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2022 ACC/AHA/HFSA Guideline for the Management of Heart Failure: Executive Summary

      ABSTRACT

      Background

      The 2022 American College of Cardiology/American Heart Association/Heart Failure Society of America (AHA/ACC/HFSA) Guideline for the Management of Heart Failure replaces the 2013 ACCF/AHA Guideline for the Management of Heart Failure and the 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. The 2022 guideline is intended to provide patient-centric recommendations for clinicians to prevent, diagnose and manage patients with heart failure.

      Methods

      A comprehensive literature search was conducted from May 2020 to December 2020, encompassing studies, reviews and other evidence conducted in human subjects that were published in English from MEDLINE (PubMed), EMBASE, the Cochrane Collaboration, the Agency for Healthcare Research and Quality, and other relevant databases. Additional relevant clinical trials and research studies published through September 2021 were also considered. This guideline was harmonized with other American Heart Association/American College of Cardiology guidelines published through December 2021.

      Results and Conclusions

      Heart failure remains a leading cause of morbidity and mortality globally. The 2022 heart failure guideline provides recommendations based on contemporary evidence for the treatment of these patients. The recommendations present an evidence-based approach to managing patients with heart failure, with the intent to improve quality of care and align with patients’ interests. Many recommendations from the earlier heart failure guidelines have been updated with new evidence, and new recommendations have been created when supported by published data. Value statements are provided for certain treatments that have high-quality published economic analyses.
      Top 10 Take-Home Messages
      • 1.
        Guideline-directed medical therapy (GDMT) for heart failure (HF) with reduced ejection fraction (HFrEF) now includes 4 medication classes, including sodium-glucose cotransporter-2 inhibitors (SGLT2i).
      • 2.
        SGLT2i have a Class of Recommendation 2a in HF with mildly reduced ejection fraction (HFmrEF). Weaker recommendations (Class of Recommendation 2b) are made for ARNi, ACEi, ARB, MRA, and beta-blocker in this population.
      • 3.
        New recommendations for HFpEF are made for SGLT2i (Class of Recommendation 2a), MRAs (Class of Recommendation 2b) and ARNi (Class of Recommendation 2b). Several prior recommendations have been renewed, including treatment of hypertension (Class of Recommendation 1), treatment of atrial fibrillation (Class of Recommendation 2a), use of ARB (Class of Recommendation 2b), and avoidance of routine use of nitrates or phosphodiesterase-5 inhibitors (Class of Recommendation 3: No Benefit).
      • 4.
        Improved left ventricular ejection fraction (LVEF) is used to refer to patients with previous HFrEF who now have LVEF > 40%. These patients should continue their treatment for HFrEF.
      • 5.
        Value statements were created for selected recommendations in which high-quality, cost-effectiveness studies of the intervention have been published.
      • 6.
        Amyloid heart disease has new recommendations for treatment, including screening for serum and urine monoclonal light chains, bone scintigraphy, genetic sequencing, tetramer stabilizer therapy, and anticoagulation.
      • 7.
        Evidence supporting increased filling pressures is important for the diagnosis of HF if the LVEF is > 40%. Evidence for increased filling pressures can be obtained from noninvasive (eg, natriuretic peptide, diastolic function on imaging) or invasive testing (eg, hemodynamic measurement).
      • 8.
        Patients with advanced HF who wish to prolong survival should be referred to a team specializing in HF. An HF specialty team reviews HF management, assesses suitability for advanced HF therapies and uses palliative care including palliative inotropes where consistent with the patient's goals of care.
      • 9.
        Primary prevention is important for those at risk for HF (stage A) or pre-HF (stage B). Stages of HF were revised to emphasize the new terminologies of at risk for HF for stage A and pre-HF for stage B.
      • 10.
        Recommendations are provided for selected patients with HF and iron deficiency, anemia, hypertension, sleep disorders, type 2 diabetes, atrial fibrillation, coronary artery disease, and malignancy.

      Purpose of the Executive Summary

      The purpose of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure (2022 HF guideline) is to provide an update and to consolidate the 2013 ACCF/AHA Guideline for the Management of Heart Failure
      • 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.
      for adults and the 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • et al.
      2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
      into a new document. Related ACC/AHA guidelines include recommendations relevant to HF and, in such cases, the HF guideline refers to these documents. For example, the 2019 primary prevention of cardiovascular disease guideline
      • Arnett DK
      • Blumenthal RS
      • Albert MA
      • et al.
      2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      includes recommendations that will be useful in preventing HF, and the 2021 valvular heart disease guideline
      • Otto CM
      • Nishimura RA
      • Bonow RO
      • et al.
      2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
      provides recommendations for mitral valve (MV) clipping in mitral regurgitation (MR).
      Areas of focus include:
      • Prevention of HF
      • Management strategies in stage C HF, including:
        • New treatment strategies in HF, including sodium-glucose cotransporter-2 inhibitors (SGLT2i) and angiotensin receptor-neprilysin inhibitors (ARNi);
        • Management of HF and atrial fibrillation (AF), including ablation of AF;
        • Management of HF and secondary MR, including MV transcatheter edge-to-edge repair;
        • Specific management strategies, including:
          • Cardiac amyloidosis,
          • Cardio-oncology,
          • Implantable devices;
      • Left ventricular assist device (LVAD) use in stage D HF.
      The intended primary target audience consists of clinicians who are involved in the care of patients with HF. The focus of the full clinical practice guideline
      • Heidenreich PA
      • Bozkurt B
      • Aguilar D
      • et al.
      2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
      is to provide the most up-to-date evidence to direct clinicians in making dicisions about the treatment of patients. This executive summary provides readers with the top 10 items they should know about the 2022 HF guideline
      • Heidenreich PA
      • Bozkurt B
      • Aguilar D
      • et al.
      2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
      and incorporates material from the full guideline along with each statement.

      Document Review and Approval

      The full clinical practice guideline was reviewed by: 2 official reviewers nominated by the AHA; 1 official reviewer nominated by the ACC; 2 official reviewers from the Heart Failure Society of America; 1 official Joint Committee on Clinical Practice Guidelines reviewer; and 32 individual content reviewers. Authors’ relationships with industry and other entities information is published in Appendix 1 of the full guideline.
      • Heidenreich PA
      • Bozkurt B
      • Aguilar D
      • et al.
      2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
      Reviewers’ relationships with industry and other entities are published in Appendix 2 of the full guideline.
      • Heidenreich PA
      • Bozkurt B
      • Aguilar D
      • et al.
      2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

      Class of Recommendation and Level of Evidence

      The Class of Recommendation (COR) indicates the strength of recommendation, encompassing the estimated magnitude and certainty of benefit in proportion to risk. The level of evidence (LOE) rates the quality of scientific evidence supporting the intervention on the basis of the type, quantity, and consistency of data from clinical trials and other sources (Table 1).
      ACCF/AHA Task Force on Practice Guidelines
      Methodology manual and policies from the ACCF/AHA Task Force on Practice Guidelines.
      Table 1Applying American College of Cardiology/American Heart Association Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient Care (Updated May 2019)*

