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Canadian Journal of Cardiology

2017 Comprehensive Update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure

Published:September 06, 2017DOI:https://doi.org/10.1016/j.cjca.2017.08.022

      Abstract

      Since the inception of the Canadian Cardiovascular Society heart failure (HF) guidelines in 2006, much has changed in the care for patients with HF. Over the past decade, the HF Guidelines Committee has published regular updates. However, because of the major changes that have occurred, the Guidelines Committee believes that a comprehensive reassessment of the HF management recommendations is presently needed, with a view to producing a full and complete set of updated guidelines. The primary and secondary Canadian Cardiovascular Society HF panel members as well as external experts have reviewed clinically relevant literature to provide guidance for the practicing clinician. The 2017 HF guidelines provide updated guidance on the diagnosis and management (self-care, pharmacologic, nonpharmacologic, device, and referral) that should aid in day-to-day decisions for caring for patients with HF. Among specific issues covered are risk scores, the differences in management for HF with preserved vs reduced ejection fraction, exercise and rehabilitation, implantable devices, revascularization, right ventricular dysfunction, anemia, and iron deficiency, cardiorenal syndrome, sleep apnea, cardiomyopathies, HF in pregnancy, cardio-oncology, and myocarditis. We devoted attention to strategies and treatments to prevent HF, to the organization of HF care, comorbidity management, as well as practical issues around the timing of referral and follow-up care. Recognition and treatment of advanced HF is another important aspect of this update, including how to select advanced therapies as well as end of life considerations. Finally, we acknowledge the remaining gaps in evidence that need to be filled by future research.

      Résumé

      Depuis la parution des Lignes directrices sur l’insuffisance cardiaque (IC) de la Société canadienne de cardiologie en 2006, les soins aux patients atteints de ce trouble ont connu d’importants changements. Au cours de la dernière décennie, le Comité des lignes directrices sur l’IC a publié des mises à jour périodiques. Toutefois, en raison des changements importants qui sont survenus, le Comité des lignes directrices a jugé qu’il était nécessaire de procéder à une réévaluation exhaustive des recommandations sur la prise en charge de l’IC afin de produire un ensemble complet de lignes directrices à jour. Les membres des comités primaire et secondaire sur l’IC de la Société canadienne de cardiologie, ainsi que des spécialistes externes, ont passé en revue la littérature pertinente afin d’indiquer aux cliniciens la marche à suivre. Les lignes directrices de 2017 donnent des indications sur le diagnostic et la prise en charge (autosoins, traitements pharmacologiques et non pharmacologiques, dispositifs et orientation des patients) destinées à faciliter la prise de décisions quotidiennes en matière de soins aux patients atteints d’IC. Parmi les questions abordées figurent notamment les cotes de risque, les différences de prise en charge selon qu’il s’agit d’IC à fraction d’éjection préservée ou réduite, l’activité physique et la réadaptation, les dispositifs implantables, la revascularisation, la dysfonction ventriculaire droite, l’anémie et la carence en fer, le syndrome cardiorénal, l’apnée du sommeil, les cardiomyopathies, l’IC pendant la grossesse, la cardio-oncologie et la myocardite. Le comité a apporté une attention particulière aux stratégies et aux traitements visant à prévenir l’IC, à l’organisation des soins aux patients atteints d’IC, à la prise en charge des comorbidités, ainsi qu’à des questions pratiques concernant les délais d’orientation du patient et les soins de suivi. La reconnaissance et le traitement de l’IC au stade avancé, et notamment le choix des thérapies à ce stade et les considérations en matière de fin de vie, représentent un autre aspect important de cette mise à jour. Enfin, le comité reconnaît les lacunes dans les données probantes qui subsistent et devront être comblées par les recherches futures.

      1. Introduction

      The Canadian Cardiovascular Society (CCS) heart failure (HF) guidelines program provides guidance to clinicians, policy makers, and health systems as to the evidence supporting existing and emerging management of patients with HF. The 2017 update is a comprehensive set of guidelines that incorporates new evidence and identifies areas of uncertainty and challenges facing health care providers in HF management. It integrates and updates the past decade of HF guidelines, along with a large body of new research and data.
      The constitution and roles of the primary and secondary panels, systematic review strategy, and methods for formulating the recommendations are available at www.ccs.ca. The recommendations were developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) standards.
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.

      Grade Working Group. The Grading of Recommendations Assessment, Development and Evaluation (GRADE). 2016. Available at: www.gradeworkinggroup.org. Accessed February 16, 2016.

      The primary panelists were principally responsible for the document, with input from secondary panelists and external content experts where needed.
      The sections on atrial fibrillation (AF), cardiac resynchronization therapy (CRT), and cardio-oncology were developed in collaboration with the respective guidelines committees, and are endorsed by those committees from a HF perspective.
      Several sections of this document have been made available as Supplementary Material, including a list of abbreviations and acronyms (see the Abbreviations and Acronyms section of the Supplementary Material).

      2. Definitions of HF

      HF is a complex clinical syndrome in which abnormal heart function results in, or increases the subsequent risk of, clinical symptoms and signs of reduced cardiac output and/or pulmonary or systemic congestion at rest or with stress. Although this has traditionally focused on patients with predominant left ventricular (LV) systolic dysfunction (LVSD), there is an increased awareness of the syndrome spanning patients with acute and chronic HF, right-sided HF, and HF across a spectrum of ventricular or valvular function. We have refrained from using other terms, often older descriptive terms (eg, dilated, congestive), unless a specific definition exists. The term “stable” is not considered to be clinically appropriate because of the inherent risk for future clinical events. We have not adopted a staging system
      • Hunt S.A.
      • Baker D.W.
      • Chin M.H.
      • et al.
      ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration With the International Society for Heart and Lung Transplantation; Endorsed by the Heart Failure Society of America.
      or alternative systems
      • Arbustini E.
      • Narula N.
      • Dec G.W.
      • et al.
      The MOGE(S) classification for a phenotype-genotype nomenclature of cardiomyopathy: endorsed by the World Heart Federation.
      for describing HF.
      Chronic HF is the preferred term representing the persistent and progressive nature of the disease. Acute HF (AHF) is defined as a gradual or rapid change in HF signs and symptoms resulting in the need for urgent therapy. Advanced HF is the term often used clinically, yet has no widely accepted definition. In the context of the guidelines, we have outlined some of the key considerations for this term in the section 7.1.4. Advanced HF Management Strategies as it pertains to selecting advanced mechanical devices, transplantation, or palliative therapies.

      2.1 Ejection fraction terminology

      This guideline uses the following terms:
      • HF with preserved ejection fraction (HFpEF): LV ejection fraction (LVEF) ≥ 50%;
      • HF with a mid-range ejection fraction (HFmEF): LVEF 41%-49%;
      • HF with reduced ejection fraction (HFrEF): LVEF ≤ 40%.
      This recognizes the uncertainty that often occurs in the measurement of LVEF, the evolving landscape of current clinical trials enrolling patients with different LVEF cutoffs, and evolving ways to evaluate cardiac function. Echocardiography is the most accessible method to evaluate LVEF in Canada. Estimates of ejection fraction (EF) might vary because of patient or technical factors, as well as therapy or clinical deterioration. The previously stated EF cut points recognize that there is a large body of evidence related to treatment for patients with HFrEF and emerging evidence for patients with HFpEF and HFmEF. HFmEF might represent many different phenotypes, including patients transitioning to and from HFpEF.
      The term “recovered EF” has also been added to the literature,
      • Kalogeropoulos A.P.
      • Fonarow G.C.
      • Georgiopoulou V.
      • et al.
      Characteristics and outcomes of adult outpatients with heart failure and improved or recovered ejection fraction.
      referring to patients who previously had HFrEF and now have an EF > 40%. These patients might eventually be classified in the HFmEF or HFpEF group but deserve recognition because despite their recovered imaging parameters, they might still carry additional risk for adverse clinical events. Uncertainty exists on strategies for management of individuals with HFmEF including surveillance, treatment, and prognosis.

      2.2 Symptoms terminology

      Symptoms are described using the New York Heart Association (NYHA) functional class I-IV (Table 1).
      Table 1New York Heart Association functional classification and other symptom descriptors
      Data from the Criteria Committee of the New York Heart Association.
      The Criteria Committee of the New York Heart Association
      Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels.
      ClassDefinitionOther descriptor
      INo symptomsAsymptomatic
      IISymptoms with ordinary activityMild symptoms
      IIISymptoms with less than ordinary activityModerate symptoms
      IVSymptoms at rest or with any minimal activitySevere symptoms

      3. Prognosis and Risk Scores

      Table 2 shows examples of HF prognostic scores that can be easily accessed and calculated, and the strengths and limitations of the studies used to develop these scores. Clinical acumen remains important to place these risk scores in context, but methodologically sound and externally valid risk scores might help the clinician and patient. Where possible, these risk scores should be incorporated into practice and used to convey risk to patients, and between clinicians to adequately characterize the overall risk of a patient. The risk scores in Table 2 are not exhaustive; others exist and could be considered by clinicians.
      Table 2Risk scores
      Score NamePopulationEnd pointOther considerationsAccessVariables
      Seattle Heart Failure Model
      • Levy W.C.
      • Mozaffarian D.
      • Linker D.T.
      • et al.
      The Seattle Heart Failure Model: prediction of survival in heart failure.
      HFrEFMortality risk at 1, 2, and 5 years with or without intervention; mean life expectancyRestricted to clinical trial patients with ‘severe’ HF; laboratory data entry non-SI units; >20 variables to enterhttps://depts.washington.edu/shfmAge, sex, NYHA class, weight, EF, SBP, ischemic etiology, diuretic dose, Na, lymphocyte count, Hgb, cholesterol, uric acid, use of ACEi/ARB/β-blocker/aldosterone blocker/allopurinol/statins, QRS > 120 ms, use of device therapy
      MAGGIC risk score
      • Pocock S.J.
      • Ariti C.A.
      • McMurray J.J.
      • et al.
      Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies.
      HFrEF and HFpEFMortality risk at 1 and 3 yearsCohorts from many sites; missing data in the overall analysiswww.heartfailurerisk.orgAge, sex, NYHA class, diabetes, COPD, timing of diagnosis, EF, smoking, SBP, creatinine, body mass index, use of β-blocker/ACEi/ARB
      3C-HF
      • Senni M.
      • Parrella P.
      • De Maria R.
      • et al.
      Predicting heart failure outcome from cardiac and comorbid conditions: the 3C-HF score.
      HFrEF and HFpEFMortality risk at 1 yearPatients from centres with experience with HF management; mostly Caucasian patients; laboratory data entry in non-SI unitshttp://www.3chf.org/site/home.phpAge, NYHA class, atrial fibrillation, valvular heart disease, EF, anemia, diabetes, hypertension, creatinine, use of ACEi/ARB or β-blockers
      BCN bio-HF
      • Lupon J.
      • de Antonio M.
      • Vila J.
      • et al.
      Development of a novel heart failure risk tool: the barcelona bio-heart failure risk calculator (BCN bio-HF calculator).
      HFrEF and HFpEFMortality risk at 1, 2, and 3 yearsLimited to patients with chronic HF treated in HF unit in a tertiary hospital; laboratory data entry in US units; use of biomarkers improves accuracy but is optionalwww.BCNBioHFcalculator.catAge, sex, NYHA class, Na, estimated glomerular filtration rate, Hgb, EF, diuretic dose, use of statins, β-blockers, or ACEi/ARB. Optional: hs-cTnT, ST2, NT-proBNP
      EFFECT
      • Lee D.S.
      • Austin P.C.
      • Rouleau J.L.
      • et al.
      Predicting mortality among patients hospitalized for heart failure: derivation and validation of a clinical model.
      Hospitalized HFrEF and HFpEF30-day and 1-year mortalityLimited to hospitalized patients; missing current clinically important variableshttp://www.ccort.ca/Research/CHFRiskModel.aspxAge, respiratory rate, SBP, BUN, Na, CVD, dementia, COPD, cirrhosis, cancer, Hgb
      EHMRG
      • Lee D.S.
      • Stitt A.
      • Austin P.C.
      • et al.
      Prediction of heart failure mortality in emergent care: a cohort study.
      HFrEF and HFpEF patients presenting to the ED7-day mortalityLimited to patients presenting to the ED and only short-term mortality; missing current clinically important variableshttps://ehmrg.ices.on.caAge, arrival by ambulance, triage SBP, triage HR, triage O2 saturation, potassium, creatinine, active cancer, metolazone, troponin; optional: BNP
      ELAN-HF
      • Salah K.
      • Kok W.E.
      • Eurlings L.W.
      • et al.
      A novel discharge risk model for patients hospitalised for acute decompensated heart failure incorporating N-terminal pro-B-type natriuretic peptide levels: a European coLlaboration on Acute decompeNsated Heart Failure: ELAN-HF Score.
      Hospitalized HFrEF and HFpEF180-day mortalityLimited to hospitalized patientsAge, edema, SBP, serum sodium, serum urea, NYHA class at discharge, NT-proBNP at discharge, and change in NT-proBNP
      ADHERE
      • Fonarow G.C.
      • Adams Jr., K.F.
      • Abraham W.T.
      • et al.
      Risk stratification for in-hospital mortality in acutely decompensated heart failure: classification and regression tree analysis.
      HFrEF and HFpEFIn-hospital mortalityLimited to hospitalized patientsBUN, creatinine, SBP
      LACE
      • van Walraven C.
      • Dhalla I.A.
      • Bell C.
      • et al.
      Derivation and validation of an index to predict early death or unplanned readmission after discharge from hospital to the community.
      Hospitalized patients30-day mortality or readmissionLimited to hospitalized patientsLength of stay, acute admission, comorbidity index, number of ED visits in past 6 months
      ACEi, angiotensin-converting enzyme inhibitor; ADHERE, Acute Decompensated Heart Failure National Registry; ARB, angiotensin receptor blocker; BCN bio-HF, Barcelona Bio-Heart Failure Risk Calculator; BNP, B-type natriuretic peptide; BUN, blood urea nitrogen; 3C-HF, Cardiac and Comorbid Conditions Heart Failure score; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; ED, emergency department; EF, ejection fraction; EFFECT, Enhanced Feedback for Effective Cardiac Treatment; EHMRG, Emergency Heart Failure Mortality Risk Grade; ELAN-HF, European Collaboration on Acute Decompensated Heart Failure; HF, heart failure; HFpEF, HF with preserved EF; HFrEF, HF with reduced EF; Hgb, hemoglobin; HR, heart rate; hs-cTnT, high-sensitivity cardiac troponin T; LACE, Length of Stay, Acuity of Admission, Comorbidities, Emergency Department Visits; MAGGIC, Meta-Analysis Global Group in Chronic Heart Failure; NT-proBNP, N-terminal propeptide B-type natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure; SI units, International System of Units; ST2, suppression of tumorigenicity 2.

      4. Prevention of HF and Asymptomatic LV Dysfunction

      4.1 Early detection of LVSD and prevention of HF

      HF often progresses from asymptomatic LVSD to symptomatic HF.
      • Wang T.J.
      • Evans J.C.
      • Benjamin E.J.
      • et al.
      Natural history of asymptomatic left ventricular systolic dysfunction in the community.
      Early detection of LVSD might allow intervention on contributing risk factors and pharmacotherapy to delay or reverse the progression of adverse LV remodelling. Data on medications, including ACEs, ARBs, and β-blockers are summarized online in evidence reviews at www.ccs.ca.
      Conventional risk factors for cardiovascular disease (CVD) are often included in clinical assessment but a detailed family history might also uncover genetic causes or susceptibility to the development of LV dysfunction. The use of NPs might be useful to identify individuals who are at higher risk for the development of HF and in whom preventative strategies have been studied. The cut point used in the Saint Vincent Screening to Prevent Heart Failure (STOP-HF)
      • Ledwidge M.
      • Gallagher J.
      • Conlon C.
      • et al.
      Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial.
      trial of BNP > 50 pg/mL to undergo echocardiography and collaborative care resulted in a higher rate of use of renin-angiotensin-aldosterone system inhibition therapies, fewer HF events, and significant reduction in hospitalizations for major cardiovascular events over a follow-up on an average of 4.2 years. The NT-proBNP Selected Prevention of Cardiac Events in a Population of Diabetic Patients Without a History of Cardiac Disease (PONTIAC) study
      • 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.
      used a cut point of NT-proBNP > 125 pg/mL to apply further cardiology consultation and individualized β-blockade and renin-angiotensin-aldosterone system uptitration. Patients in the group randomized to intensified therapy had a 65% relative risk reduction (RRR) in the primary combined event rate of hospitalization or death due to cardiac disease at 2 years. Therapies used in these 2 trials are guideline-based, reinforcing the opportunity to enhance neurohormonal therapy in all individuals with cardiovascular risk factors, limited only by the availability of NP measurement to identify patients.
      Exercise as a strategy to prevent ischemic heart disease has supported guideline-recommended minimum physical activity of at least 150 minutes per week of moderate intensity activity (approximately 500 metabolic equivalents of task minutes). A meta-analysis of 12 prospective cohort studies by Pandey et al.
      • Pandey A.
      • Garg S.
      • Khunger M.
      • et al.
      Dose-response relationship between physical activity and risk of heart failure: a meta-analysis.
      reported the risk of HF is reduced by 10%, 19%, and 35% in people who were participating in leisure activity of 500, 1000, and 2000 metabolic equivalents of task minutes per week, respectively, compared with individuals with no physical activity. This article noted an inverse dose-response relationship between physical activity and development of HF.
      The importance of prevention of HF is supported by evidence that preventing and treating cardiovascular risk factors and conditions that cause atherosclerotic disease leads to fewer patients developing HF. Many of these risk factors also contribute to the development of HF independently from atherosclerotic disease (Table 3). Previous HF guidelines have reviewed the substantial evidence supporting the screening and management of common risk factors for the development of HF such as hypertension, diabetes, smoking, dyslipidemia, obesity, alcohol use, and sedentary behaviour.
      • Eriksson H.
      • Svardsudd K.
      • Larsson B.
      • et al.
      Risk factors for heart failure in the general population: the study of men born in 1913.
      • Ho K.K.
      • Pinsky J.L.
      • Kannel W.B.
      • Levy D.
      The epidemiology of heart failure: the Framingham Study.
      • Nicklas B.J.
      • Cesari M.
      • Penninx B.W.
      • et al.
      Abdominal obesity is an independent risk factor for chronic heart failure in older people.
      • Kenchaiah S.
      • Gaziano J.M.
      • Vasan R.S.
      Impact of obesity on the risk of heart failure and survival after the onset of heart failure.
      • Kenchaiah S.
      • Evans J.C.
      • Levy D.
      • et al.
      Obesity and the risk of heart failure.
      • Aune D.
      • Sen A.
      • Norat T.
      • et al.
      Body mass index, abdominal fatness, and heart failure incidence and mortality: a systematic review and dose-response meta-analysis of prospective studies.
      • Baena-Diez J.M.
      • Byram A.O.
      • Grau M.
      • et al.
      Obesity is an independent risk factor for heart failure: Zona Franca Cohort study.
      • Fitchett D.
      • Zinman B.
      • Wanner C.
      • et al.
      Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial.
      Patients with established coronary artery disease (CAD) and/or previous acute coronary syndrome (ACS) should have these appropriately treated to prevent future HF events.
      • 1.
        We suggest clinical assessment in all patients to identify known or potential risk factors for the development of HF (Weak Recommendation; Moderate-Quality Evidence).
      • 2.
        We recommend an angiotensin-converting enzyme (ACE) inhibitor (ACEi) be used in all asymptomatic patients with an EF < 35% (Strong Recommendation; Moderate-Quality Evidence).
      • 3.
        We recommend that an ACEi should be prescribed in established effective doses to reduce the risk of developing HF in patients with evidence of vascular disease or diabetes with end organ damage (Strong Recommendation; High-Quality Evidence).
      • 4.
        We recommend that in ACE-intolerant patients, an angiotensin receptor blocker (ARB) be considered for reduction of the risk of developing HF in patients with evidence of vascular disease or diabetes with end organ damage (Strong Recommendation; High-Quality Evidence).
      • 5.
        We recommend that health professionals caring for overweight or obese individuals should educate them about the increased risk of HF (Strong Recommendation; Moderate-Quality Evidence).
      • 6.
        We recommend physical activity to reduce the risk of developing HF in all individuals (Strong Recommendation; Moderate-Quality Evidence).
      Table 3Selected risk markers for the development of heart failure
      Demographic and lifestyleMedical historyMarkers
      Older ageHypertension
      Important public health targets for prevention.
      Abnormal ECG
      Male sexCoronary artery diseaseIncreased cardiothoracic ratio on CXR
      Heavy alcohol useDiabetes mellitus
      Important public health targets for prevention.
      Elevated neurohormonal biomarkers
      Smoking
      Important public health targets for prevention.
      Hyperlipidemia
      Important public health targets for prevention.
      Elevated resting heart rate
      Physical inactivity
      Important public health targets for prevention.
      Obesity
      Important public health targets for prevention.
      Microalbuminuria
      CXR, chest x-ray; ECG, electrocardiogram.
      Important public health targets for prevention.
      Practical tip. Natriuretic peptide (NP) screening of individuals at risk for the development of HF can aid decision-making on whom to send for echocardiography. A value of B-type (BNP) > 50 pg/mL or N-terminal propeptide BNP (NT-proBNP) > 125 pg/mL should prompt a request for specialist consultation and imaging, and/or initiation or intensification of neurohormonal blocking agents and lifestyle interventions.
      Practical tip. Dyslipidemia should be treated in patients with evidence of vascular disease or diabetes with lipid-lowering drugs, especially statins.
      Practical tip. Smoking cessation, improved cardiorespiratory fitness, and weight reduction for overweight or obese individuals are important preventive strategies for HF.
      Practical tip. Patients at high risk for developing HF should receive annual influenza vaccine and periodic pneumococcal pneumonia immunizations.

      4.2 Preventing HF in patients with hypertension

      Hypertension has been well documented as a risk factor for HF and the treatment of hypertension has been shown to reduce the risk of developing HF.
      • Levy D.
      • Larson M.G.
      • Vasan R.S.
      • Kannel W.B.
      • Ho K.K.
      The progression from hypertension to congestive heart failure.
      • Bell D.S.
      Heart failure: the frequent, forgotten, and often fatal complication of diabetes.
      • Turnbull F.
      Blood Pressure Lowering Treatment Trialists' Collaboration
      Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials.
      In addition to the high-quality meta-analyses, more recent evidence from the Systolic Blood Pressure Intervention Trial (SPRINT) supports a more aggressive approach to hypertension management.
      • Williamson J.D.
      • Supiano M.A.
      • Applegate W.B.
      • et al.
      Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥75 years: a randomized clinical trial.
      This trial of 9361 participants deemed high risk for a cardiovascular event, randomized to intensive (systolic BP < 120 mm Hg) vs standard (systolic BP < 140 mm Hg) BP control showed there was a 25% risk reduction in the primary outcome of myocardial infarction (MI), ACS, stroke, HF, or death from cardiovascular causes after only a median of 3.26 years. There was a 33% reduction of future HF outcomes (patients with a history of symptomatic HF in the past 6 months or with LVEF < 35% were excluded). Readers are directed to Hypertension Canada's 2017 Guidelines (http://www.onlinecjc.ca/article/S0828-282X(17)30110-1/fulltext) for additional information.
      • 7.
        We recommend that most patients should have their blood pressure (BP) controlled to < 140/90 mm Hg; those with diabetes or at high risk for cardiovascular events should be treated to a systolic BP of < 130 mm Hg to reduce the risk of developing HF (Strong Recommendation; Moderate-Quality Evidence).
      • 8.
        We recommend that β-blockers should be considered in all asymptomatic patients with an LVEF < 40% (Strong Recommendation; Moderate-Quality Evidence).

      4.3 Preventing HF in patients with diabetes

      Diabetes mellitus (DM) is an established risk factor for the development of HF.
      • Bell D.S.
      Heart failure: the frequent, forgotten, and often fatal complication of diabetes.
      • Kannel W.B.
      • Hjortland M.
      • Castelli W.P.
      Role of diabetes in congestive heart failure: the Framingham study.
      • He J.
      • Ogden L.G.
      • Bazzano L.A.
      • et al.
      Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study.
      However, the relationship between glycemic control and the development of HF is inconsistent and complicated further by the long-term effects of diabetes on other organ systems (eg, kidneys) or development of CAD.
      • Sharma A.
      • Ezekowitz J.A.
      Diabetes, impaired fasting glucose, and heart failure: it's not all about the sugar.
      It is recognized, however, that DM can produce HF independently of CAD by causing a diabetic cardiomyopathy.
      • Bell D.S.
      Heart failure: the frequent, forgotten, and often fatal complication of diabetes.
      In several studies, the incidence of HF was two- and fourfold higher in patients with DM than in those without.
      • Kannel W.B.
      • Hjortland M.
      • Castelli W.P.
      Role of diabetes in congestive heart failure: the Framingham study.
      • He J.
      • Ogden L.G.
      • Bazzano L.A.
      • et al.
      Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study.
      • Nichols G.A.
      • Gullion C.M.
      • Koro C.E.
      • Ephross S.A.
      • Brown J.B.
      The incidence of congestive heart failure in type 2 diabetes: an update.
      • Thrainsdottir I.S.
      • Aspelund T.
      • Thorgeirsson G.
      • et al.
      The association between glucose abnormalities and heart failure in the population-based Reykjavik study.
      • Bertoni A.G.
      • Hundley W.G.
      • Massing M.W.
      • et al.
      Heart failure prevalence, incidence, and mortality in the elderly with diabetes.
      • Johansson S.
      • Wallander M.A.
      • Ruigomez A.
      • Garcia Rodriguez L.A.
      Incidence of newly diagnosed heart failure in UK general practice.
      Approximately 12% of DM patients have HF,
      • Nichols G.A.
      • Gullion C.M.
      • Koro C.E.
      • Ephross S.A.
      • Brown J.B.
      The incidence of congestive heart failure in type 2 diabetes: an update.
      and older than the age of 64 years, the prevalence increases to 22%.
      • Bertoni A.G.
      • Hundley W.G.
      • Massing M.W.
      • et al.
      Heart failure prevalence, incidence, and mortality in the elderly with diabetes.
      It is thought that diabetes promotes the development of myocardial fibrosis and diastolic dysfunction, autonomic dysfunction, and worsened renal and endothelial function.
      Moreover, there has been uncertainty regarding whether any glucose-lowering strategy, or specific therapeutic agent, is safe from a cardiovascular standpoint or can decrease cardiovascular risk. Older trials on the effects on cardiovascular outcomes of specific glucose-lowering strategies or medications either have been insufficiently powered or have shown no significant cardiovascular benefit or an increased risk of death or HF.

      4.3.1 Glycemic control in diabetes to prevent HF

      In the past, several diabetes guidelines have advocated for tight glycemic control (lower Hb A1c); however, there is no evidence that this approach improves cardiovascular outcomes and some studies suggest harm, including increased HF, not to mention increased risk for hypoglycemia. There are no specific studies targeting patients with HF. Data are largely extrapolated from the Diabetes Control and Complications Trial (DCCT) study of patients with type 1 diabetes,
      The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group.
      the UK Prospective Diabetes Study (UKPDS) study,
      Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.
      the UKPDS Follow Up study,
      • Holman R.R.
      • Paul S.K.
      • Bethel M.A.
      • Matthews D.R.
      • Neil H.A.
      10-Year follow-up of intensive glucose control in type 2 diabetes.
      the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study,
      • Gerstein H.C.
      • Miller M.E.
      • et al.
      Action to Control Cardiovascular Risk in Diabetes Study Group
      Effects of intensive glucose lowering in type 2 diabetes.
      • Group A.S.
      • Gerstein H.C.
      • Miller M.E.
      • et al.
      Long-term effects of intensive glucose lowering on cardiovascular outcomes.
      the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR-Controlled Evaluation (ADVANCE) study,
      • Group A.C.
      • Patel A.
      • MacMahon S.
      • et al.
      Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
      and the Veterans Affairs Diabetes Trial (VADT) study.
      • Duckworth W.
      • Abraira C.
      • Moritz T.
      • et al.
      Glucose control and vascular complications in veterans with type 2 diabetes.
      With the available evidence, an intensive glycemic control strategy cannot be recommended for all patients with diabetes. Instead, each individual should be assessed for his or her optimal glycemic target for the prevention of macrovascular events or HF.
      • 9.
        We recommend that diabetes should be treated according to the Canadian Diabetes Association's national guidelines to achieve optimal control of blood glucose levels (Strong Recommendation; Moderate-Quality Evidence).
      Values and preferences. There is no convincing evidence from randomized controlled trials (RCTs) that tighter glycemic control reduces cardiovascular outcomes. Potential risks of tight glycemic control might outweigh its benefits in certain individuals such as those with a long duration of diabetes, frequent episodes of hypoglycemia, those with advanced CVD, advanced age, frailty, or multiple comorbidities.
      Practical tip. Each individual patient should be assessed for his or her “optimal” glycemic control hemoglobin (Hb) A1c target. Considerations include an individual's risk of hypoglycemia, the duration of diabetes, the presence or absence of CVD, kidney function, overweight or not, or frailty, among others.

      Metformin

      Metformin is still considered first-line pharmacological therapy for type 2 diabetes. It is effective, has a known safety profile, and is well tolerated in patients with HF.
      • MacDonald M.R.
      • Eurich D.T.
      • Majumdar S.R.
      • et al.
      Treatment of type 2 diabetes and outcomes in patients with heart failure: a nested case-control study from the U.K. General Practice Research Database.
      • 10.
        We suggest that metformin might be considered a first-line agent for type 2 diabetes treatment (Weak Recommendation; Moderate-Quality Evidence).
      Values and preferences. Metformin is the current Canadian Diabetes Association first-line treatment for type 2 diabetes.
      Practical tip. If the estimated glomerular filtration rate (eGFR) is < 30 mL/min, a temporary discontinuation of metformin and certain other diabetes medications should be considered.

      SGLT-2 inhibitors

      The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients -Removing Excess Glucose (EMPA-REG OUTCOME) trial,
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      is an RCT to show cardiovascular benefit in the treatment of diabetes. A sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin was compared with placebo in 7020 patients with type 2 diabetes and established CVD and eGFR ≥ 30 mL/min. The primary composite outcome was death from cardiovascular causes, nonfatal MI, or nonfatal stroke. The primary end point occurred less commonly in the patients treated with empagliflozin (10.5%) than in those who received placebo (hazard ratio [HR], 12.1%; 95% confidence interval [CI], 0.74-0.99). Moreover, empagliflozin had an RRR for cardiovascular mortality of 38%, all-cause mortality of 32%, and HF hospitalization of 35%. SGLT-2 inhibitors have not yet been studied in populations of patients with HF. Of note, only a subgroup of approximately 10% of patients in the EMPA-REG OUTCOME trial had a reported history of HF. There are ongoing trials of SGLT-2 inhibitors, and those might affect future recommendations, namely for patients with established HF.
      • 11.
        We suggest that the use of empagliflozin, an SGLT-2 inhibitor, be considered for patients with type 2 diabetes and established CVD for the prevention of HF-related outcomes (Weak Recommendation; Low-Quality Evidence).
      Values and preferences. This recommendation places weight on the fact that empagliflozin is the first diabetes-related medication to show a reduction in HF hospitalization. Empagliflozin was well tolerated and associated with an acceptable side effect profile within the clinical trial establishing its efficacy and safety. There are ongoing trials of this class of medications that might change this recommendation.

      DPP-4 inhibitors

      The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial
      • Scirica B.M.
      • Bhatt D.L.
      • Braunwald E.
      • et al.
      Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
      randomized 16,492 patients with type 2 diabetes who had a history of, or were at risk for, cardiovascular events to receive the dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin or placebo and followed them for a median of 2.1 years. The primary end point was a composite of cardiovascular death, MI, or ischemic stroke. At a median follow-up of 2.1 years, rates of composite cardiovascular events were similar with saxagliptin and placebo, but hospitalization for HF was higher with saxagliptin (3.5% vs 2.8%; HR, 1.27; P = 0.007).
      In contrast, the Trial Evaluating Cardiovascular Outcomes With Sitagliptin (TECOS) study,
      • Green J.B.
      • Bethel M.A.
      • Armstrong P.W.
      • et al.
      Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.
      an RCT of 14,671 patients comparing another DPP-4 inhibitor, sitagliptin, with placebo showed no increase in HF hospitalization (HR, 1.00; 95% CI, 0.83-1.20; P = 0.98). Studies involving other DPP-4 inhibitors alogliptin
      • Zannad F.
      • Cannon C.P.
      • Cushman W.C.
      • et al.
      Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial.
      and linagliptin
      • Rosenstock J.
      • Marx N.
      • Neubacher D.
      • et al.
      Cardiovascular safety of linagliptin in type 2 diabetes: a comprehensive patient-level pooled analysis of prospectively adjudicated cardiovascular events.
      have not shown additional increases in the risk of HF events.
      • 12.
        We do not recommend the use of the DPP-4 inhibitor saxagliptin in patients with or at risk for HF (Strong Recommendation; Moderate-Quality Evidence).
      • 13.
        We suggest that if a DPP-4 inhibitor is to be used, linagliptin or sitagliptin should be considered for patients with diabetes and with, or at risk for HF (Weak Recommendation; Moderate-Quality Evidence).
      Values and preferences. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus (SAVOR) trial showed an increase in HF hospitalizations with use of saxagliptin. Other DPP-4 inhibitors (eg, sitagliptin, alogliptin, linagliptin) did not have the same adverse effect as saxagliptin of HF hospitalization; there are ongoing trials of other DPP-4 inhibitors.

      Glucagon-like peptide

      Human glucagon-like peptide (GLP-1) agonists have been tested in patients with diabetes for the outcomes of cardiovascular events. One such agent, liraglutide, was tested in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, and 14% of the patients had a clinical history of HF. Overall, liraglutide was shown to be noninferior to placebo, and had fewer cardiovascular events overall. There was no statistically significant decrease or increase in the number of HF events. There are ongoing trials with other GLP-1 agonists that will inform a recommendation on this class of agents for the prevention of HF.
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.

      Thiazolidinediones

      Two such drugs (pioglitazone and rosiglitazone) have each been shown to increase the risk of HF events.
      Prospective Pioglitazone Clinical Trial in Macro Vascular Events (PROactive)
      • Erdmann E.
      • Charbonnel B.
      • Wilcox R.G.
      • et al.
      Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: data from the PROactive study (PROactive 08).
      was a randomized study of 5238 type 2 diabetic patients, comparing pioglitazone with placebo. More pioglitazone (5.7%) than placebo patients (4.1%) had a serious HF event during the study (P = 0.007). Of patients in the placebo group, 108 needed hospital admission for HF (153 admissions) compared with 149 (209 admissions) in the pioglitazone group (HR, 1.41; 95% CI, 1.10-1.80; P = 0.007).
      Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD)
      • Komajda M.
      • McMurray J.J.
      • Beck-Nielsen H.
      • et al.
      Heart failure events with rosiglitazone in type 2 diabetes: data from the RECORD clinical trial.
      was an RCT of 4447 people with type 2 diabetes randomized to add-on rosiglitazone (n = 2220) or to a combination of metformin and sulfonylurea (n = 2227). Patients with any HF were excluded. Rosiglitazone-treated patients had a greater risk for at least 1 admission to hospital for HF compared with the placebo group (HR, 2.6; 95% CI, 1.1-4.1; P = 0.001). A meta-analysis of 42 trials of rosiglitazone
      • Nissen S.E.
      • Wolski K.
      Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.
      showed a 43% increase in MI and a 64% increase in death from cardiovascular causes with use of rosiglitazone.
      • 14.
        We recommend that thiazolidinediones should not be used in patients with HF (Strong Recommendation; High-Quality Evidence).

      5. Diagnosis of HF

      5.1 General considerations

      HF is a complex clinical syndrome in which abnormal heart function results in, or increases the subsequent risk of, clinical symptoms and signs of reduced cardiac output and/or pulmonary or systemic congestion at rest or with stress. The cardinal triad of edema, fatigue, and dyspnea is not a sensitive or a specific manifestation of HF, and atypical presentations should be recognized, particularly when evaluating women, obese patients, and elderly patients (Table 4). A thorough clinical history and physical examination should be performed in all patients, and initial investigations should be targeted to confirm or exclude HF as the diagnosis as well as to identify systemic disorders (eg, thyroid dysfunction) that might affect its development or progression (Fig. 1, Table 5). Measurement of plasma NPs is helpful because low concentrations are very useful in excluding HF and high concentrations can confirm HF in patients who present with dyspnea when the clinical diagnosis remains uncertain.
      • Moe G.W.
      BNP in the diagnosis and risk stratification of heart failure.
      Table 4Clinical presentations of heart failure
      CommonUncommon
      DyspneaCognitive impairment
      Might be a more common presentation in elderly patients.
      OrthopneaAltered mentation or delirium
      Might be a more common presentation in elderly patients.
      Paroxysmal nocturnal dyspneaNausea
      FatigueAbdominal discomfort
      WeaknessOliguria
      Exercise intoleranceAnorexia
      Dependent edemaCyanosis
      Cough
      Weight gain
      Abdominal distension
      Nocturia
      Cool extremities
      Might be a more common presentation in elderly patients.
      Figure thumbnail gr1
      Figure 1Algorithm for the diagnosis of heart failure in the ambulatory care setting. For patients with heart failure, a history, physical exam, and initial investigations should be supplemented with natriuretic peptides and/or imaging tests. Natriuretic peptides are not available in all jurisdictions in Canada. Includes systolic as well as diastolic parameters (eg, numeric left ventricular ejection fraction, transmitral and pulmonary venous flow patterns, or mitral annulus velocities); a preserved ejection function on a routine echocardiogram does not rule out the clinical syndrome of heart failure and therefore clinical judgement is required if other indicators point to heart failure as a diagnosis. A lower BNP cutoff for suspecting heart failure in the ambulatory setting facilitates earlier implementation of guideline-directed care. BNP, B-type natriuretic peptide; CBC, complete blood count; CMR, cardiac magnetic resonance; CT, computed tomography; MIBI, myocardial perfusion scan; MUGA, multigated acquisition scan; NT-proBNP, N-terminal propeptide B-type natriuretic peptide.
      Table 5Suggested timing for measurement of LVEF, according to clinical scenario
      Clinical scenarioTiming of measurementModality of measurementComments
      New-onset HFImmediately or within 2 weeks for baseline assessmentECHO (preferred when available); or CMRIReport should include numeric EF or small range of EF and diastolic function evaluation
      After titration of triple therapy for HFrEF, or consideration of ICD/CRT implantation3 months after completion of titrationECHO or CMRI (preferably the same modality and laboratory test as initial test)LVEF after medical therapy might increase, obviating device therapy
      Stable HFApproximately every 1-3 years, and possibly less frequent if EF is persistently > 40%ECHO or CMRIClinical rationale is to identify improving (better prognosis) or worsening ventricular function (worse prognosis, need for additional therapy such as ICD/CRT)
      After significant clinical event (ie, after some HF hospitalizations)Within 30 days, during hospitalization if possible; not necessary when repeated admissions occur without need to identify a causeECHO or CMRIFrequently helpful information such as EF, degree of valvular dysfunction, and RVSP
      Nuclear, computed tomography, or other measures are appropriate and acceptable in certain circumstances taking into account radiation, cost, and information gained.
      CMRI, cardiac magnetic resonance imaging; CRT, cardiac resynchronization therapy; ECHO, echocardiogram; EF, ejection fraction; HF, heart failure; HFrEF, heart failure with reduced EF; ICD, implantable cardioverter-defibrillator; LVEF, left ventricular EF; RVSP, right ventricular systolic pressure.
      Two-dimensional and Doppler transthoracic echocardiography are the initial imaging modalities of choice in patients suspected to have HF because they are used to assess systolic and diastolic ventricular function, wall thickness, chamber sizes, valvular function, and pericardial disease. Contrast echocardiography or radionuclide angiography might be useful in patients in whom echocardiographic images are poor. Cardiac catheterization with hemodynamic measurements and contrast ventriculography, computed tomography (CT), and CMR imaging can be used when other noninvasive tests are inconclusive and might be required for specific cardiomyopathies (see the section 7.5.1. Cardiomyopathies and Figs. 1 and 2).
      • 15.
        We recommend the choice of investigations should first be guided by careful history and physical examination and when clinical evidence suggests a possible cause and the planned test(s) result(s) would be reasonably expected to lead to a change in clinical care (Strong Recommendation; Low-Quality Evidence).
      • 16.
        We recommend that a 12-lead electrocardiogram (ECG) be performed to determine heart rhythm, heart rate, QRS duration, and morphology, and to detect possible etiologies (Strong Recommendation; Low-Quality Evidence).
      • 17.
        We recommend that echocardiography be performed in all patients with suspected HF to assess cardiac structure and function, to quantify systolic function for planning and monitoring of treatment, and for prognostic stratification (Strong Recommendation; Moderate-Quality Evidence).
      • 18.
        We recommend that cardiac magnetic resonance (CMR) imaging might be used when echocardiographic imaging (including contrast echocardiography) is nondiagnostic, or help to elucidate the etiologies (eg, myocarditis) (Strong Recommendation; Low-Quality Evidence).
      • 19.
        We recommend that in a patient suspected to have a cardiomyopathy, an inquiry should be made regarding family history, concomitant illnesses, previous malignancy requiring radiation or chemotherapy, symptoms of hypo- or hyperthyroidism, pheochromocytoma, acromegaly, previous travel, occupational exposure to chemicals or heavy metals, nutritional status, alternative medicine or naturopathic agents, illicit drug use, and exposure to HIV (Table 6, Table 7, Table 8) (Strong Recommendation; Low-Quality Evidence).
      • 20.
        We recommend that tachycardia-induced cardiomyopathy should be suspected when LVSD, with or without typical HF signs or symptoms, occurs with a persistent inappropriate tachycardia or tachyarrhythmia without another identified cause for the heart dysfunction (Strong Recommendation; Low-Quality Evidence).
      Figure thumbnail gr2
      Figure 2General guidance as to the workup to identify the most probable etiology for a patient's heart failure (HF). At all stages, a thorough clinical history and physical exam should aid in the selection of additional investigations. A detailed family history is invaluable, especially in patients who are younger or do not have an obvious etiology. Testing should be placed in context of the pretest probability, availability, and expertise of the test. More common etiologies (eg, coronary artery disease, hypertension) should be considered first, and further testing should be encouraged if another etiology is suspected in addition to a more common etiology (eg, hemachromatosis in a patient with known coronary artery disease). Patients might have mixed etiology of HF. A detailed medical and family history might guide investigations and should be completed in all patients (see Recommendation 19 in ). Direct testing on the basis of pretest probability, availability, and expertise. ARVC, arrhythmogenic right ventricular cardiomyopathy; CAD, coronary artery disease; CBC, complete blood count; CMP, cardiomyopathy; CMR, cardiac magnetic resonance; ECG, electrocardiogram; HCM, hypertrophic cardiomyopathy; HFmEF, heart failure with a midrange ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HTN, hypertension; Hx, history; LV, left ventricle; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; NP, natriuretic peptide; PPCM, peripartum cardiomyopathy; Rx, prescription; TSH, thyroid-stimulating hormone.
      Table 6Toxins associated with cardiomyopathies
      ToxinCausesSymptoms and signsDiagnosisTreatment
      AlcoholExcessive alcohol use.

      Heavy drinking: for women more than 1 drink per day and for men more than 2 drinks per day.

      Binge drinking: for women > 3 drinks and for men > 4 drinks
      Symptoms and signs of heart failure and/or chronic liver diseaseDetailed history, blood levelAbstaining from alcohol; usual heart failure medications
      Illicit drugs and medicationsHistory of drug or chemotherapy use.

      Might be related to the dose and duration.

      Includes herbal, nutraceutical, and alternative therapies
      Symptoms and signs of heart failureCareful history-taking of present or previous use of prescribed and over-the-counter medicationsDiscontinue the drug; supportive measures; usual heart failure medications
      Cocaine Methamphetamine, antidepressants, corticosteroids, anabolic steroids, phenothiazinesCocaine might cause thrombosis, coronary spasm, chest pain, and myocardial infraction. Might also cause myocarditis and aortic dissectionPrevious or recent history of cocaine use; urinary metabolitesCalcium channel blockers might be useful in cocaine-induced chest pain or coronary spasm
      Chemotherapy,
      • Virani S.A.
      • Dent S.
      • Brezden-Masley C.
      • et al.
      Canadian Cardiovascular Society guidelines for evaluation and management of cardiovascular complications of cancer therapy.
      anthracycline (doxorubicin, daunorubicin), bleomycin, adriamycin; cyclophosphamide; cytostatic agents; interferons, interleukin-2, trastuzumab
      Cardiotoxic drugs used to treat cancerSymptoms and signs of heart failure. Symptoms, signs, or history of malignancyHistory of malignancies with chemotherapy. Might need myocardial biopsyStandard heart failure treatment might reverse the abnormalities. Avoid using these agents again
      Heavy metals (cobalt, chromium, mercury, phosphorus, iron, gold, silver)Outbreaks of cardiomyopathy occurred among heavy consumers of cobalt-fortified beerThe 2 main target organs are the skin and the respiratory tract. Cobalt itself might cause allergic dermatitis, rhinitis, and asthmaAvoid exposure. Usual heart failure treatment
      HerbalChinese herbal mixture, blue cohoshSymptoms and signs of heart failureHistory of herbal product useStandard heart failure treatment
      RadiationRadiation might cause microcirculatory damage, interstitial fibrosis, accelerated atherosclerosisSymptoms and signs of diastolic heart failureHistory of radiationStandard heart failure treatment. Avoid further radiation
      Table 7Endocrine disorders associated with cardiomyopathies
      SyndromeCausesSymptoms and signsDiagnosisTreatment
      AcromegalyGrowth hormone and insulin-like growth factor 1 excessTachycardia and hypertension, diabetes, rhythm disturbances; biventricular hypertrophy and diastolic dysfunctionNonsuppressibility of serum growth hormone levels after glucose loadingSurgery or pharmacotherapy might improve cardiovascular morbidity
      Adrenal insufficiency (Addison disease)Lack of ACTHHypotension, hypokalemia, syncope, bradycardia, prolonged QT, low voltage, and heart failureDecrease response of the adrenal cortex to ACTHReplacement of the deficient steroid hydrocortisone
      Cushing diseaseExcess production of glucocorticoids and androgensHypertension, central obesity, proximal muscle weakness, myocardial infarction, stroke, and cardiomyopathyLack of appropriate suppression of cortisol secretion by dexamethasoneTreat specific cause
      Hypothyroidism (myxedema)Low production of T3 and T4Cardiac dilation, bradycardia, weak arterial pulses, angina, hypotension, distant heart sounds, low voltage, and peripheral edemaTSH, free T4Hormone replacement
      HyperthyroidismExcess production of T3 and T4Tachycardia, wide pulse pressure, hyperkinetic cardiac apex, high CO heart failureTSH, free T4Treat thyroid disease. Be careful with the use of β-blockers
      PheochromocytomaCatecholamine-producing tumourHypertension ‘paroxysmal,’ sweating, acute pulmonary edema, tachycardia, LVH, short PR interval, ST abnormalities, heart failure, myocarditisMetanephrine levelsPhenoxybenzamine hydrochloride, β-blockers, and surgery
      ACTH, adrenocorticotropic hormone; LVH, left ventricular hypertrophy; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone.
      Table 8Nutritional disorders associated with cardiomyopathies
      SyndromeCausesSymptoms and signsDiagnosisTreatment
      Carnitine deficiencyLow carnitine intakeSymptoms of heart failure; might see signs of malnutritionBlood level; endomyocardial biopsyExogenous carnitine administration
      Hypovitaminosis D and other causes of severe hypophosphatemiaInadequate endogenous production of vitamin D3; poor diet or malabsorptionRickets in children, osteomalacia in adultsGood history and physical. Ca, Mg; low 1,25(0H)2D; hypophosphatemiaTreat underlying cause; endocrine consultation; might need supplement
      Selenium deficiencySelenium deficiency is associated with heart failure in geographic areas where dietary selenium is lowSymptoms of heart failureHistory and physicalSelenium supplement
      Protein intake insufficient (kwashiorkor)Heart failure is most likely secondary to selenium deficit in infants and young childrenSymptoms of heart failure; hypothermia, hypotension, tachycardia, edema, low pulse volume, dermatitis, and othersHistory and physicalCorrection of fluid and electrolytes; management of associated problems
      Thiamine deficiency (beriberi)At least 3 months of diet deficient in thiamine (eg ‘polished rice’): alcoholEdema; high CO heart failure; peripheral neuritis; midsystolic murmur, third heart soundHistory and physical; decreased serum thiamine levelThiamine replacement
      Anorexia nervosaMalnutrition, poor dietSinus bradycardia, prolonged QT, arrhythmias, cardiomegalyHistory, physical, body mass index, electrolytes, blood urea nitrogen, creatinine, echocardiography, electrocardiogramSupportive; good nutrition; psychological support; monitor serum electrolytes
      Practical tip. Patients might have HF even without a history or current evidence of volume overload.
      Practical tip. An imaging-based assessment (typically with echocardiography) of valvular abnormalities should be done early in the diagnosis of HF.

      6. Biomarkers/NPs

      Biomarkers, for the context of this guideline, refer to substances measured in the blood other than commonly used laboratory tests and imaging studies. Several general criteria have been proposed for what constitutes a relevant biomarker in cardiovascular medicine.
      • Ahmad T.
      • Fiuzat M.
      • Pencina M.J.
      • et al.
      Charting a roadmap for heart failure biomarker studies.
      Over the past decade, the NPs became the gold standard for biomarkers in HF and have been extensively investigated in various clinical settings. NPs might be elevated in relation with other cardiovascular conditions leading to increased LV filling pressures, such as valvular heart disease, ischemia, or uncontrolled hypertension.
      • Burke M.A.
      • Cotts W.G.
      Interpretation of B-type natriuretic peptide in cardiac disease and other comorbid conditions.
      Noncardiac conditions, such as increasing age, renal dysfunction, anemia, pulmonary diseases, and sepsis have also been associated with increased NP levels.
      • Burke M.A.
      • Cotts W.G.
      Interpretation of B-type natriuretic peptide in cardiac disease and other comorbid conditions.
      • Thygesen K.
      • Mair J.
      • Mueller C.
      • et al.
      Recommendations for the use of natriuretic peptides in acute cardiac care: a position statement from the Study Group on Biomarkers in Cardiology of the ESC Working Group on Acute Cardiac Care.
      Obesity has been associated with lower NP levels.
      • Daniels L.B.
      • Clopton P.
      • Bhalla V.
      • et al.
      How obesity affects the cut-points for B-type natriuretic peptide in the diagnosis of acute heart failure. Results from the Breathing Not Properly Multinational Study.
      The prognostic utility of NPs has been shown in HF.
      • Moe G.W.
      • Ezekowitz J.A.
      • O'Meara E.
      • et al.
      The 2014 Canadian Cardiovascular Society heart failure management guidelines focus update: anemia, biomarkers, and recent therapeutic trial implications.
      • Ponikowski P.
      • Voors A.A.
      • Anker S.D.
      • et al.
      2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      • Yancy C.W.
      • 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.
      • van Veldhuisen D.J.
      • Linssen G.C.
      • Jaarsma T.
      • et al.
      B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction.
      The availability of NPs in Canada remains challenging because of the associated costs and/or the perceived variable effect on clinical decisions.
      • Sepehrvand N.
      • Bakal J.A.
      • Lin M.
      • et al.
      Factors associated with natriuretic peptide testing in patients presenting to emergency departments with suspected heart failure.
      The use of NPs does not eliminate the need for cardiac imaging in most cases. Hence, NPs provide additional evidence in favour of HF but need to be placed within the clinical context (Fig. 1).

      6.1 NPs and optimization of medical therapy

      One of the reasons for the so-called “mismatch” between risk and treatment is the lack of reliable markers to guide the titration of effective treatments. Persistently elevated or increasing NP levels are associated with an increased risk of hospitalization and mortality. In otherwise clinically stable patients with HF, a change in NP levels ≥ 30% between visits indicates a change greater than would be expected from daily variation
      • Troughton R.
      • Michael Felker G.
      • Januzzi Jr., J.L.
      Natriuretic peptide-guided heart failure management.
      and is likely clinically relevant and should therefore call for more intensive follow-up and/or intensified medical treatments.
      Data suggest that serial monitoring of NP levels can provide powerful information about response to therapy and residual risk.
      • Masson S.
      • Latini R.
      • Anand I.S.
      • et al.
      Direct comparison of B-type natriuretic peptide (BNP) and amino-terminal proBNP in a large population of patients with chronic and symptomatic heart failure: the Valsartan Heart Failure (Val-HeFT) data.
      • Doust J.A.
      • Pietrzak E.
      • Dobson A.
      • Glasziou P.
      How well does B-type natriuretic peptide predict death and cardiac events in patients with heart failure: systematic review.
      • Cleland J.G.
      • McMurray J.J.
      • Kjekshus J.
      • et al.
      Plasma concentration of amino-terminal pro-brain natriuretic peptide in chronic heart failure: prediction of cardiovascular events and interaction with the effects of rosuvastatin: a report from CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure).
      Initial studies on NP-guided therapy
      • Berger R.
      • Moertl D.
      • Peter S.
      • et al.
      N-terminal pro-B-type natriuretic peptide-guided, intensive patient management in addition to multidisciplinary care in chronic heart failure a 3-arm, prospective, randomized pilot study.
      • Sanders-van Wijk S.
      • Muzzarelli S.
      • Neuhaus M.
      • et al.
      Safety and tolerability of intensified, N-terminal pro brain natriuretic peptide-guided compared with standard medical therapy in elderly patients with congestive heart failure: results from TIME-CHF.
      • Motiwala S.R.
      • Januzzi Jr., J.L.
      The role of natriuretic peptides as biomarkers for guiding the management of chronic heart failure.
      have targeted a large reduction or a very low NP level in the intervention group; and generally compared this intervention with contemporary guideline-directed medical therapy (GDMT). Targeting a specific reduction in NP levels (or “NP-guided therapy”) has shown an improvement in clinical outcomes, although these studies were smaller and ongoing studies will provide further guidance.
      • Stienen S.
      • Salah K.
      • Moons A.H.
      • et al.
      Rationale and design of PRIMA II: a multicenter, randomized clinical trial to study the impact of in-hospital guidance for acute decompensated heart failure treatment by a predefined NT-PRoBNP target on the reduction of readmIssion and Mortality rAtes.
      • Felker G.M.
      • Ahmad T.
      • Anstrom K.J.
      • et al.
      Rationale and design of the GUIDE-IT study: guiding evidence based therapy using biomarker intensified treatment in heart failure.
      NP concentrations have been shown to decrease in response to commonly used therapies for either acute or chronic HF. This includes loop diuretics, ACE inhibitors (ACEis), ARBs, mineralocorticoid receptor antagonists (MRAs), and CRT.
      • Motiwala S.R.
      • Januzzi Jr., J.L.
      The role of natriuretic peptides as biomarkers for guiding the management of chronic heart failure.
      • Cleland J.
      • Freemantle N.
      • Ghio S.
      • et al.
      Predicting the long-term effects of cardiac resynchronization therapy on mortality from baseline variables and the early response a report from the CARE-HF (Cardiac Resynchronization in Heart Failure) Trial.
      • Shanmugam N.
      • Campos A.G.
      • Prada-Delgado O.
      • et al.
      Effect of atrioventricular optimization on circulating N-terminal pro brain natriuretic peptide following cardiac resynchronization therapy.
      With β-blockers, an initial increase in NP levels might be seen during the first 8-12 weeks followed by a decrease.
      • Davis M.E.
      • Richards A.M.
      • Nicholls M.G.
      • et al.
      Introduction of metoprolol increases plasma B-type cardiac natriuretic peptides in mild, stable heart failure.
      The interaction between NP levels and neprilysin inhibitors is more complex but evidence suggests that NT-proBNP might more reliably reflect the patient status at least in the first 8 months of treatment with sacubitril/valsartan (Fig. 3).
      • Packer M.
      • McMurray J.J.
      • Desai A.S.
      • et al.
      Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure.
      Figure thumbnail gr3
      Figure 3Algorithm for the use of natriuretic peptides in different heart failure (HF)-related clinical scenarios. Clinical evaluation and the risks and benefits of the action suggested should be considered. BNP, B-type natriuretic peptide; NT-proBNP, N-terminal propeptide B-type natriuretic peptide.

      6.1.1 HFpEF and NPs

      Although elevated NP levels have been proposed as an additional diagnostic criterion for HFpEF,
      • Paulus W.J.
      • Tschope C.
      • Sanderson J.E.
      • et al.
      How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology.
      older age and comorbidities common in this population might also influence NP levels.
      • Jeevanantham V.
      • Shrivastava R.
      • Nannapaneni S.
      • et al.
      Elevated B-type natriuretic peptide level: use with caution in patients with multiple co-morbidities and presenting with dyspnea.
      Among patients with HFpEF, the presence of an elevated NP level is an established marker of risk and discriminates prognosis comparable with that of HFrEF.
      • Carlsen C.M.
      • Bay M.
      • Kirk V.
      • et al.
      Prevalence and prognosis of heart failure with preserved ejection fraction and elevated N-terminal pro brain natriuretic peptide: a 10-year analysis from the Copenhagen Hospital Heart Failure Study.
      In the subset of 375 patients randomized in the Perindopril in Elderly People with Chronic Heart Failure Trial (PEP-CHF) with available measurements of NT-proBNP at baseline, those in the highest quartile (> 1035 pg/mL) had more than a fourfold risk of all-cause mortality or HF-related hospitalization over those in the lowest quartile (< 176 pg/mL), and this relationship was independent of therapy.
      • Cleland J.G.
      • Taylor J.
      • Freemantle N.
      • et al.
      Relationship between plasma concentrations of N-terminal pro brain natriuretic peptide and the characteristics and outcome of patients with a clinical diagnosis of diastolic heart failure: a report from the PEP-CHF study.
      Similarly, in the larger cohort of 3480 patients with measured NT-proBNP levels in the Irbesartan in Patients With Heart Failure and Preserved Ejection fraction (I-PRESERVE) trial, values above the median of 339 pg/mL at baseline were independently associated with a twofold increase in risk of all-cause mortality.
      • Anand I.S.
      • Rector T.S.
      • Cleland J.G.
      • et al.
      Prognostic value of baseline plasma amino-terminal pro-brain natriuretic peptide and its interactions with irbesartan treatment effects in patients with heart failure and preserved ejection fraction: findings from the I-PRESERVE trial.
      In the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial, patients randomized in the trial on the basis of elevated NPs derived outcome benefits from spironolactone, whereas those randomized on the basis of a previous hospitalization for HF did not.
      • Williamson J.D.
      • Supiano M.A.
      • Applegate W.B.
      • et al.
      Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥75 years: a randomized clinical trial.
      These findings might have been influenced by significant regional variations in the trial
      • Pfeffer M.A.
      • Claggett B.
      • Assmann S.F.
      • et al.
      Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial.
      but nevertheless, they show the utility of NPs in selecting patients who might respond to a specific treatment.
      • Ibrahim N.E.
      • Gaggin H.K.
      • Konstam M.A.
      • Januzzi Jr., J.L.
      Established and emerging roles of biomarkers in heart failure clinical trials.

      6.1.2 NPs for the diagnosis and management of HF

      The levels of NPs for ruling in and ruling out a diagnosis of HF are shown in Table 9. NP levels differ for the diagnosis of patients seen in the acute (eg, emergency department [ED]) vs in the outpatient settings. Several high-quality studies have reported on the utility of NPs for the diagnosis of HF in the outpatient setting where NPs are ideally suited to assist in ruling out HF as a diagnosis, but cannot be used independent of signs, symptoms, and other diagnostic information.
      • 21.
        We recommend that BNP/NT-proBNP levels be measured to help confirm or rule out a diagnosis of HF in the acute or ambulatory care setting in patients in whom the cause of dyspnea is in doubt (Strong Recommendation; High-Quality Evidence).
      Values and preferences. High-quality RCT evidence in the Canadian setting also shows favourable cost-effectiveness. Elevated NP levels are recommended as an additional diagnostic criterion for HFpEF and are associated with increased risk, although the levels might be lower than in HFrEF. Older age and comorbidities might also influence variations in NP levels.
      • 22.
        We recommend that measurement of BNP/NT-proBNP levels be considered in patients with an established diagnosis of HFrEF for prognostic stratification, in view of optimizing medical therapy (Strong Recommendation; High-Quality Evidence).
      Table 9Natriuretic peptide cut points for the diagnosis of HF
      Age, yearsHF is unlikelyHF is possible but other diagnoses need to be consideredHF is very likely
      Acute setting
       BNPAll< 100 pg/mL100-400 pg/mL> 400 pg/mL
       NT-proBNP< 50< 300 pg/mL300-450 pg/mL> 450 pg/mL
      50-75< 300 pg/mL450-900 pg/mL> 900 pg/mL
      > 75< 300 pg/mL900-1800 pg/mL> 1800 pg/mL
      Ambulatory care setting
       BNPAll< 50 pg/mL
       NT-proBNPAll< 125 pg/mL
      BNP, B-type natriuretic peptide; HF, heart failure; NT-proBNP, N-terminal propeptide BNP.
      Practical tip. For patients receiving an angiotensin receptor-neprilysin inhibitor (ARNI) (see section 7.1.1.5. ARNI), the use of NT-proBNP (rather than BNP) should be preferred to evaluate prognosis during the first year of treatment. BNP levels will be increased as a consequence of the ARNI's mechanisms of action over at least the first 8 months of treatment.

      6.1.3 NPs for the management of chronic HFrEF

      • 23.
        We suggest, in ambulatory patients with HFrEF, measurement of BNP or NT-proBNP to guide management should be considered to decrease HF-related hospitalizations and potentially reduce mortality. The benefit is uncertain in individuals older than 75 years of age (Weak Recommendation; Moderate-Quality Evidence).
      Values and preferences. These recommendations are on the basis of multiple small RCTs, most of which showed benefit, and 3 meta-analyses, which universally showed benefit. An ongoing RCT is likely to affect this recommendation.
      Practical tip. A change in NP levels by > 30% probably reflects more than daily variation in patients with compensated HF.
      Practical tip. The timing of NP measurements in outpatient settings should be dictated according to clinical status; NP measurements should be used when they might aid in clinical decision-making.

      6.1.4 NPs for the management of decompensated chronic HFrEF

      • 24.
        We suggest that measurement of BNP or NT-proBNP in patients hospitalized for HF should be considered before discharge, because of the prognostic value of these biomarkers in predicting rehospitalization and mortality (Strong Recommendation; Moderate-Quality Evidence).
      Values and preferences. This recommendation is on the basis of multiple small RCTs, all of which showed an association with clinical outcomes.
      Practical tip. A patient with persistently elevated NP levels might need closer follow-up to reduce the risk of rehospitalization.
      Practical tip. For patients who are about to be discharged from the hospital after a HF hospitalization, the NP level should be lower than that on admission. If NP levels remain elevated, clinicians should re-evaluate the patient's condition and consider the possibility of delaying discharge from the hospital to optimize therapy and further reduce the NP level.

      6.1.5 Myocardial injury, myocyte death, and troponins

      In the Valsartan in Heart Failure Trial (Val-HeFT), 10.4% of subjects had detectable cardiac troponin T (cTnT) with a fourth-generation clinical assay (detection limit 0.01 ng/mL) and this proportion increased to 92% when an hs assay (hs-cTnT; detection limit 0.001 ng/mL) was used.
      • Latini R.
      • Masson S.
      • Anand I.S.
      • et al.
      Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic heart failure.
      Although the pathophysiology of cardiac troponin release in HF remains uncertain, several factors including subendocardial ischemia and myocyte necrosis, cardiomyocyte damage from inflammatory cytokines, or oxidative stress, apoptosis, and leakage of troponin from the cytosolic pool due to increased membrane permeability have been invoked (Table 10).
      • Kociol R.D.
      • Pang P.S.
      • Gheorghiade M.
      • et al.
      Troponin elevation in heart failure prevalence, mechanisms, and clinical implications.
      The degree of troponin elevation is a powerful predictor of mortality and cardiovascular events in ambulatory as well as acutely decompensated patients with chronic HFrEF, even after adjustment for traditional risk predictors including NPs.
      • Latini R.
      • Masson S.
      • Anand I.S.
      • et al.
      Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic heart failure.
      • Pascual-Figal D.A.
      • Manzano-Fernandez S.
      • Boronat M.
      • et al.
      Soluble ST2, high-sensitivity troponin T- and N-terminal pro-B-type natriuretic peptide: complementary role for risk stratification in acutely decompensated heart failure.
      • Masson S.
      • Anand I.
      • Favero C.
      • et al.
      Serial measurement of cardiac troponin T using a highly sensitive assay in patients with chronic heart failure: data from 2 large randomized clinical trials.
      Limited data are available regarding the prognostic significance of cTnT elevations in the ambulatory population with HFpEF, although levels do appear to be elevated to an extent comparable with that seen in HFrEF.
      • Santhanakrishnan R.
      • Chong J.P.
      • Ng T.P.
      • et al.
      Growth differentiation factor 15, ST2, high-sensitivity troponin T, and N-terminal pro brain natriuretic peptide in heart failure with preserved vs. reduced ejection fraction.
      In an analysis of the Acute Decompensated Heart Failure National Registry (ADHERE) of 84,872 patients hospitalized with acutely decompensated congestive HF, patients with positive cardiac troponins had a higher in-hospital mortality independent of other predictive variables in patients with HF.
      • Peacock W.F.
      • De Marco T.
      • Fonarow G.C.
      • et al.
      Cardiac troponin and outcome in acute heart failure.
      Latini et al tested the prognostic value of the hs-cTnT assay in 4053 patients with chronic HF and showed that cTnT was detectable in 10.4% with the currently available assay compared with 92% using the hs-cTnT assay. Patients with hs-cTnT levels above the median had more severe HF and worse outcomes.
      • Latini R.
      • Masson S.
      • Anand I.S.
      • et al.
      Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic heart failure.
      • 25.
        We recommend that high-sensitivity (hs) troponins be measured on admission for AHF, to rule out ACS and for prognostic stratification (Strong Recommendation; High-Quality Evidence).
      Values and preferences. The degree of hs troponin elevation is a powerful predictor of mortality and cardiovascular events in ambulatory as well as acutely decompensated patients with chronic HFrEF, even after adjustment for traditional risk predictors including NPs. However, it is yet unclear how the use of serial hs troponin measurements in addition to NPs for HFrEF management would provide additional and cost-effective benefits in terms of improving outcomes. Also, limited data are available regarding the prognostic significance of hs troponin elevations in ambulatory patients with HFpEF.
      Table 10Selected biomarkers with potential for future clinical use in the management of HF
      Biomarker
      This list is not exhaustive; multiple biomarkers have been and are being studied.
      Pathophysiological pathways/comorbid conditions with prognostic implicationsHF populations targetedAdvantagesPotential benefitsChallenges before implementation
      Cardiac high-sensitivity troponinsMyocyte deathAcute and chronic HFVery sensitive marker predicting higher risk of CV events regardless of etiologyOptimization of therapy in patients with elevated hs-cTn should be more aggressivePrognostication improves only for mortality and use to modify therapy has not been tested
      sST2Fibrosis/inflammation/immunityAcute and chronic HFrEF, HFpEF, and previously low EF recoveredAdditional prognostic value beyond NPs suspected low week-to-week variationsCould provide additional value for short- and long-term prognostication, regardless of LVEFUnclear if using sST2 in acute or chronic HF to modify therapies improves clinical outcomes
      ProcalcitoninBacterial infectionAcute HFEarly detection of bacterial infectionGuiding antibiotic therapy in acute HF and suspected respiratory infectionLevels are increased in HF without ongoing bacterial infection. No clear cutoff has been identified in the HF population
      Galectin-3Cardiac and vascular fibrosisIncident HF, HFrEF, and HFpEFEarly detection of risk and long-term prognostication in HFPreventive measures and therapy optimization on the basis of levels could improve outcomesST2 might be superior to galectin-3 in a multivariable risk prediction model
      Cystatin CRenal functionAcute and chronic HFMore sensitive detection of changes in renal functionSame as aboveUnclear if using cystatin C, over using eGFR, to modify clinical management provides further clinical benefit
      NGALRenal functionAcute HFEarly detection of renal function deteriorationAdjusting therapy to improve prognosis by avoiding acute renal failure progressionUnclear if using NGAL in acute HF to modify therapies improves clinical outcomes
      CV, cardiovascular; EF, ejection fraction; eGFR, estimated glomerular filtration rate; HF, heart failure; HFpEF, HF with preserved ejection fraction; HFrEF, HF with reduced ejection fraction; hs-cTn, high-sensitivity cardiac troponin; LVEF, left ventricular ejection fraction; NGAL, neutrophil gelatinase-associated lipocalin; NPs, natriuretic peptides; sST2, soluble toll-like receptor-2; ST2, suppression of tumorigenicity 2.
      This list is not exhaustive; multiple biomarkers have been and are being studied.

      7. Treatment

      7.1 Chronic HF

      Pharmacotherapy has been shown to change the natural history of HFrEF. HFpEF however, has been identified as major public health issue and to date, the etiology, diagnosis, characterization, and treatment has remained challenging. Goals of HF therapy include improving survival and reducing morbidity such as hospitalizations and symptoms, while improving functional capacity and quality of life. Figure 4 shows a therapeutic approach to patients with HFrEF that is considered optimal medical therapy and defined as GDMT throughout this section. The evidence-based medications and doses of GDMT are shown in Table 11.
      Figure thumbnail gr4
      Figure 4Therapeutic approach to patients with symptoms of heart failure (HF) and a reduced ejection fraction. Sacubitril or valsartan. Refer to . ACEi, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; BB, β-blocker; bpm, beats per minute; CRT, cardiac resynchronization therapy; HR, heart rate; ICD, implantable cardioverter defibrillator; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; SR, sinus rhythm.
      Table 11Evidence-based drugs and oral doses as shown in large clinical trials
      DrugStart doseTarget dose
      ACEi
       Enalapril1.25-2.5 mg BID10 mg BID/20 BID in NYHA class IV
       Lisinopril2.5-5 mg daily20-35 mg daily
       Perindopril2-4 mg daily4-8 mg
       Ramipril1.25-2.5 mg BID5 mg BID
       Trandolapril1-2 mg daily4 mg daily
      ARB
       Candesartan4-8 mg daily32 mg daily
       Valsartan40 mg BID160 mg BID
      β-Blockers
       Carvedilol3.125 mg BID25 mg BID/50 mg BID (> 85 kg)
       Bisoprolol1.25 mg daily10 mg daily
       Metoprolol CR/XL
      Limited evidence of short-acting metoprolol tartrate in HF. Metoprolol CR/XL is not available in Canada.
      12.5-25 mg daily200 mg daily
      MRA
       Spironolactone12.5 mg daily50 mg daily
       Eplerenone25 mg daily50 mg daily
      ARNI
       Sacubitril/valsartan50-100 mg BID200 mg BID
      If inhibitor
       Ivabradine2.5-5 mg BID7.5 mg BID
      Vasodilators
       Isosorbide dinitrate20 mg TID40 mg TID
       Hydralazine37.5 mg TID75-100 mg TID or QID
      ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; BID, twice per day; HF, heart failure; If, inhibiting f-channel; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; QID, 4 times per day; TID, 3 times per day.
      Limited evidence of short-acting metoprolol tartrate in HF. Metoprolol CR/XL is not available in Canada.

      7.1.1 HFrEF pharmacological treatment

      Contemporary treatment for most patients with HFrEF encompasses triple therapy, which includes the combination of: (1) an ACEi (or ARB if ACEi-intolerant); (2) a β-blocker; and (3) an MRA. Working on various pathways of the neurohormonal system, the combination of these agents has been shown to improve survival in patients with HFrEF. There are many landmark trials and meta-analyses that support the use of ACEis
      • Pfeffer M.A.
      • Braunwald E.
      • Moye L.A.
      • 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.
      Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group.
      • Kober L.
      • Torp-Pedersen C.
      • Carlsen J.E.
      • et al.
      A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group.
      • Yusuf S.
      • Pitt B.
      • et al.
      SOLVD Investigators
      Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.
      • Garg R.
      • Yusuf S.
      Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials.
      • 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.
      Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.
      and β-blockers
      • Shibata M.C.
      • Flather M.D.
      • Wang D.
      Systematic review of the impact of beta blockers on mortality and hospital admissions in heart failure.
      • Dargie H.J.
      Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial.
      Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).
      The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.
      • Packer M.
      • Coats A.J.
      • Fowler M.B.
      • et al.
      Effect of carvedilol on survival in severe chronic heart failure.
      in all patients across the spectrum of HFrEF. ARBs have been shown to be superior to placebo in those intolerant to ACEis and are considered a good second-line agent.
      • Pfeffer M.A.
      • McMurray J.J.
      • Velazquez E.J.
      • et al.
      Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both.
      • Cohn J.N.
      • Tognoni G.
      Valsartan Heart Failure Trial Investigators
      A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure.
      • Granger C.B.
      • McMurray J.J.
      • Yusuf S.
      • et al.
      Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial.
      • Lee V.C.
      • Rhew D.C.
      • Dylan M.
      • et al.
      Meta-analysis: angiotensin-receptor blockers in chronic heart failure and high-risk acute myocardial infarction.
      Likewise, there are 2 key clinical trials and 1 meta-analysis
      • Ezekowitz J.A.
      • McAlister F.A.
      Aldosterone blockade and left ventricular dysfunction: a systematic review of randomized clinical trials.
      • Zannad F.
      • McMurray J.J.
      • Krum H.
      • et al.
      Eplerenone in patients with systolic heart failure and mild symptoms.
      • Pitt B.
      • Zannad F.
      • Remme W.J.
      • et al.
      The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators.
      that support the additional use of an MRA with this combination with an improvement in survival across the spectrum of symptomatic patients with HFrEF. Most recently, the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) expanded the use of aldosterone receptor antagonists in HFrEF patients with mild symptoms.
      • Zannad F.
      • McMurray J.J.
      • Krum H.
      • et al.
      Eplerenone in patients with systolic heart failure and mild symptoms.
      In EMPHASIS-HF the effects of eplerenone on clinical outcomes were examined in patients 55 years of age or older, with NYHA II symptoms, LVEF < 30% (if > 30%-35%, a QRS duration of > 130 ms), treated with an ACEi and/or ARB, and β-blockers. A total of 2737 patients with a median follow-up of 21 months were enrolled. There was a 37% reduction in the primary composite outcome of death from cardiovascular causes or first hospitalization for HF with eplerenone.

      7.1.1.1 Pharmacologic therapy

      In addition to initiating, titrating, and monitoring pharmacologic therapy, there are circumstances in which some therapies may be withdrawn (Table 12). There are additionally some common effects of GDMT requiring active surveillance and management. A suggested approach to hyperkalemia is presented in Table 13.
      • 26.
        We recommend that most patients with HFrEF be treated with triple therapy including an ACEi (or an ARB in those who are ACEi-intolerant), a β-blocker and an MRA unless specific contraindications exist (Strong Recommendation; Moderate-Quality Evidence).
      Values and preferences. Preference is given to the use of pharmacotherapy in most patients with HFrEF across the spectrum of symptoms. There are limited clinical trial data to inform decision-making surrounding the use of MRAs as part of GDMT in those without symptoms of HF or high-risk features.
      • 27.
        We recommend preferentially using the specific drugs at target doses that have been proven to be beneficial in clinical trials as optimal medical therapy. If these doses cannot be achieved, the maximally tolerated dose is acceptable (Table 11) (Strong Recommendation; High-Quality Evidence).
      Table 12Potential scenarios in which evidence-based medical therapy for heart failure might be withdrawn
      Clinical presentationConditions to justify stepwise withdrawal of GDMT after 6-12 months of full medical therapyComments
      Tachycardia-related CM
      • Normal EF and LV volumes
      • NYHA I
      • Underlying tachycardia controlled
      Usually due to atrial fibrillation/flutter with increased HR, might rarely occur because of PVCs. Might need long-term BB for rate control
      Alcoholic CM
      • Normal EF and LV volumes
      • NYHA I
      • Abstinence ETOH
      Nutritional deficiency, obesity, and obstructive sleep apnea might coexist and require therapy
      Chemotherapy-related CM
      • Normal EF and LV volumes
      • NYHA I
      • No further drug exposure
      Certain types of chemotherapy are more likely to reverse than others (trastuzumab—high rate of LVEF improvement when it is discontinued whereas patients who received anthracyclines should continue LV enhancement therapy)

      Long-term surveillance strongly recommended
      Peripartum CM
      • Normal EF and LV volumes
      • NYHA I
      Repeat pregnancy might be possible for some. Consultation at high-risk maternal centre should be undertaken
      Valve replacement surgery
      • Normal EF and LV volumes
      • NYHA I
      • Normally functioning valve
      Less consensus on regurgitant lesions with ongoing dilation of LV
      BB, β-blocker; CM, cardiomyopathy; EF, ejection fraction; ETOH, ethanol; GDMT, guideline-directed medical therapy; HR, heart rate; LV, left ventricle; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PVC, premature ventricular contraction.
      Table 13Suggested management approach for hyperkalemia, according to severity
      Severity of hyperkalemia
      The above actions are suggested on the basis of the assumption that the potassium level is correctly measured. For instance, hemolysis of blood might occur, which falsely increases the potassium level. In this instance, a repeat measure is necessary.
      Initial managementWhen to recheck electrolytes and potassiumWhen to restart and/or retitrate RAAS inhibitors
      Mild (serum K+ 5.0-5.5 mmol/L)
      • Continue all RAAS unless new and major increase in K+ (if so, stop most recently added RAAS agent)
      • Reinforce potassium restriction
      • Avoid other sources of K+
      • Ensure patient is not hypovolemic
      • Review all medications
      • Routine measurement unless K+ has been gradually increasing over time
      • If RAAS agent has been stopped, recheck within 72 hours
      • Usually not applicable
      • If RAAS agent has been stopped, restart when serum potassium decreases to within the patients usual level, or < 5.0 mmol/L, (whichever is higher) and
      • Any concomitant condition contributing to recent changes is under control
      Moderate (serum K+ 5.6-5.9 mmol/L)
      • Continue all RAAS at half previous dose unless K+ has been increasing over time or major increase in K+ (if so, stop most recently added RAAS agent)
      • Reinforce potassium restriction
      • Avoid other sources of K+
      • Ensure patient is not hypovolemic
      • Review all medications
      • Recheck K+ and renal function within 72 hours
      • With repeated K+ > 5.5, stop at least 1 RAAS agent and repeat measurement within 72 hours
      • With a second K+ > 5.5, consider calcium or sodium polystyrene 30 g administration
      • When serum potassium decreases to within the patients' usual level, or < 5.0 mmol/L, (whichever is higher) and
      • Any concomitant condition contributing to recent changes is under control
      • RAAS medications should usually be reintroduced 1 at a time with intervening measurement of renal function and electrolytes
      Serious or severe (serum K+ > 5.9 mmol/L)
      • Contact patient to proceed to health centres for clinical assessment and 12-lead electrocardiogram
      • Patient to undergo treatment according to local protocols for serious hyperkalemia
      • Hold all RAAS inhibiting agents until reassessment
      • Review all medications
      • Within 4-24 hours, depending on local acute hyperkalemia protocol (when symptomatic or if there are electrocardiographic changes consistent with hyperkalemia)
      • Again approximately 72 hours later
      • When serum potassium decreases to within the patients' usual level, or < 5.0 mmol/L, (whichever is higher) and
      • Any concomitant condition contributing to recent changes is under control
      • RAAS-inhibiting medications should usually be reintroduced 1 at a time with intervening measurement of renal function and electrolytes
      RAAS, renin-angiotensin-aldosterone system.
      The above actions are suggested on the basis of the assumption that the potassium level is correctly measured. For instance, hemolysis of blood might occur, which falsely increases the potassium level. In this instance, a repeat measure is necessary.
      Practical tip (general). If a drug with proven mortality or morbidity benefits does not appear to be tolerated by the patient (eg, low BP, low heart rate, or renal dysfunction), other concomitant drugs, including diuretics, with less proven benefit should be carefully re-evaluated to determine whether their dose can be reduced or the drug discontinued.
      Practical tip (general). HFrEF GDMT should be continued at the usual dose during acute intercurrent illness (eg, pneumonia, exacerbation of chronic obstructive pulmonary disease, other systemic infection, etc), unless they are not tolerated (eg, if significant reactive airway disease is present). GDMT should be restarted before discharge if temporarily withheld.
      Practical tip (general). In a life-threatening complication, GDMT may be discontinued abruptly, but generally, if there is concern about their use, the dose should be decreased by one-half, and the patient should be reassessed. If the dose is reduced, it should be uptitrated to the previous tolerated dose as soon as safely possible.
      Practical tip (general). If symptomatic hypotension persists with GDMT, consider separating the administration of the dose from the timing of other medications that could also lower BP.
      Practical tip (ACEi/ARB). ACEi intolerance describes a patient who is unable to tolerate ACEi therapy secondary to a bothersome cough (most commonly, 10%-20%) or those who experience angioedema with ACEi therapy (uncommon; < 1%). ARB therapy is a reasonable alternative in both of these cases, however, caution should be used in patients who develop angioedema while receiving ACEi therapy because there have been case reports of patients who subsequently develop angioedema with ARB therapy. There is no significant difference in rates of hypotension, hyperkalemia, or renal dysfunction between these agents to warrant a substitution between agents.
      Practical tip (ACEi/ARB). An increase in serum creatinine or eGFR of up to 30% is not unexpected when an ACEi or ARB is introduced; if the increase stabilizes at ≤ 30%, there is no immediate need to decrease the drug dose but closer long-term monitoring might be required.
      Practical tip (ACEi/ARB). BP might lower when an ACEi or ARB is introduced, especially if introduced at a high dose or in combination with diuretic therapy. Check BP with the patient supine and erect to detect whether hypotension is present, requiring slower uptitration.
      Practical tip (ACEi/ARB). Cough occurs in 10%-20% of patients receiving ACEis and does not require discontinuation of the agent unless it is bothersome to the patient.
      Practical tip (β-blockers). Objective improvement in cardiac function might not be apparent for 6-12 months after β-blocker initiation.
      Practical tip (β-blockers). Patients in NYHA class I or II can be safely initiated and titrated with a β-blocker by nonspecialist physicians.
      Practical tip (β-blockers). Patients in NYHA class III or IV should have their β-blocker therapy initiated by a specialist experienced in HF management and titrated in the setting of close follow-up, such as can be provided in a specialized clinic, if available.
      Practical tip (β-blockers). The starting dose of β-blockers should be low and increased slowly (eg, double the dose every 2-4 weeks). Transient fluid retention might occur with initiation or uptitration of β-blockers and might require assessment of diuretic dosage (eg, might consider deferring dosage reduction).
      Practical tip (β-blockers). If concomitant reactive airways disease is present, consider using more selective β-1 blockade (eg, bisoprolol).
      Practical tip (β-blockers). If atrioventricular (AV) block is present, consider decreasing other AV-blocking drugs, such as digoxin or amiodarone (when appropriate). The type and severity of AV block and the patient's history of arrhythmias will help guide the most appropriate treatment modifications.
      Practical tip (MRA). MRAs can increase serum potassium, especially during an acute dehydrating illness in which renal dysfunction can worsen, and close monitoring of serum creatinine and potassium is required. High-risk groups include those with diabetes, pre-existing renal dysfunction, and older age.

      7.1.1.2 ACEi/ARB

      There are extensive data on the use of ACEi and β-blocker treatment for patients with HFrEF to reduce morbidity and mortality and improve quality of life.
      • Flather M.D.
      • Yusuf S.
      • Kober L.
      • et al.
      Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group.
      • Shekelle P.G.
      • Rich M.W.
      • Morton S.C.
      • et al.
      Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta-analysis of major clinical trials.
      A notable deletion from these guidelines is the recommendation to consider combination ACEi and ARB therapy, previously recommended. The combination of an ACEi with an ARB is no longer recommended. Although some evidence exists to support a reduction in clinically relevant outcomes with the combination, there is also substantial evidence that was published after the previous recommendation, outlining harm in terms of adverse effects (eg, hypotension, hyperkalemia, and renal dysfunction).
      • Lee V.C.
      • Rhew D.C.
      • Dylan M.
      • et al.
      Meta-analysis: angiotensin-receptor blockers in chronic heart failure and high-risk acute myocardial infarction.
      • McMurray J.J.
      • Ostergren J.
      • Swedberg K.
      • et al.
      Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial.
      • Lakhdar R.
      • Al-Mallah M.H.
      • Lanfear D.E.
      Safety and tolerability of angiotensin-converting enzyme inhibitor versus the combination of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker in patients with left ventricular dysfunction: a systematic review and meta-analysis of randomized controlled trials.
      More contemporary treatments with MRAs and ARNIs have a stronger evidence base across the spectrum of outcomes (eg, morbidity and mortality) and therefore further limit the role of combination ACEi and ARB therapy.
      • 28.
        We recommend an ACEi, or ARB in those with ACEi intolerance, in patients with acute MI with HF or an EF < 40% post-MI to be used as soon as safely possible post-MI and be continued indefinitely (Strong Recommendation; High-Quality Evidence).

      7.1.1.3 β-Adrenergic receptor blocker (β-blocker)

      • 29.
        We recommend NYHA class IV patients be stabilized before initiation of a β-blocker (Strong Recommendation; High-Quality Evidence).
      • 30.
        We recommend that β-blockers be initiated as soon as possible after diagnosis of HF, including during the index hospitalization, provided that the patient is hemodynamically stable. Clinicians should not wait until hospital discharge to start a β-blocker in stabilized patients (Strong Recommendation; High-Quality Evidence).
      • 31.
        We recommend that β-blockers be initiated in all patients with an LVEF < 40% with previous MI (Strong Recommendation; Moderate-Quality Evidence).
      β-Blockers are part of the first-line therapy in the treatment of HFrEF, because they have been proven to improve survival and decrease hospitalizations in this population of patients, in a number of large clinical trials.
      • Dargie H.J.
      Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial.
      The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.
      • Packer M.
      • Bristow M.R.
      • Cohn J.N.
      • et al.
      The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group.
      • Hjalmarson A.
      • Goldstein S.
      • Fagerberg B.
      • et al.
      Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group.
      • Packer M.
      • Fowler M.B.
      • Roecker E.B.
      • 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.
      • Bristow M.R.
      • Gilbert E.M.
      • Abraham W.T.
      • et al.
      Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators.
      Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Australia/New Zealand Heart Failure Research Collaborative Group.
      A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). CIBIS Investigators and Committees.

      7.1.1.4 MRAs

      A single RCT supports the use of eplerenone (target 50 mg daily) compared with placebo post-MI.
      • Pitt B.
      • Remme W.
      • Zannad F.
      • et al.
      Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction.
      The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial enrolled 6642 patients who had an MI 3-14 days previously with an LVEF < 40% and symptoms of HF or an LVEF < 30% and diabetes without symptoms of HF. The primary outcome included all-cause mortality and cardiovascular mortality or hospitalization for cardiovascular events. After a median follow-up of 16 months, there was a 15% relative decrease in mortality and 13% relative decrease in cardiovascular mortality or hospitalization for cardiovascular events in the eplerenone group. There was more hyperkalemia in the eplerenone group.
      • 32.
        We recommend an MRA for patients with acute MI with EF < 40% and HF or with acute MI and an EF < 30% alone in the presence of diabetes (Strong Recommendation; High-Quality Evidence).

      7.1.1.5 ARNI

      In those who remain symptomatic despite triple therapy, consideration should be made to change an ACEi/ARB to an ARNI. Neprilysin, a neutral endopeptidase, degrades several endogenous vasoactive peptides, including NPs, bradykinin, and adrenomedullin. Inhibition of neprilysin increases the levels of these substances, countering the neurohormonal overactivation that contributes to vasoconstriction, sodium retention, and maladaptive remodelling.
      • Maric C.
      • Zheng W.
      • Walther T.
      Interactions between angiotensin II and atrial natriuretic peptide in renomedullary interstitial cells: the role of neutral endopeptidase.
      • Cruden N.L.
      • Fox K.A.
      • Ludlam C.A.
      • Johnston N.R.
      • Newby D.E.
      Neutral endopeptidase inhibition augments vascular actions of bradykinin in patients treated with angiotensin-converting enzyme inhibition.
      In the Prospective Comparison of ARNi With ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, the ARNI sacubitril/valsartan was compared with enalapril in patients with HFrEF.
      • McMurray J.J.
      • Packer M.
      • Desai A.S.
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      A total of 8442 patients were randomized to sacubitril/valsartan 200 mg twice daily or enalapril 10 mg twice daily after a 6-8 week run-in phase. