      • et al.
      Readmissions after ventricular assist device: etiologies, patterns, and days out of hospital.
      As our experience in managing patients with LVADs grows, we learn more about optimal strategies for follow-up. Echocardiographic monitoring is an important component of the longitudinal care of LVAD recipients, and there is a growing body of literature on both normal and abnormal echocardiographic values post-LVAD implantation
      • Fine N.M.
      • Topilsky Y.
      • Oh J.K.
      • et al.
      Role of echocardiography in patients with intravascular hemolysis due to suspected continuous-flow LVAD thrombosis.
      • Topilsky Y.
      • Hasin T.
      • Oh J.K.
      • et al.
      Echocardiographic variables after left ventricular assist device implantation associated with adverse outcome.
      • Topilsky Y.
      • Oh J.K.
      • Atchison F.W.
      • et al.
      Echocardiographic findings in stable outpatients with properly functioning HeartMate II left ventricular assist devices.
      (Table 4).
      Table 4Echocardiographic Parameters in Patients with Left Ventricular Assist Devices
      Data from Circ Cardiovasc Imaging
      • Topilsky Y.
      • Hasin T.
      • Oh J.K.
      • et al.
      Echocardiographic variables after left ventricular assist device implantation associated with adverse outcome.
      and J Am Soc Echocardiogr.
      • Topilsky Y.
      • Oh J.K.
      • Atchison F.W.
      • et al.
      Echocardiographic findings in stable outpatients with properly functioning HeartMate II left ventricular assist devices.
      Changes in echocardiographic variables postoperatively in patients with normal LVAD function
       Signs of decreased left ventricular filling pressures
      Increase in mitral inflow deceleration time
      Decrease in left atrial volume
      Decrease in E/e' ratio
      Neutral or slightly leftward position of the interventricular and atrial septum
       Decreased estimated right atrial pressure
       Improvement in RV function both qualitatively and quantitatively (RIMP, fractional area change)
       Decreased severity of mitral regurgitation
       Increased severity of aortic regurgitation
      Variables associated with adverse outcome in patients with LVADs
       Increased estimated left atrial pressure
       Mitral deceleration index <2 (ratio of deceleration time to E-wave velocity)
       Decreased tricuspid lateral annulus velocity
      LVAD = left ventricular assist device; RIMP = right ventricular index of myocardial performance; RV = right ventricular.
      Although the cost-effectiveness has improved with the current continuous flow LVADs, costs remain high ($198,184 per quality-adjusted life-year
      • Rogers J.G.
      • Bostic R.R.
      • Tong K.B.
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      Cost-effectiveness analysis of continuous-flow left ventricular assist devices as destination therapy.
      ) compared with other cardiac device–related therapies such as CRT.
      • Noyes K.
      • Veazie P.
      • Hall W.J.
      • et al.
      Cost-effectiveness of cardiac resynchronization therapy in the MADIT-CRT trial.
      The cost-effectiveness may continue to improve if the cost of devices declines and as we continue to achieve better patient outcomes. Attaining the best patient outcomes requires both optimal patient selection and appropriate timing of implantation along the HF trajectory. As device technology improves, we may be able to offer MCS to “less sick” patients with advanced HF
      • Jeevanandam V.
      Are we ready to implant left ventricular assist devices in “less sick” patients?.
      while still improving their outcomes compared with usual medical therapy. In addition, although LVADs have historically been used as a treatment for patients with dilated and ischemic cardiomyopathy, some centers are implanting LVADs in selected patients with hypertrophic and restrictive cardiomyopathy.
      • Topilsky Y.
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      Left ventricular assist device therapy in patients with restrictive and hypertrophic cardiomyopathy.
      Mechanical circulatory support technology continues to advance and evolve.
      • Stewart G.C.
      • Givertz M.M.
      Mechanical circulatory support for advanced heart failure: patients and technology in evolution.
      Implantable miniature pumps, such as the CircuLite Synergy,
      • Meyns B.
      • Klotz S.
      • Simon A.
      • et al.
      Proof of concept: hemodynamic response to long-term partial ventricular support with the synergy pocket micro-pump.
      are being developed that may provide long-term partial support (fewer liters per minute than the current LVADs) but have the benefit of not requiring cardiopulmonary bypass or a sternotomy for implantation. Thoratec Corporation's HeartMate III has a compact design but can still provide full support (up to 10 L/ min). Biventricular support is already being provided in some patients with the total artificial heart, a pump that is implanted with removal of both native ventricles and most of both atria. The SynCardia Systems, Inc, Total Artificial Heart has been approved by the US Food and Drug Administration for bridge to transplant therapy since 2001 and more recently for compassionate use as destination therapy. Furthermore, there have been case reports of successful use of continuous flow pumps in both ventricles.
      • Saito S.
      • Sakaguchi T.
      • Miyagawa S.
      • et al.
      Biventricular support using implantable continuous-flow ventricular assist devices.
      • Hetzer R.
      • Krabatsch T.
      • Stepanenko A.
      • Hennig E.
      • Potapov E.V.
      Long-term biventricular support with the HeartWare implantable continuous flow pump [letter].