      Take-home Message No. 1

      Guideline-directed medical therapy (GDMT) for HF with reduced ejection fraction (HFrEF) now includes 4 medication classes that include SGLT2i. The 4 groups are: (1) renin-angiotensin system inhibition with angiotensin receptor-neprilysin inhibitors (ARNi), angiotensin-converting enzyme inhibitors (ACEi), or angiotensin (II) receptor blockers (ARB) alone; (2) beta-blockers; (3) mineralocorticoid receptor antagonists (MRAs); and (4) the new group, SGLT2i (Fig. 1).
      Fig 1
      Fig. 1Treatment of HFrEF stages C and D. Colors correspond to COR in . Treatment recommendations for patients with HFrEF are displayed. Step 1 medications may be started simultaneously at initial (low) doses recommended for HFrEF. Alternatively, these medications may be started sequentially, with the sequence guided by clinical or other factors, without the need to achieve target dosing before initiating the next medication. Medication dosages should be increased to target as tolerated. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor-neprilysin inhibitor; COR, Class of Recommendation; CRT, cardiac resynchronization therapy; GDMT, guideline-directed medical therapy; HF, heart failure; HFimpEF, heart failure with improved ejection fraction; HFrEF, heart failure with reduced ejection fraction; hydral-nitrates, hydralazine and isosorbide dinitrate; ICD, implantable cardioverter-defibrillator; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; MCS, mechanical circulatory support; MRA, mineralocorticoid receptor antagonist; NSR, normal sinus rhythm; NYHA, New York Heart Association; and SGLT2i, sodium-glucose cotransporter 2 inhibitor. *Participation in investigational studies is appropriate for stage C, NYHA classes II and III HF.
      Recommendations for Renin-Angiotensin System Inhibition With Acei or ARB or Arni
      (Referenced studies that support the recommendations are summarized in the Online Data Supplements.)
      Tabled 1
      CORLOERecommendations
      1AIn patients with HFrEF and New York Heart Association (NYHA) class II–III symptoms, the use of ARNi is recommended to reduce morbidity and mortality.
      • McMurray JJ
      • Packer M
      • Desai AS
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      • Wachter R
      • Senni M
      • Belohlavek J
      • et al.
      Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study.
      • Velazquez EJ
      • Morrow DA
      • DeVore AD
      • et al.
      Angiotensin-neprilysin inhibition in acute decompensated heart failure.
      • Desai AS
      • Solomon SD
      • Shah AM
      • et al.
      Effect of sacubitril-valsartan vs enalapril on aortic stiffness in patients with heart failure and reduced ejection fraction: a randomized clinical trial.
      • Wang Y
      • Zhou R
      • Lu C
      • et al.
      Effects of the angiotensin-receptor neprilysin inhibitor on cardiac reverse remodeling: meta-analysis.
      1AIn patients with previous or current symptoms of chronic HFrEF, the use of ACEi is beneficial to reduce morbidity and mortality when the use of ARNi is not feasible.
      Consensus Trial Study Group
      Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).
      SOLVD Investigators
      Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.
      • Packer M
      • Poole-Wilson PA
      • Armstrong PW
      • et al.
      Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group.
      • Pfeffer MA
      • Braunwald E
      • Moyé LA
      • et al.
      Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial; The SAVE Investigators.
      Acute Infarction Ramipril Efficacy (AIRE) Study Investigators
      Effect......Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure.
      • Køber L
      • Torp-Pedersen C
      • Carlsen JE
      Trandolapril Cardiac Evaluation (TRACE) Study Group
      A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction.
      • Garg R
      • Yusuf S.
      Collaborative Group on ACE Inhibitor Trials
      Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure.
      • Woodard-Grice AV
      • Lucisano AC
      • Byrd JB
      • et al.
      Sex-dependent and race-dependent association of XPNPEP2 C-2399A polymorphism with angiotensin-converting enzyme inhibitor-associated angioedema.
      1AIn patients with previous or current symptoms of chronic HFrEF who are intolerant to ACEi because of cough or angioedema and when the use of ARNi is not feasible, the use of ARB is recommended to reduce morbidity and mortality.
      • Cohn JN
      • Tognoni G
      Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure.
      • Pfeffer MA
      • McMurray JJ
      • Velazquez EJ
      • et al.
      Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both.
      • Konstam MA
      • Neaton JD
      • Dickstein K
      • et al.
      Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.
      • Yusuf S
      • Teo KK
      • et al.
      ONTARGET Investigators
      Telmisartan, ramipril, or both in patients at high risk for vascular events.
      • Yusuf S
      • Teo K
      Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators
      Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial.
      1B-RIn patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACEi or ARB, replacement by an ARNi is recommended to further reduce morbidity and mortality.
      • McMurray JJ
      • Packer M
      • Desai AS
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      • Wachter R
      • Senni M
      • Belohlavek J
      • et al.
      Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study.
      • Velazquez EJ
      • Morrow DA
      • DeVore AD
      • et al.
      Angiotensin-neprilysin inhibition in acute decompensated heart failure.
      • Desai AS
      • Solomon SD
      • Shah AM
      • et al.
      Effect of sacubitril-valsartan vs enalapril on aortic stiffness in patients with heart failure and reduced ejection fraction: a randomized clinical trial.
      • Wang Y
      • Zhou R
      • Lu C
      • et al.
      Effects of the angiotensin-receptor neprilysin inhibitor on cardiac reverse remodeling: meta-analysis.
      Recommendation for Beta Blockers
      (Referenced studies that support the recommendation are summarized in the Online Data Supplements)
      Tabled 1
      CORLOERecommendation
      1AIn patients with HFrEF, with current or previous symptoms, use of 1 of the 3 beta-blockers proven to reduce mortality (eg, bisoprolol, carvedilol, sustained-release metoprolol succinate) is recommended to reduce mortality and hospitalizations.
      Authors
      The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.
      Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF)
      Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL.
      • Packer M
      • Fowler MB
      • Roecker EB
      • et al.
      Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study.
      Recommendation for MRAs
      (Referenced studies that support the recommendation are summarized in the Online Data Supplements.)
      Tabled 1
      CORLOERecommendation
      1AIn patients with HFrEF and NYHA class II–IV symptoms, an MRA (spironolactone or eplerenone) is recommended to reduce morbidity and mortality, if estimated glomerular filtration rate is > 30 mL/min/1.73 m2 and serum potassium is < 5.0 mEq/L. Careful monitoring of potassium, renal function, and diuretic dosing should be performed at initiation and closely monitored thereafter to minimize risk of hyperkalemia and renal insufficiency.
      • Pitt B
      • Zannad F
      • Remme WJ
      • et al.
      The effect of spironolactone on morbidity and mortality in patients with severe heart failure.
      • Pitt B
      • Remme W
      • Zannad F
      • et al.
      Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction.
      • Zannad F
      • McMurray JJ
      • Krum H
      • et al.
      Eplerenone in patients with systolic heart failure and mild symptoms.
      Recommendation for SGLT2i
      (Referenced studies that support the recommendation are summarized in the Online Data Supplements.)
      Tabled 1
      CORLOERecommendation
      1AIn patients with symptomatic chronic HFrEF, an SGLT2i is recommended to reduce hospitalization for HF and cardiovascular mortality, irrespective of the presence of type 2 diabetes.
      • McMurray JJV
      • Solomon SD
      • Inzucchi SE
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      ,
      • Packer M
      • Anker SD
      • Butler J
      • et al.
      Cardiovascular and renal outcomes with empagliflozin in heart failure.

      Take-Home Message No. 2

      Mildly reduced LVEF has new medication recommendations, including use of SGLT2i (Fig. 2). SGLT2i has a COR 2a in HF with mildly reduced EF (HFmrEF). Weaker recommendations (COR 2b) are made for ARNi, ACEi, ARB, MRA, and beta-blockers in this population.
      Fig 2
      Fig. 2Recommendations for patients with mildly reduced LVEF (41%–49%). Colors correspond to COR in . Medication recommendations for HFmrEF are displayed. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor-neprilysin inhibitor; HRmrEF, heart failure with mildly reduced ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium-glucose cotransporter 2 inhibitor.
      Recommendations for HFmrEF
      (Referenced studies that support the recommendations are summarized in the Online Data Supplements)
      Tabled 1
      CORLOERecommendations
      2aB-RIn patients with HFmrEF, SGLT2i can be beneficial in decreasing HF hospitalizations and cardiovascular mortality.
      • Anker SD
      • Butler J
      • Filippatos G
      • et al.
      Empagliflozin in heart failure with a preserved ejection fraction.
      2bB-NRIn patients with current or previous symptomatic HFmrEF (LVEF, 41%–49%), use of evidence-based beta-blockers for HFrEF, ARNi, ACEi, or ARB, and MRAs may be considered to reduce the risk of HF hospitalization and cardiovascular mortality, particularly among patients with LVEF on the lower end of this spectrum.
      • Cleland JGF
      • Bunting KV
      • Flather MD
      • et al.
      Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials.
      • Solomon SD
      • McMurray JJV
      • Anand IS
      • et al.
      Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction.
      • Halliday BP
      • Wassall R
      • Lota AS
      • et al.
      Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial.
      • Nilsson BB
      • Lunde P
      • Grogaard HK
      • et al.
      Long-term results of high-intensity exercise-based cardiac rehabilitation in revascularized patients for symptomatic coronary artery disease.
      • Solomon SD
      • Claggett B
      • Desai AS
      • et al.
      Influence of ejection fraction on outcomes and efficacy of sacubitril/valsartan (lcz696) in heart failure with reduced ejection fraction: the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial.
      • Tsuji K
      • Sakata Y
      • Nochioka K
      • et al.
      Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study.
      • Solomon SD
      • Vaduganathan M
      • et al.
      Sacubitril/valsartan across the spectrum of ejection fraction in heart failure.
      • Zheng SL
      • Chan FT
      • Nabeebaccus AA
      • et al.
      Drug treatment effects on outcomes in heart failure with preserved ejection fraction: a systematic review and meta-analysis.

      Take-Home Message No. 3

      Preserved LVEF has new medication recommendations, including use of SGLT2i (Fig. 3). New recommendations for HF with preserved EF (HFpEF) are made for SGLT2i (COR 2a), MRAs (COR 2b), and ARNi (COR 2b). Several previous recommendations have been renewed, including treatment of hypertension (COR 1), treatment of AF (COR 2a), use of ARB (COR 2b), and avoidance of routine use of nitrates or phosphodiesterase-5 inhibitors (COR 3: no benefit).
      Fig 3
      Fig. 3Recommendations for patients with preserved LVEF (≥ 50%). Colors correspond to COR in . Medication recommendations for HFpEF are displayed. ARB, angiotensin receptor blocker; ARNi, angiotensin receptor-neprilysin inhibitor; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium-glucose cotransporter-2 inhibitor. *Greater benefit in patients with LVEF closer to 50%.
      New Recommendations for HFpEF
      (Referenced studies that support the recommendations are summarized in the Online Data Supplements.)
      Tabled 1
      CORLOERecommendations
      2aB-RIn patients with HFpEF, SGLT2i can be beneficial in decreasing HF hospitalizations and cardiovascular mortality.
      • Anker SD
      • Butler J
      • Filippatos G
      • et al.
      Empagliflozin in heart failure with a preserved ejection fraction.
      2bB-RIn selected patients with HFpEF, MRA may be considered to decrease hospitalizations, particularly in patients with LVEF on the lower end of this spectrum.
      • Solomon SD
      • Claggett B
      • Desai AS
      • et al.
      Influence of ejection fraction on outcomes and efficacy of sacubitril/valsartan (lcz696) in heart failure with reduced ejection fraction: the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial.
      ,
      • Pitt B
      • Pfeffer MA
      • Assmann SF
      • et al.
      Spironolactone for heart failure with preserved ejection fraction.
      ,
      • Pfeffer MA
      • Claggett B
      • Assmann SF
      • et al.
      Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial.
      2bB-RIn selected patients with HFpEF, ARNi may be considered to decrease hospitalizations, particularly in patients with LVEF on the lower end of this spectrum.
      Renewed Recommendations for HFpEF
      (Referenced studies that support the recommendations are summarized in the Online Data Supplements.)
      Tabled 1
      CORLOERecommendations
      1C-LDPatients with HFpEF and hypertension should have medication titrated to attain blood pressure targets in accordance with published clinical practice guidelines to prevent morbidity.
      • Thomopoulos C
      • Parati G
      • Zanchetti A.
      Effects of blood-pressure-lowering treatment in hypertension: 9. Discontinuations for adverse events attributed to different classes of antihypertensive drugs: meta-analyses of randomized trials.
      • Williamson JD
      • Supiano MA
      • Applegate WB
      • et al.
      Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥ 75 years: a randomized clinical trial.
      • Wright Jr, JT
      • Williamson JD
      • et al.
      SPRINT Research Group
      A randomized trial of intensive versus standard blood-pressure control.
      2aC-EOIn patients with HFpEF, management of AF can be useful to improve symptoms.
      2bB-RIn selected patients with HFpEF, the use of ARB may be considered to decrease hospitalizations, particularly in patients with LVEF on the lower end of this spectrum.
      • Yusuf S
      • Pfeffer MA
      • Swedberg K
      • et al.
      Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial.
      ,
      • Lund LH
      • Claggett B
      • Liu J
      • et al.
      Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum.
      3: No BenefitB-RIn patients with HFpEF, routine use of nitrates or phosphodiesterase-5 inhibitors to increase activity or quality of life is ineffective.
      • Redfield MM
      • Anstrom KJ
      • Levine JA
      • et al.
      Isosorbide mononitrate in heart failure with preserved ejection fraction.
      ,
      • Redfield MM
      • Chen HH
      • Borlaug BA
      • et al.
      Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial.

      Take-Home Message No. 4

      The term improved LVEF is used to refer to those with previous HFrEF who now have LVEF > 40% (Fig. 4). These patients should continue their HFrEF treatments.
      Fig 4
      Fig. 4Classification and trajectories of HF based on LVEF. The classification for baseline and subsequent LVEF is shown. Patients with HFrEF who improve their LVEF to > 40% are considered to have HFimpEF and should continue HFrEF treatment. See Appendix 1 for suggested thresholds for laboratory findings. HF, heart failure; HFimpEF, heart failure with improved ejection fraction; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction. *There is limited evidence to guide therapy for patients who improve their LVEF from mildly reduced (41%–49%) to ≥ 50%. It is unclear whether to treat these patients as having HFpEF or HFmrEF.
      Recommendation for HF With Improved EF (HFimpEF)
      (Referenced studies that support the recommendation are summarized in the Online Data Supplements.)
      Tabled 1
      CORLOERecommendation
      1B-RIn patients with HFimpEF after treatment, GDMT should be continued to prevent relapse of HF and left ventricular dysfunction, even in patients who may become asymptomatic.
      • Halliday BP
      • Wassall R
      • Lota AS
      • et al.
      Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial.

      Take-Home Message No. 5

      Value statements have been created for many treatments. In accordance with ACC/AHA methodology,
      • Anderson JL
      • Heidenreich PA
      • Barnett PG
      • et al.
      ACC/AHA statement on cost/value methodology in clinical practice guidelines and performance measures: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures and Task Force on Practice Guidelines.
      value statements were created for select recommendations where high-quality, cost-effectiveness studies of the intervention have been published. High value is defined as < $60,000/quality-adjusted life year gained (< 1 U.S. GDP/capita/QALY). Low value is defined as > $180,000/quality-adjusted life year gained (> 3 U.S. GDP/capita/QALY). High-value therapies include ARNi, ACEi, ARB, beta-blocker, MRA, implantable cardioverter-defibrillator, and cardiac resynchronization therapy. Intermediate-value therapies include SGLT2i and cardiac transplantation. The only therapy identified as low value was tafamidis for cardiac amyloidosis. The value of mechanical circulatory support and pulmonary pressure monitoring was considered uncertain.
      Tabled 1
      Value Statements
      LevelStatements
      HighIn patients with previous or current symptoms of chronic HFrEF in whom ARNi is not feasible, treatment with an ACEi or ARB provides high economic value.
      • Banka G
      • Heidenreich PA
      • Fonarow GC.
      Incremental cost-effectiveness of guideline-directed medical therapies for heart failure.
      • Dasbach EJ
      • Rich MW
      • Segal R
      • et al.
      The cost-effectiveness of losartan versus captopril in patients with symptomatic heart failure.
      • Glick H
      • Cook J
      • Kinosian B
      • et al.
      Costs and effects of enalapril therapy in patients with symptomatic heart failure: an economic analysis of the Studies of Left Ventricular Dysfunction (SOLVD) Treatment Trial.
      • Paul SD
      • Kuntz KM
      • Eagle KA
      • et al.
      Costs and effectiveness of angiotensin converting enzyme inhibition in patients with congestive heart failure.
      • Reed SD
      • Friedman JY
      • Velazquez EJ
      • et al.
      Multinational economic evaluation of valsartan in patients with chronic heart failure: results from the Valsartan Heart Failure Trial (Val-HeFT).
      • Shekelle P
      • Morton S
      • Atkinson S
      • et al.
      Pharmacologic management of heart failure and left ventricular systolic dysfunction: effect in female, Black, and diabetic patients, and cost-effectiveness.
      • Tsevat J
      • Duke D
      • Goldman L
      • et al.
      Cost-effectiveness of captopril therapy after myocardial infarction.
      HighIn patients with chronic symptomatic HFrEF, treatment with an ARNi instead of an ACEi provides high economic value.
      • Gaziano TA
      • Fonarow GC
      • Claggett B
      • et al.
      Cost-effectiveness analysis of sacubitril/valsartan vs enalapril in patients with heart failure and reduced ejection fraction.
      • Gaziano TA
      • Fonarow GC
      • Velazquez EJ
      • et al.
      Cost-effectiveness of sacubitril-valsartan in hospitalized patients who have heart failure with reduced ejection fraction.
      • King JB
      • Shah RU
      • Bress AP
      • et al.
      Cost-effectiveness of sacubitril-valsartan combination therapy compared with enalapril for the treatment of heart failure with reduced ejection fraction.
      • Sandhu AT
      • Goldhaber-Fiebert JD
      • Owens DK
      • et al.
      Cost-effectiveness of implantable pulmonary artery pressure monitoring in chronic heart failure.
      HighIn patients with HFrEF with current or previous symptoms, beta-blocker therapy provides high economic value.
      • Banka G
      • Heidenreich PA
      • Fonarow GC.
      Incremental cost-effectiveness of guideline-directed medical therapies for heart failure.
      ,
      • Caro JJ
      • Migliaccio-Walle K
      • O'Brien JA
      • et al.
      Economic implications of extended-release metoprolol succinate for heart failure in the MERIT-HF trial: a US perspective of the MERIT-HF trial.
      • Delea TE
      • Vera-Llonch M
      • Richner RE
      • et al.
      Cost effectiveness of carvedilol for heart failure.
      • Gregory D
      • Udelson JE
      • Konstam MA.
      Economic impact of beta blockade in heart failure.
      • Vera-Llonch M
      • Menzin J
      • Richner RE
      • et al.
      Cost-effectiveness results from the US Carvedilol Heart Failure Trials Program.
      HighIn patients with HFrEF and NYHA class II–IV symptoms, MRA therapy provides high economic value.
      • Banka G
      • Heidenreich PA
      • Fonarow GC.
      Incremental cost-effectiveness of guideline-directed medical therapies for heart failure.
      ,
      • Glick HA
      • Orzol SM
      • Tooley JF
      • et al.
      Economic evaluation of the randomized aldactone evaluation study (RALES): treatment of patients with severe heart failure.
      • Weintraub WS
      • Zhang Z
      • Mahoney EM
      • et al.
      Cost-effectiveness of eplerenone compared with placebo in patients with myocardial infarction complicated by left ventricular dysfunction and heart failure.
      • Zhang Z
      • Mahoney EM
      • Kolm P
      • et al.
      Cost effectiveness of eplerenone in patients with heart failure after acute myocardial infarction who were taking both ACE inhibitors and beta-blockers: subanalysis of the EPHESUS.
      HighFor patients self-identified as African American with NYHA class III–IV HFrEF who are receiving optimal medical therapy with ACEi or ARB, beta-blocker and MRA, the combination of hydralazine and isosorbide dinitrate provides high economic value.
      • Angus DC
      • Linde-Zwirble WT
      • Tam SW
      • et al.
      Cost-effectiveness of fixed-dose combination of isosorbide dinitrate and hydralazine therapy for blacks with heart failure.
      HighA transvenous implantable cardioverter-defibrillator provides high economic value in the primary prevention of sudden cardiac death, particularly when the patient's risk of death caused by ventricular arrythmia is deemed high and the risk of nonarrhythmic death (either cardiac or noncardiac) is deemed low, based on the patient's burden of comorbidities and functional status.
      • Al-Khatib SM
      • Anstrom KJ
      • Eisenstein EL
      • et al.
      Clinical and economic implications of the Multicenter Automatic Defibrillator Implantation Trial-II.
      • Cowie MR
      • Marshall D
      • Drummond M
      • et al.
      Lifetime cost-effectiveness of prophylactic implantation of a cardioverter defibrillator in patients with reduced left ventricular systolic function: results of Markov modelling in a European population.
      • Mark DB
      • Nelson CL
      • Anstrom KJ
      • et al.
      Cost-effectiveness of defibrillator therapy or amiodarone in chronic stable heart failure: results from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT).
      • Mushlin AI
      • Hall WJ
      • Zwanziger J
      • et al.
      The cost-effectiveness of automatic implantable cardiac defibrillators: results from MADIT. Multicenter Automatic Defibrillator Implantation Trial.
      • Sanders GD
      • Hlatky MA
      • Owens DK.
      Cost-effectiveness of implantable cardioverter-defibrillators.
      • Zwanziger J
      • Hall WJ
      • Dick AW
      • et al.
      The cost-effectiveness of implantable cardioverter-defibrillators: results from the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II.
      HighFor patients who have LVEF ≤ 35%, sinus rhythm, left bundle branch block with a QRS duration of ≥ 150 ms, and NYHA class II, III or ambulatory IV symptoms on GDMT, cardiac resynchronization therapy implantation provides high economic value.
      • Feldman AM
      • de Lissovoy G
      • Bristow MR
      • et al.
      Cost-effectiveness of cardiac resynchronization therapy in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial.
      • Gold MR
      • Padhiar A
      • Mealing S
      • et al.
      Economic value and cost-effectiveness of cardiac resynchronization therapy among patients with mild heart failure: projections from the REVERSE long-term follow-up.
      • Heerey A
      • Lauer M
      • Alsolaiman F
      • et al.
      Cost-effectiveness of biventricular pacemakers in heart failure patients.
      • Nichol G
      • Kaul P
      • Huszti E
      • et al.
      Cost-effectiveness of cardiac resynchronization therapy in patients with symptomatic heart failure.
      • Noyes K
      • Veazie P
      • Hall WJ
      • et al.
      Cost-effectiveness of cardiac resynchronization therapy in the MADIT-CRT trial.
      • Woo CY
      • Strandberg EJ
      • Schmiegelow MD
      • et al.
      Cost-effectiveness of adding cardiac resynchronization therapy to an implantable cardioverter-defibrillator among patients with mild heart failure.
      IntermediateIn patients with symptomatic chronic HFrEF, SGLT2i therapy provides intermediate economic value.
      • Parizo JT
      • Goldhaber-Fiebert JD
      • Salomon JA
      • et al.
      Cost-effectiveness of dapagliflozin for treatment of patients with heart failure with reduced ejection fraction.
      ,
      • Isaza N
      • Calvachi P
      • Raber I
      • et al.
      Cost-effectiveness of dapagliflozin for the treatment of heart failure with reduced ejection fraction.
      IntermediateIn patients with stage D (advanced) HF despite GDMT, cardiac transplantation provides intermediate economic value.
      • Long EF
      • Swain GW
      • Mangi AA.
      Comparative survival and cost-effectiveness of advanced therapies for end-stage heart failure.
      LowAt 2020 list prices, tafamidis provides low economic value (> $180,000 per QALY gained) in patients with HF with wild-type or variant transthyretin cardiac amyloidosis.
      • Kazi DS
      • Bellows BK
      • Baron SJ
      • et al.
      Cost-effectiveness of tafamidis therapy for transthyretin amyloid cardiomyopathy.
      UncertainIn patients with advanced HFrEF who have NYHA class IV symptoms despite GDMT, durable mechanical circulatory support devices provide low to intermediate economic value based on current costs and outcomes.
      • Long EF
      • Swain GW
      • Mangi AA.
      Comparative survival and cost-effectiveness of advanced therapies for end-stage heart failure.
      ,
      • Baras Shreibati J
      • Goldhaber-Fiebert JD
      • Banerjee D
      • et al.
      Cost-effectiveness of left ventricular assist devices in ambulatory patients with advanced heart failure.
      • Mahr C
      • McGee Jr., E
      • Cheung A
      • et al.
      Cost-effectiveness of thoracotomy approach for the implantation of a centrifugal left ventricular assist device.
      • Rogers JG
      • Bostic RR
      • Tong KB
      • et al.
      Cost-effectiveness analysis of continuous-flow left ventricular assist devices as destination therapy.
      • Silvestry SC
      • Mahr C
      • Slaughter MS
      • et al.
      Cost-effectiveness of a small intrapericardial centrifugal left ventricular assist device.
      UncertainIn patients with NYHA class III HF with an HF hospitalization within the previous year, wireless monitoring of the pulmonary artery pressure by an implanted hemodynamic monitor provides uncertain value.
      • Sandhu AT
      • Goldhaber-Fiebert JD
      • Owens DK
      • et al.
      Cost-effectiveness of implantable pulmonary artery pressure monitoring in chronic heart failure.
      ,
      • Martinson M
      • Bharmi R
      • Dalal N
      • et al.
      Pulmonary artery pressure-guided heart failure management: US cost-effectiveness analyses using the results of the CHAMPION clinical trial.
      • Schmier JK
      • Ong KL
      • Fonarow GC.
      Cost-effectiveness of remote cardiac monitoring with the cardiomems heart failure system.
      • Lindenfeld J
      • Zile MR
      • Desai AS
      • et al.
      Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial.

      Take-Home Message No. 6

      Amyloid heart disease has new recommendations for treatment. Specific strategies for diagnosis and treatment of cardiac amyloidosis are recommended (Fig. 5). In patients with clinical suspicion for cardiac amyloidosis, screening for serum and urine monoclonal light chains with serum and urine immunofixation electrophoresis and serum-free light chains is recommended. If there is no evidence of serum or urine monoclonal light chains, bone scintigraphy is recommended to confirm the presence of transthyretin cardiac amyloidosis. If transthyretin cardiac amyloidosis is identified, genetic sequencing of the TTR gene is recommended to differentiate hereditary variant from wild-type transthyretin cardiac amyloidosis because confirmation of a hereditary variant would trigger genetic counseling and potential screening of family members. Transthyretin tetramer stabilizer therapy (tafamidis) is recommended in selected patients with wild-type or variant transthyretin cardiac amyloidosis. Anticoagulation is a reasonable treatment strategy to reduce the risk of stroke in patients with cardiac amyloidosis and AF.
      Fig 5
      Fig. 5Diagnostic and treatment of transthyretin cardiac amyloidosis algorithm. Colors correspond to COR in . AF, atrial fibrillation; AL-CM, amyloid cardiomyopathy; ATTR-CM, transthyretin amyloid cardiomyopathy; ATTRv, variant transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; CHA2DS2-VASc, congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke or transient ischemic attack (TIA), vascular disease, age 65 to 74 years, sex category; ECG, electrocardiogram; H/CL, heart to contralateral chest; HFrEF, heart failure with reduced ejection fraction; IFE, immunofixation electrophoresis; MRI, magnetic resonance imaging; NYHA, New York Heart Association; PYP, pyrophosphate; Tc, technetium; and TTR, transthyretin.
      Recommendations for Diagnosis of Cardiac Amyloidosis
      (Referenced studies that support the recommendations are summarized in the Online Data Supplements.)
      Tabled 1
      CORLOERecommendations
      1B-NRPatients in whom there is a clinical suspicion of cardiac amyloidosis*
      • Castano A
      • Narotsky DL
      • Hamid N
      • et al.
      Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement.
      • Gonzalez-Lopez E
      • Gallego-Delgado M
      • Guzzo-Merello G
      • et al.
      Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction.
      • Sperry BW
      • Reyes BA
      • Ikram A
      • et al.
      Tenosynovial and cardiac amyloidosis in patients undergoing carpal tunnel release.
      • Westermark P
      • Westermark GT
      • Suhr OB
      • et al.
      Transthyretin-derived amyloidosis: probably a common cause of lumbar spinal stenosis.
      • Maurer MS
      • Hanna M
      • Grogan M
      • et al.
      Genotype and phenotype of transthyretin cardiac amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey).
      should have screening for serum and urine monoclonal light chains with serum and urine immunofixation electrophoresis and serum-free light chains.
      • Muchtar E
      • Gertz MA
      • Kyle RA
      • et al.
      A modern primer on light chain amyloidosis in 592 patients with mass spectrometry-verified typing.
      1B-NRIn patients with high clinical suspicion for cardiac amyloidosis, without evidence of serum or urine monoclonal light chains, bone scintigraphy should be performed to confirm the presence of transthyretin cardiac amyloidosis.
      • Gillmore JD
      • Maurer MS
      • Falk RH
      • et al.
      Nonbiopsy diagnosis of cardiac transthyretin amyloidosis.
      1B-NRIn patients in whom a diagnosis of transthyretin cardiac amyloidosis is made, genetic testing with TTR gene sequencing is recommended to differentiate hereditary variant from wild-type transthyretin cardiac amyloidosis.
      • Brown EE
      • Lee YZJ
      • Halushka MK
      • et al.
      Genetic testing improves identification of transthyretin amyloid (ATTR) subtype in cardiac amyloidosis.
      *Left ventricular wall thickness ≥ 14 mm in conjunction with fatigue, dyspnea or edema, especially in the context of discordance between wall thickness on echocardiogram and QRS voltage on ECG, and in the context of aortic stenosis, HFpEF, carpal tunnel syndrome, spinal stenosis, and autonomic or sensory polyneuropathy.
      Recommendations for Treatment of Cardiac Amyloidosis
      (Referenced studies that support the recommendations are summarized in the Online Data Supplements.)
      Tabled 1
      CORLOERecommendations
      1B-RIn selected patients with wild-type or variant transthyretin cardiac amyloidosis and NYHA class I–III HF symptoms, transthyretin tetramer stabilizer therapy (tafamidis) is indicated to reduce cardiovascular morbidity and mortality.
      • Maurer MS
      • Schwartz JH
      • Gundapaneni B
      • et al.
      Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy.
      2aC-LDIn patients with cardiac amyloidosis and AF, anticoagulation is reasonable to reduce the risk of stroke, regardless of the CHA2DS2-VASc (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke or transient ischemic attack [TIA], vascular disease, age 65–74 years, sex category) score.
      • El-Am EA
      • Dispenzieri A
      • Melduni RM
      • et al.
      Direct current cardioversion of atrial arrhythmias in adults with cardiac amyloidosis.
      ,
      • Feng D
      • Syed IS
      • Martinez M
      • et al.
      Intracardiac thrombosis and anticoagulation therapy in cardiac amyloidosis.

      Take-Home Message No. 7

      Evidence supporting increased filling pressures is important for the diagnosis of HF if the LVEF is > 40% (Table 2). The signs and symptoms of HF are nonspecific and, thus, a diagnosis of HF requires supporting evidence. Increased cardiac filling pressure is a feature of HF, and this is assumed for patients with LVEF ≤ 40%. However, if the LVEF is 41%–49% (mildly reduced) or ≥ 50% (preserved), evidence of spontaneous or provokable increased LV filling pressures is needed to confirm a diagnosis of HF. Evidence of increased filling pressures can be obtained from noninvasive testing (eg, natriuretic peptide, diastolic function on imaging) or invasive testing (eg, hemodynamic measurement).
      Table 2Classification of HF by LVEF
      Type of HF According to LVEFCriteria
      HFrEF (HF with reduced EF)LVEF ≤ 40%
      HFimpEF (HF with improved EF)Previous LVEF ≤ 40% and a follow-up measurement of LVEF > 40%
      HFmrEF (HF with mildly reduced EF)LVEF 41%–49%

      Evidence of spontaneous or provokable increased LV filling pressures (eg, elevated natriuretic peptide, noninvasive and invasive hemodynamic measurement)
      HFpEF (HF with preserved EF)LVEF ≥ 50%

      Evidence of spontaneous or provokable increased LV filling pressures (eg, elevated natriuretic peptide, noninvasive and invasive hemodynamic measurement)
      Please see Appendix 1 for suggested thresholds for structural heart disease and evidence of increased filling pressures.
      HF, heart failure; LV, left ventricular; LVEF, left ventricular ejection fraction.

      Take-Home Message No. 8

      Patients with advanced HF who wish to prolong survival should be referred to a team specializing in HF. An HF specialty team, typically located in an advanced HF center, reviews HF management, assesses suitability for advanced HF therapies (eg, left ventricular assist devices, cardiac transplantation) and uses palliative care, including palliative inotropes where they are consistent with the patient's goals of care.
      Recommendation for Specialty Referral for Advanced HF
      Tabled 1
      CORLOERecommendation
      1C-LDIn patients with advanced HF, when consistent with the patient's goals of care, timely referral for HF specialty care is recommended to review HF management and assess suitability for advanced HF therapies (eg, left ventricular assist device, cardiac transplantation, palliative care, and palliative inotropes).
      • Crespo-Leiro MG
      • Metra M
      • Lund LH
      • et al.
      Advanced heart failure: a position statement of the Heart Failure Association of the European Society of Cardiology.
      • Fang JC
      • Ewald GA
      • Allen LA
      • et al.
      Advanced (stage D) heart failure: a statement from the Heart Failure Society of America Guidelines Committee.
      • Greenberg B
      • Fang J
      • Mehra M
      • et al.
      Advanced heart failure: trans-atlantic perspectives on the Heart Failure Association of the European Society of Cardiology position statement.
      • Hunt SA
      • Abraham WT
      • Chin MH
      • et al.
      2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines; developed in collaboration with the International Society for Heart and Lung Transplantation.
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • et al.
      2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
      • Thomas R
      • Huntley A
      • Mann M
      • et al.
      Specialist clinics for reducing emergency admissions in patients with heart failure: a systematic review and meta-analysis of randomised controlled trials.

      Take-Home Message No. 9

      Primary prevention is important for those at risk for HF (stage A) or pre-HF (stage B). Stages of HF were revised to emphasize the new terminologies of at-risk for HF for stage A and pre-HF for stage B (Fig. 6) (Table 3). In the full guideline, primary prevention included all health care strategies that prevent the development of symptomatic HF (stage C). Healthy lifestyle habits, such as maintaining regular physical activity, maintaining normal weight, and consuming a healthful diet, are recommended. Blood pressure should be controlled in accordance with published clinical practice guidelines. SGLT2i are recommended in patients with type 2 diabetes and either established cardiovascular disease or at high risk for cardiovascular disease. Natriuretic peptide biomarker–based screening followed by team-based care, including a cardiovascular specialist, can be useful to prevent the development of left ventricular dysfunction (systolic or diastolic) or new-onset HF (pre-HF, stage B). Validated multivariable risk scores can also be useful to estimate subsequent risk of incident HF. In asymptomatic patients with LVEF ≤ 40% (pre-HF, stage B), ACEi, ARB, evidence-based beta-blockers, statins, and implantable cardioverter-defibrillators are recommended in certain patients.
      Fig 6
      Fig. 6ACC/AHA Stages of HF. The ACC/AHA stages of HF are shown. ACC indicates American College of Cardiology; AHA, American Heart Association; CVD, cardiovascular disease; GDMT, guideline-directed medical therapy; and HF, heart failure.
      Table 3Stages of HF
      StagesDefinition and Criteria
      Stage A: At risk for HFAt risk for HF but without symptoms, structural heart disease, or cardiac biomarkers of stretch or injury (eg, patients with hypertension, atherosclerotic CVD, diabetes, metabolic syndrome and obesity, exposure to cardiotoxic agents, genetic variant for cardiomyopathy, or positive family history of cardiomyopathy).
      Stage B: Pre-HFNo symptoms or signs of HF and evidence of 1 of the following:
      Structural heart disease
      For thresholds of cardiac structural, functional changes, elevated filling pressures, and biomarker elevations, refer to Appendix 1. CKD, chronic kidney disease; CVD, cardiovascular disease; GDMT, guideline-directed medical therapy; HF, heart failure.


      Reduced left or right ventricular systolic function

      Reduced ejection fraction, reduced strain

      Ventricular hypertrophy

      Chamber enlargement

      Wall motion abnormalities

      Valvular heart disease
      Evidence of increased filling pressures
      For thresholds of cardiac structural, functional changes, elevated filling pressures, and biomarker elevations, refer to Appendix 1. CKD, chronic kidney disease; CVD, cardiovascular disease; GDMT, guideline-directed medical therapy; HF, heart failure.


      By invasive hemodynamic measurements

      By noninvasive imaging suggesting elevated filling pressures (eg, Doppler echocardiography)
      Patients with risk factors and

      Increased levels of B-type natriuretic peptides
      For thresholds of cardiac structural, functional changes, elevated filling pressures, and biomarker elevations, refer to Appendix 1. CKD, chronic kidney disease; CVD, cardiovascular disease; GDMT, guideline-directed medical therapy; HF, heart failure.
      or

      Persistently elevated cardiac troponin

      in the absence of competing diagnoses, resulting in such biomarker elevations such as acute coronary syndrome, CKD, pulmonary embolus, or myopericarditis
      Stage C: Symptomatic HFStructural heart disease with current or previous symptoms of HF.
      Stage D: Advanced HFMarked HF symptoms that interfere with daily life and with recurrent hospitalizations despite attempts to optimize GDMT.
      low asterisk For thresholds of cardiac structural, functional changes, elevated filling pressures, and biomarker elevations, refer to Appendix 1. CKD, chronic kidney disease; CVD, cardiovascular disease; GDMT, guideline-directed medical therapy; HF, heart failure.
      Recommendations for Patients at Risk for HF (Stage A: Primary Prevention)
      (Referenced studies that support the recommendations are summarized in the Online Data Supplements.)
      Tabled 1
      CORLOERecommendations
      1AIn patients with hypertension, blood pressure should be controlled in accordance with GDMT for hypertension to prevent symptomatic HF.
      • Wright Jr, JT
      • Williamson JD
      • et al.
      SPRINT Research Group
      A randomized trial of intensive versus standard blood-pressure control.
      ,
      • Beckett NS
      • Peters R
      • Fletcher AE
      • et al.
      Treatment of hypertension in patients 80 years of age or older.
      • Ettehad D
      • Emdin CA
      • Kiran A
      • et al.
      Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis.
      • Kostis JB
      • Davis BR
      • Cutler J
      • et al.
      Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. SHEP Cooperative Research Group.
      • Staessen JA
      • Fagard R
      • Thijs L
      • et al.
      the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension.
      • Thomopoulos C
      • Parati G
      • Zanchetti A.
      Effects of blood pressure-lowering treatment. 6. Prevention of heart failure and new-onset heart failure: meta-analyses of randomized trials.
      • Upadhya B
      • Rocco M
      • Lewis CE
      • et al.
      Effect of intensive blood pressure treatment on heart failure events in the Systolic Blood Pressure Reduction Intervention Trial.
      • Levy D
      • Larson MG
      • Vasan RS
      • et al.
      The progression from hypertension to congestive heart failure.
      • Butler J
      • Kalogeropoulos AP
      • Georgiopoulou VV
      • et al.
      Systolic blood pressure and incident heart failure in the elderly: the Cardiovascular Health Study and the Health, Ageing and Body Composition Study.
      1AIn patients with type 2 diabetes and either established cardiovascular disease or at high cardiovascular risk, SGLT2i should be used to prevent hospitalizations for HF.
      • Neal B
      • Perkovic V
      • Mahaffey KW
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      • Wiviott SD
      • Raz I
      • Bonaca MP
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      • Zinman B
      • Wanner C
      • Lachin JM
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      1B-NRIn the general population, healthful lifestyle habits, such as regular physical activity, maintaining normal weight, healthful dietary patterns, and avoiding smoking, are helpful to reduce future risk of HF.
      • Del Gobbo LC
      • Kalantarian S
      • Imamura F
      • et al.
      Contribution of major lifestyle risk factors for incident heart failure in older adults: the Cardiovascular Health Study.
      • Wang Y
      • Tuomilehto J
      • Jousilahti P
      • et al.
      Lifestyle factors in relation to heart failure among Finnish men and women.
      • Young DR
      • Reynolds K
      • Sidell M
      • et al.
      Effects of physical activity and sedentary time on the risk of heart failure.
      • Hu G
      • Jousilahti P
      • Antikainen R
      • et al.
      Joint effects of physical activity, body mass index, waist circumference, and waist-to-hip ratio on the risk of heart failure.
      • Folsom AR
      • Shah AM
      • Lutsey PL
      • et al.
      American Heart Association's Life's Simple 7: avoiding heart failure and preserving cardiac structure and function.
      • Tektonidis TG
      • Åkesson A
      • Gigante B
      • et al.
      Adherence to a Mediterranean diet is associated with reduced risk of heart failure in men.
      • Levitan EB
      • Wolk A
      • Mittleman MA.
      Consistency with the DASH diet and incidence of heart failure.
      • Levitan EB
      • Wolk A
      • Mittleman MA.
      Relation of consistency with the dietary approaches to stop hypertension diet and incidence of heart failure in men aged 45 to 79 years.
      • Lara KM
      • Levitan EB
      • Gutierrez OM
      • et al.
      Dietary patterns and incident heart failure in U.S. adults without known coronary disease.
      2aB-RFor patients at risk of developing HF, natriuretic peptide biomarker–based screening followed by team-based care, including a cardiovascular specialist optimizing GDMT, can be useful to prevent the development of LV dysfunction (systolic or diastolic) or new-onset HF.
      • Ledwidge M
      • Gallagher J
      • Conlon C
      • et al.
      Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial.
      ,
      • Huelsmann M
      • Neuhold S
      • Resl M
      • et al.
      PONTIAC (NT-proBNP selected prevention of cardiac events in a population of diabetic patients without a history of cardiac disease): a prospective randomized controlled trial.
      2aB-NRIn the general population, validated multivariable risk scores can be useful to estimate subsequent risk of incident HF.
      • Kannel WB
      • D'Agostino RB
      • Silbershatz H
      • et al.
      Profile for estimating risk of heart failure.
      • Butler J
      • Kalogeropoulos A
      • Georgiopoulou V
      • et al.
      Incident heart failure prediction in the elderly: the health ABC heart failure score.
      • Agarwal SK
      • Chambless LE
      • Ballantyne CM
      • et al.
      Prediction of incident heart failure in general practice: the Atherosclerosis Risk in Communities (ARIC) Study.
      Recommendations for Management of Stage B: Preventing the Syndrome of Clinical HF in Patients With Pre-HF
      (Referenced studies that support the recommendations are summarized in the Online Data Supplements.)
      Tabled 1
      CORLOERecommendations
      1AIn patients with LVEF ≤ 40%, ACEi should be used to prevent symptomatic HF and reduce mortality.
      • Pfeffer MA
      • Braunwald E
      • Moyé LA
      • et al.
      Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial; The SAVE Investigators.
      ,
      • Køber L
      • Torp-Pedersen C
      • Carlsen JE
      Trandolapril Cardiac Evaluation (TRACE) Study Group
      A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction.
      ,
      • Yusuf S
      • Pitt B
      • et al.
      SOLVD Investigators
      Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions.
      ,
      • Jong P
      • Yusuf S
      • Rousseau MF
      • et al.
      Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study.
      1AIn patients with recent or remote histories of myocardial infarction or acute coronary syndrome, statins should be used to prevent symptomatic HF and adverse cardiovascular events.
      • Afilalo J
      • Majdan AA
      • Eisenberg MJ.
      Intensive statin therapy in acute coronary syndromes and stable coronary heart disease: a comparative meta-analysis of randomised controlled trials.
      • Emberson JR
      • Ng LL
      Heart Protection Study Collaborative Group
      N-terminal pro-B-type natriuretic peptide, vascular disease risk, and cholesterol reduction among 20,536 patients in the MRC/BHF heart protection study.
      • Preiss D
      • Campbell RT
      • Murray HM
      • et al.
      The effect of statin therapy on heart failure events: a collaborative meta-analysis of unpublished data from major randomized trials.
      • Scirica BM
      • Morrow DA
      • Cannon CP
      • et al.
      Intensive statin therapy and the risk of hospitalization for heart failure after an acute coronary syndrome in the PROVE IT-TIMI 22 study.
      • Strandberg TE
      • Holme I
      • Faergeman O
      • et al.
      Comparative effect of atorvastatin (80 mg) versus simvastatin (20 to 40 mg) in preventing hospitalizations for heart failure in patients with previous myocardial infarction.
      1B-RIn patients with recent myocardial infarction and LVEF ≤ 40% who are intolerant to ACEi, ARB should be used to prevent symptomatic HF and reduce mortality.
      • Velazquez EJ
      • Pfeffer MA
      • McMurray JV
      • et al.
      VALsartan In Acute myocardial iNfarcTion (VALIANT) trial: baseline characteristics in context.
      1B-RIn patients with recent or remote histories of myocardial infarction or acute coronary syndrome and LVEF ≤ 40%, evidence-based beta-blockers should be used to reduce mortality.
      • Dargie HJ.
      Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial.
      • Exner DV
      • Dries DL
      • Waclawiw MA
      • et al.
      Beta-adrenergic blocking agent use and mortality in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a post hoc analysis of the studies of left ventricular dysfunction.
      • Vantrimpont P
      • Rouleau JL
      • Wun CC
      • et al.
      Additive beneficial effects of beta-blockers to angiotensin-converting enzyme inhibitors in the Survival and Ventricular Enlargement (SAVE) Study. SAVE Investigators.
      1B-RIn patients who are at least 40 days post-myocardial infarction with LVEF ≤ 30% and NYHA class I symptoms while receiving GDMT and have reasonable expectation of meaningful survival for > 1 year, an implantable cardioverter-defibrillator is recommended for primary prevention of sudden cardiac death to reduce total mortality.
      • Moss AJ
      • Zareba W
      • Hall WJ
      • et al.
      Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction.
      1C-LDIn patients with LVEF ≤ 40%, beta-blockers should be used to prevent symptomatic HF.
      • Exner DV
      • Dries DL
      • Waclawiw MA
      • et al.
      Beta-adrenergic blocking agent use and mortality in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a post hoc analysis of the studies of left ventricular dysfunction.
      ,
      • Vantrimpont P
      • Rouleau JL
      • Wun CC
      • et al.
      Additive beneficial effects of beta-blockers to angiotensin-converting enzyme inhibitors in the Survival and Ventricular Enlargement (SAVE) Study. SAVE Investigators.
      3 HarmB-RIn patients with LVEF < 50%, thiazolidinediones should not be used because they increase the risk of HF, including hospitalization.
      • Dargie HJ
      • Hildebrandt PR
      • Riegger GA
      • et al.
      A randomized, placebo-controlled trial assessing the effects of rosiglitazone on echocardiographic function and cardiac status in type 2 diabetic patients with New York Heart Association functional class I or II heart failure.
      3 HarmC-LDIn patients with LVEF < 50%, nondihydropyridine calcium channel blockers with negative inotropic effects may be harmful.
      Multicenter Diltiazem Postinfarction Trial Research Group
      The effect of diltiazem on mortality and reinfarction after myocardial infarction.
      ,
      • Goldstein RE
      • Boccuzzi SJ
      • Cruess D
      • et al.
      Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction.

      Take-Home Message No. 10

      Specific-treatment recommendations are provided for patients with HF and certain comorbidities (Fig. 7). Recommendations are provided for selected patients with HF and iron deficiency, anemia, hypertension, sleep disorders, type 2 diabetes, AF, coronary artery disease, and malignancy.
      Fig 7
      Fig. 7Recommendations for Treatment of Patients With HF and Selected Comorbidities. Colors correspond to COR in . Recommendations for treatment of patients with HF and select comorbidities are displayed. *Patients with chronic HF with permanent-persistent-paroxysmal AF and a CHA2DS2-VASc score of ≥ 2 (for men) and ≥ 3 (for women). ACEi, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; AV, atrioventricular; CHA2DS2-VASc, congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack (TIA), vascular disease, age 65–74 years, sex category; CPAP, continuous positive airway pressure; CRT, cardiac resynchronization therapy; EF, ejection fraction; GDMT, guideline-directed medical therapy; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; IV, intravenous; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; SGLT2i, sodium-glucose cotransporter 2 inhibitor; and VHD, valvular heart disease.
      Recommendations for the Management of Comorbidities in Patients With HF
      (Referenced studies that support the recommendations are summarized in the Online Data Supplements.)
      Tabled 1
      CORLOERecommendations
      Management of Anemia or Iron Deficiency
      2aB-RIn patients with HFrEF and iron deficiency with or without anemia, intravenous iron replacement is reasonable to improve functional status and quality of life.
      • Anker SD
      • Comin Colet J
      • Filippatos G
      • et al.
      Ferric carboxymaltose in patients with heart failure and iron deficiency.
      • Ponikowski P
      • van Veldhuisen DJ
      • Comin-Colet J
      • et al.
      Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiencydagger.
      • Beck-da-Silva L
      • Piardi D
      • Soder S
      • et al.
      IRON-HF study: a randomized trial to assess the effects of iron in heart failure patients with anemia.
      • Ponikowski P
      • Kirwan BA
      • Anker SD
      • et al.
      Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial.
      3: HarmB-RIn patients with HF and anemia, erythropoietin-stimulating agents should not be used to improve morbidity and mortality.
      • Swedberg K
      • Young JB
      • Anand IS
      • et al.
      Treatment of anemia with darbepoetin alfa in systolic heart failure.
      ,
      • Kang J
      • Park J
      • Lee JM
      • et al.
      The effects of erythropoiesis stimulating therapy for anemia in chronic heart failure: a meta-analysis of randomized clinical trials.
      Management of Hypertension
      1C-LDIn patients with HFrEF and hypertension, uptitration of GDMT to the maximally tolerated target dosage is recommended.
      • Banach M
      • Bhatia V
      • Feller MA
      • et al.
      Relation of baseline systolic blood pressure and long-term outcomes in ambulatory patients with chronic mild to moderate heart failure.
      • Lee TT
      • Chen J
      • Cohen DJ
      • et al.
      The association between blood pressure and mortality in patients with heart failure.
      • Whelton PK
      • Carey RM
      • Aronow WS
      • et al.
      2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      Management of Sleep Disorders
      2aB-RIn patients with HF and obstructive sleep apnea, continuous positive airway pressure may be reasonable to improve sleep quality and decrease daytime sleepiness.
      • Arzt M
      • Schroll S
      • Series F
      • et al.
      Auto-servoventilation in heart failure with sleep apnoea: a randomised controlled trial.
      • O'Connor CM
      • Whellan DJ
      • Fiuzat M
      • et al.
      Cardiovascular outcomes with minute ventilation-targeted adaptive servo-ventilation therapy in heart failure: the CAT-HF trial.
      • Cowie MR
      • Woehrle H
      • Wegscheider K
      • et al.
      Adaptive servo-ventilation for central sleep apnea in systolic heart failure.
      • Yamamoto S
      • Yamaga T
      • Nishie K
      • et al.
      Positive airway pressure therapy for the treatment of central sleep apnoea associated with heart failure.
      2aC-LDIn patients with HF and suspicion of sleep-disordered breathing, a formal sleep assessment is reasonable to confirm the diagnosis and differentiate between obstructive and central sleep apnea.
      • Arzt M
      • Schroll S
      • Series F
      • et al.
      Auto-servoventilation in heart failure with sleep apnoea: a randomised controlled trial.
      ,
      • Arzt M
      • Floras JS
      • Logan AG
      • et al.
      Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP).
      3: HarmB-RIn patients with NYHA class II to IV HFrEF and central sleep apnea, adaptive servo-ventilation causes harm.
      • Cowie MR
      • Woehrle H
      • Wegscheider K
      • et al.
      Adaptive servo-ventilation for central sleep apnea in systolic heart failure.
      ,
      • Yamamoto S
      • Yamaga T
      • Nishie K
      • et al.
      Positive airway pressure therapy for the treatment of central sleep apnoea associated with heart failure.
      Management of Diabetes
      1AIn patients with HF and type 2 diabetes, the use of SGLT2i is recommended for the management of hyperglycemia and to reduce HF-related morbidity and mortality.
      • McMurray JJV
      • Solomon SD
      • Inzucchi SE
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      ,
      • Packer M
      • Anker SD
      • Butler J
      • et al.
      Cardiovascular and renal outcomes with empagliflozin in heart failure.
      ,
      • Zannad F
      • Ferreira JP
      • Pocock SJ
      • et al.
      SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials.
      ,
      • Kato ET
      • Silverman MG
      • Mosenzon O
      • et al.
      Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus.
      Recommendations for Management of AF in HF
      (Referenced studies that support the recommendations are summarized in the Online Data Supplements.)
      Tabled 1
      CORLOERecommendations
      1APatients with chronic HF with permanent-persistent-paroxysmal AF and a CHA2DS2-VASc score of ≥ 2 (for men) and ≥ 3 (for women) should receive chronic anticoagulant therapy.
      • Mason PK
      • Lake DE
      • DiMarco JP
      • et al.
      Impact of the CHA2DS2-VASc score on anticoagulation recommendations for atrial fibrillation.
      • Connolly SJ
      • Ezekowitz MD
      • Yusuf S
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Patel MR
      • Mahaffey KW
      • Garg J
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      • Granger CB
      • Alexander JH
      • McMurray JJ
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Giugliano RP
      • Ruff CT
      • Braunwald E
      • et al.
      Edoxaban versus warfarin in patients with atrial fibrillation.
      1AFor patients with chronic HF with permanent-persistent-paroxysmal AF, a direct-acting oral anticoagulant is recommended over warfarin in eligible patients.
      • Connolly SJ
      • Ezekowitz MD
      • Yusuf S
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Patel MR
      • Mahaffey KW
      • Garg J
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      • Granger CB
      • Alexander JH
      • McMurray JJ
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Giugliano RP
      • Ruff CT
      • Braunwald E
      • et al.
      Edoxaban versus warfarin in patients with atrial fibrillation.
      • Ferreira J
      • Ezekowitz MD
      • Connolly SJ
      • et al.
      Dabigatran compared with warfarin in patients with atrial fibrillation and symptomatic heart failure: a subgroup analysis of the RE-LY trial.
      • McMurray JJ
      • Ezekowitz JA
      • Lewis BS
      • et al.
      Left ventricular systolic dysfunction, heart failure, and the risk of stroke and systemic embolism in patients with atrial fibrillation: insights from the ARISTOTLE trial.
      • Siller-Matula JM
      • Pecen L
      • Patti G
      • et al.
      Heart failure subtypes and thromboembolic risk in patients with atrial fibrillation: the PREFER in AF-HF substudy.
      • Magnani G
      • Giugliano RP
      • Ruff CT
      • et al.
      Efficacy and safety of edoxaban compared with warfarin in patients with atrial fibrillation and heart failure: insights from ENGAGE AF-TIMI 48.
      • Savarese G
      • Giugliano RP
      • Rosano GM
      • et al.
      Efficacy and safety of novel oral anticoagulants in patients with atrial fibrillation and heart failure: a meta-analysis.
      2aB-RFor patients with HF and symptoms caused by AF, AF ablation is reasonable to improve symptoms and quality of life.
      • Di Biase L
      • Mohanty P
      • Mohanty S
      • et al.
      Ablation versus amiodarone for treatment of persistent atrial fibrillation in patients with congestive heart failure and an implanted device: results from the AATAC multicenter randomized trial.
      • Marrouche NF
      • Brachmann J
      • Andresen D
      • et al.
      Catheter ablation for atrial fibrillation with heart failure.
      • Chen S
      • Purerfellner H
      • Meyer C
      • et al.
      Rhythm control for patients with atrial fibrillation complicated with heart failure in the contemporary era of catheter ablation: a stratified pooled analysis of randomized data.
      • Packer DL
      • Piccini JP
      • Monahan KH
      • et al.
      Ablation versus drug therapy for atrial fibrillation in heart failure: results from the CABANA trial.
      2aB-RFor patients with AF and LVEF ≤ 50%, if a rhythm-control strategy fails or is not desired, and ventricular rates remain rapid despite medical therapy, atrioventricular nodal ablation with implantation of a cardiac resynchronization therapy device is reasonable.
      • Wood MA
      • Brown-Mahoney C
      • Kay GN
      • et al.
      Clinical outcomes after ablation and pacing therapy for atrial fibrillation: a meta-analysis.
      • Brignole M
      • Menozzi C
      • Gianfranchi L
      • et al.
      Assessment of atrioventricular junction ablation and VVIR pacemaker versus pharmacological treatment in patients with heart failure and chronic atrial fibrillation: a randomized, controlled study.
      • Doshi RN
      • Daoud EG
      • Fellows C
      • et al.
      Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study).
      • Brignole M
      • Gammage M
      • Puggioni E
      • et al.
      Comparative assessment of right, left, and biventricular pacing in patients with permanent atrial fibrillation.
      • Brignole M
      • Botto G
      • Mont L
      • et al.
      Cardiac resynchronization therapy in patients undergoing atrioventricular junction ablation for permanent atrial fibrillation: a randomized trial.
      • Brignole M
      • Pokushalov E
      • Pentimalli F
      • et al.
      A randomized controlled trial of atrioventricular junction ablation and cardiac resynchronization therapy in patients with permanent atrial fibrillation and narrow QRS.
      • Chatterjee NA
      • Upadhyay GA
      • Ellenbogen KA
      • et al.
      Atrioventricular nodal ablation in atrial fibrillation: a meta-analysis of biventricular vs. right ventricular pacing mode.
      • Prabhu S
      • Taylor AJ
      • Costello BT
      • et al.
      Catheter ablation versus medical rate control in atrial fibrillation and systolic dysfunction: the CAMERA-MRI study.
      2aB-NRFor patients with chronic HF and permanent-persistent-paroxysmal AF, chronic anticoagulant therapy is reasonable for men and women without additional risk factors.
      • Freudenberger RS
      • Hellkamp AS
      • Halperin JL
      • et al.
      Risk of thromboembolism in heart failure: an analysis from the Sudden Cardiac Death in Heart Failure Trial (SCD-HEFT).
      • Camm AJ
      • Kirchhof P
      • Lip GY
      • et al.
      Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC).
      • Melgaard L
      • Gorst-Rasmussen A
      • Lane DA
      • et al.
      Assessment of the CHA2DS2-VASc score in predicting ischemic stroke, thromboembolism, and death in patients with heart failure with and without atrial fibrillation.
      • Mogensen UM
      • Jhund PS
      • Abraham WT
      • et al.
      Type of atrial fibrillation and outcomes in patients with heart failure and reduced ejection fraction.
      Recommendation for Revascularization for Coronary Artery Disease
      (Referenced studies that support the recommendation are summarized in the Online Data Supplements.)
      Tabled 1
      CORLOERecommendation
      1B-RIn selected patients with HF, reduced EF (EF ≤ 35%) and suitable coronary anatomy, surgical revascularization plus GDMT is beneficial to improve symptoms, cardiovascular hospitalizations, and long-term all-cause mortality.
      • Caracciolo EA
      • Davis KB
      • Sopko G
      • et al.
      Comparison of surgical and medical group survival in patients with left main equivalent coronary artery disease: long-term CASS experience.
      • Howlett JG
      • Stebbins A
      • Petrie MC
      • et al.
      CABG improves outcomes in patients with ischemic cardiomyopathy: 10-year follow-up of the STICH Trial.
      • Mark DB
      • Knight JD
      • Velazquez EJ
      • et al.
      Quality-of-life outcomes with coronary artery bypass graft surgery in ischemic left ventricular dysfunction: a randomized trial.
      • Park S
      • Ahn JM
      • Kim TO
      • et al.
      Revascularization in patients with left main coronary artery disease and left ventricular dysfunction.
      • Petrie MC
      • Jhund PS
      • She L
      • et al.
      Ten-year outcomes after coronary artery bypass grafting according to age in patients with heart failure and left ventricular systolic dysfunction: an analysis of the extended follow-up of the STICH Trial (Surgical Treatment for Ischemic Heart Failure).
      • Tam DY
      • Dharma C
      • Rocha R
      • et al.
      Long-term survival after surgical or percutaneous revascularization in patients with diabetes and multivessel coronary disease.
      • Velazquez EJ
      • Lee KL
      • Deja MA
      • et al.
      Coronary-artery bypass surgery in patients with left ventricular dysfunction.
      • Velazquez EJ
      • Lee KL
      • Jones RH
      • et al.
      Coronary-artery bypass surgery in patients with ischemic cardiomyopathy.
      Recommendations for Cardio-oncology
      (Referenced studies that support the recommendations are summarized in the Online Data Supplements.)
      Tabled 1
      CORLOERecommendations
      1B-NRIn patients who develop cancer therapy–related cardiomyopathy or HF, a multidisciplinary discussion involving the patient about the risk-benefit ratio of cancer therapy interruption, discontinuation or continuation is recommended to improve management.
      • Wang SY
      • Long JB
      • Hurria A
      • et al.
      Cardiovascular events, early discontinuation of trastuzumab, and their impact on survival.
      ,
      • Guarneri V
      • Lenihan DJ
      • Valero V
      • et al.
      Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. Anderson Cancer Center experience.
      2aB-NRIn asymptomatic patients with cancer therapy–related cardiomyopathy (EF < 50%), ARB, ACEi and beta-blocker are reasonable to prevent progression to HF and improve cardiac function.
      • Guarneri V
      • Lenihan DJ
      • Valero V
      • et al.
      Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. Anderson Cancer Center experience.
      • Cardinale D
      • Colombo A
      • Lamantia G
      • et al.
      Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy.
      • Cardinale D
      • Colombo A
      • Bacchiani G
      • et al.
      Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy.
      2aB-NRIn patients with cardiovascular risk factors or known cardiac disease being considered for potentially cardiotoxic anticancer therapies, pretherapy evaluation of cardiac function is reasonable to establish baseline cardiac function and guide the choice of cancer therapy.
      • Guarneri V
      • Lenihan DJ
      • Valero V
      • et al.
      Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. Anderson Cancer Center experience.
      ,
      • Chavez-MacGregor M
      • Zhang N
      • Buchholz TA
      • et al.
      Trastuzumab-related cardiotoxicity among older patients with breast cancer.
      • Goldhar HA
      • Yan AT
      • Ko DT
      • et al.
      The temporal risk of heart failure associated with adjuvant trastuzumab in breast cancer patients: a population study.
      • Armenian SH
      • Sun CL
      • Shannon T
      • et al.
      Incidence and predictors of congestive heart failure after autologous hematopoietic cell transplantation.
      • Henry ML
      • Niu J
      • Zhang N
      • et al.
      Cardiotoxicity and cardiac monitoring among chemotherapy-treated breast cancer patients.
      • Wang L
      • Tan TC
      • Halpern EF
      • et al.
      Major cardiac events and the value of echocardiographic evaluation in patients receiving anthracycline-based chemotherapy.
      • Seferina SC
      • de Boer M
      • Derksen MW
      • et al.
      Cardiotoxicity and cardiac monitoring during adjuvant trastuzumab in daily Dutch practice: a study of the Southeast Netherlands Breast Cancer Consortium.
      • Abu-Khalaf MM
      • Safonov A
      • Stratton J
      • et al.
      Examining the cost-effectiveness of baseline left ventricular function assessment among breast cancer patients undergoing anthracycline-based therapy.
      • Truong SR
      • Barry WT
      • Moslehi JJ
      • et al.
      Evaluating the utility of baseline cardiac function screening in early-stage breast cancer treatment.
      • Jeyakumar A
      • DiPenta J
      • Snow S
      • et al.
      Routine cardiac evaluation in patients with early-stage breast cancer before adjuvant chemotherapy.
      • Steuter J
      • Bociek R
      • Loberiza F
      • et al.
      Utility of prechemotherapy evaluation of left ventricular function for patients with lymphoma.
      • Conrad AL
      • Gundrum JD
      • McHugh VL
      • et al.
      Utility of routine left ventricular ejection fraction measurement before anthracycline-based chemotherapy in patients with diffuse large B-cell lymphoma.
      • O'Brien P
      • Matheson K
      • Jeyakumar A
      • et al.
      The clinical utility of baseline cardiac assessments prior to adjuvant anthracycline chemotherapy in breast cancer: a systematic review and meta-analysis.
      2aB-NRIn patients with cardiovascular risk factors or known cardiac disease receiving potentially cardiotoxic anticancer therapies, monitoring of cardiac function is reasonable for the early identification of drug-induced cardiomyopathy.
      • Guarneri V
      • Lenihan DJ
      • Valero V
      • et al.
      Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. Anderson Cancer Center experience.
      ,
      • Cardinale D
      • Colombo A
      • Bacchiani G
      • et al.
      Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy.
      ,
      • Goldhar HA
      • Yan AT
      • Ko DT
      • et al.
      The temporal risk of heart failure associated with adjuvant trastuzumab in breast cancer patients: a population study.
      ,
      • Henry ML
      • Niu J
      • Zhang N
      • et al.
      Cardiotoxicity and cardiac monitoring among chemotherapy-treated breast cancer patients.
      2bB-RIn patients at risk of cancer therapy–related cardiomyopathy, initiation of beta-blocker and ACEi/ARB for the primary prevention of drug-induced cardiomyopathy is of uncertain benefit.
      • Akpek M
      • Ozdogru I
      • Sahin O
      • et al.
      Protective effects of spironolactone against anthracycline-induced cardiomyopathy.
      • Avila MS
      • Ayub-Ferreira SM
      • de Barros Wanderley Jr, MR
      • et al.
      Carvedilol for prevention of chemotherapy-related cardiotoxicity: the CECCY trial.
      • Bosch X
      • Rovira M
      • Sitges M
      • et al.
      Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies).
      • Cardinale D
      • Colombo A
      • Sandri MT
      • et al.
      Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition.
      • Guglin M
      • Krischer J
      • Tamura R
      • et al.
      Randomized trial of lisinopril versus carvedilol to prevent trastuzumab cardiotoxicity in patients with breast cancer.
      • Gulati G
      • Heck SL
      • Ree AH
      • et al.
      Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 x 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol.
      • Kalay N
      • Basar E
      • Ozdogru I
      • et al.
      Protective effects of carvedilol against anthracycline-induced cardiomyopathy.
      • Pituskin E
      • Mackey JR
      • Koshman S
      • et al.
      Multidisciplinary approach to novel therapies in cardio-oncology research (MANTICORE 101-Breast): a randomized trial for the prevention of trastuzumab-associated cardiotoxicity.
      • Shah P
      • Garris R
      • Abboud R
      • et al.
      Meta-analysis comparing usefulness of beta blockers to preserve left ventricular function during anthracycline therapy.
      • Cardinale D
      • Ciceri F
      • Latini R
      • et al.
      Anthracycline-induced cardiotoxicity: a multicenter randomised trial comparing two strategies for guiding prevention with enalapril: the International CardioOncology Society-one trial.
      • Vaduganathan M
      • Hirji SA
      • Qamar A
      • et al.
      Efficacy of neurohormonal therapies in preventing cardiotoxicity in patients with cancer undergoing chemotherapy.
      • Wittayanukorn S
      • Qian J
      • Westrick SC
      • et al.
      Prevention of trastuzumab and anthracycline-induced cardiotoxicity using angiotensin-converting enzyme inhibitors or beta-blockers in older adults with breast cancer.
      2bC-LDIn patients being considered for potentially cardiotoxic therapies, serial measurement of cardiac troponin might be reasonable for further risk stratification.
      • Cardinale D
      • Sandri MT
      • Colombo A
      • et al.
      Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy.
      • Cardinale D
      • Colombo A
      • Torrisi R
      • et al.
      Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation.
      • Cardinale D
      • Sandri MT
      • Martinoni A
      • et al.
      Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy.
      • Zardavas D
      • Suter TM
      • Van Veldhuisen DJ
      • et al.
      Role of troponins I and T and N-terminal prohormone of brain natriuretic peptide in monitoring cardiac safety of patients with early-stage human epidermal growth factor receptor 2-positive breast cancer receiving trastuzumab: a herceptin adjuvant study cardiac marker substudy.

      Appendix B. Supplementary materials

      Appendix

      Table A1
      Table A1Appendix for Tables 2 and 3: Suggested Thresholds for Structural Heart Disease and Evidence of Increased Filling Pressures
      MorphologyLAVI ≥29 mL/m2

      LVMI >116/95 g/m2

      RWT >0.42

      LV wall thickness ≥ 12 mm
      Ventricular systolic functionLVEF < 50%

      GLS < 16%
      Ventricular diastolic functionAverage E/eʹ ≥ 15 for increased filling pressures

      Septal eʹ < 7 cm/s

      Lateral eʹ < 10 cm/s

      TR velocity > 2.8 m/s

      Estimated PA systolic pressure > 35 mmHg
      BiomarkerBNP ≥ 35 pg/mL
      Cutoffs provided for natriuretic peptide levels may have lower specificity, especially in older patients or in patients with AF or CKD. Usually, higher cutoff values are recommended for the diagnosis of HF in these patients. Natriuretic peptide cutoffs selected for population screening for pre-HF (stage B HF) may be < 99% reference limits and need to be defined according to the population at risk. AF, atrial fibrillation; BNP, brain natriuretic peptide; CKD, chronic kidney disease; GLS, global longitudinal strain; HF, heart failure; LAVI, left atrial volume index; LVMI, left ventricular mass index; NT-proBNP, natriuretic peptide tests; PA, pulmonary artery; RWT, relative wall thickness; and TR, tricuspid regurgitation.


      NT-proBNP ≥ 125 pg/mL
      Cutoffs provided for natriuretic peptide levels may have lower specificity, especially in older patients or in patients with AF or CKD. Usually, higher cutoff values are recommended for the diagnosis of HF in these patients. Natriuretic peptide cutoffs selected for population screening for pre-HF (stage B HF) may be < 99% reference limits and need to be defined according to the population at risk. AF, atrial fibrillation; BNP, brain natriuretic peptide; CKD, chronic kidney disease; GLS, global longitudinal strain; HF, heart failure; LAVI, left atrial volume index; LVMI, left ventricular mass index; NT-proBNP, natriuretic peptide tests; PA, pulmonary artery; RWT, relative wall thickness; and TR, tricuspid regurgitation.
      low asterisk Cutoffs provided for natriuretic peptide levels may have lower specificity, especially in older patients or in patients with AF or CKD. Usually, higher cutoff values are recommended for the diagnosis of HF in these patients. Natriuretic peptide cutoffs selected for population screening for pre-HF (stage B HF) may be < 99% reference limits and need to be defined according to the population at risk.AF, atrial fibrillation; BNP, brain natriuretic peptide; CKD, chronic kidney disease; GLS, global longitudinal strain; HF, heart failure; LAVI, left atrial volume index; LVMI, left ventricular mass index; NT-proBNP, natriuretic peptide tests; PA, pulmonary artery; RWT, relative wall thickness; and TR, tricuspid regurgitation.

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