      Advance Care Planning

      All patients with stage D HF should participate in advance care planning. The highest rate of hospitalizations and cumulative resource utilization in patients with HF occurs at the end of life
      • Desai A.S.
      • Stevenson L.W.
      Rehospitalization for heart failure: predict or prevent?.
      • Dunlay S.M.
      • Shah N.D.
      • Shi Q.
      • et al.
      Lifetime costs of medical care after heart failure diagnosis.
      despite the fact that most patients with chronic conditions say that they would want to avoid hospitalization as they near death.

      ES F. The Dartmouth Atlas of Health Care. In: KK B, ed. End of Life Care; 2007. http://www.dartmouthatlas.org/data/topic/topic.aspx?cat=18. Accessed January 31, 2014.

      There are numerous models available to predict death and readmission in HF, with the Seattle Heart Failure Model
      • Levy W.C.
      • Mozaffarian D.
      • Linker D.T.
      • et al.
      The Seattle Heart Failure Model: prediction of survival in heart failure.
      being the most widely used in clinical practice. Although models are imperfect at predicting outcomes for an individual, they are generally more accurate than clinical judgment, which tends to overestimate time to death. Combining risk prediction models with adaptation based on clinical knowledge of an individual's situation may be the best approach to providing accurate individualized risk prediction.
      • Allen L.A.
      • Stevenson L.W.
      • Grady K.L.
      • et al.
      American Heart Association; Council on Quality of Care and Outcomes Research; Council on Cardiovascular Nursing; Council on Clinical Cardiology; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Surgery and Anesthesia
      Decision making in advanced heart failure: a scientific statement from the American Heart Association.
      Because HF is a clinical syndrome that often follows an unpredictable trajectory, it is important for physicians to periodically review patients' preferences for care in the case of both expected and unexpected occurrences. Advance directives, an important component of advance care planning and documentation of wishes regarding care, are completed in only 41% of patients with HF.
      • Dunlay S.M.
      • Swetz K.M.
      • Mueller P.S.
      • Roger V.L.
      Advance directives in community patients with heart failure.
      They should ideally be completed and revised as needed after discussion among patients, physicians, and families. Palliative care, the aim of which is to improve quality of life and support patients and families as they deal with chronic and complex illnesses,
      • Adler E.D.
      • Goldfinger J.Z.
      • Kalman J.
      • Park M.E.
      • Meier D.E.
      Palliative care in the treatment of advanced heart failure.
      is associated with improved patient and family satisfaction and decreased health care utilization and costs

      Whitford K, Shah ND, Moriarty J, Branda M, Thorsteinsdottir B. Impact of a palliative care consult service [published online ahead of print April 2, 2013]. Am J Hosp Palliat Care. http://dx.doi.org/10.1177/1049909113482746.

      • Morrison R.S.
      • Penrod J.D.
      • Cassel J.B.
      • et al.
      Palliative Care Leadership Centers' Outcomes Group
      Cost savings associated with US hospital palliative care consultation programs.
      and should be considered as an option in patients with stage D HF. In addition to enhancing transitions to end-of-life care and hospice when appropriate, palliative medicine can also help with preparedness planning before use of advanced therapies such as LVAD

      Swetz KM, Kamal AH, Matlock DD, et al. Preparedness planning before mechanical circulatory support: a “how-to” guide for palliative medicine clinicians [published online ahead of print October 2, 2013]. J Pain Symptom Manage. http://dx.doi.org/10.1016/j.jpainsymman.2013.06.006.

      and transplant.

      Conclusion

      Since 2010, no revolutionary new therapies have been developed for HF, but there have been ongoing advances in our ability to diagnose and treat patients with HF. In particular, the ongoing improvement in MCS has offered some patients with end-stage HF new life-prolonging options. Because the prevalence of HF has continued to increase, it is important to remain committed to searching for effective ways to prevent the development of active HF in patients with stage A and B HF and to finding efficacious therapies to treat the growing number of patients with HFpEF.

      Supplemental Online Material

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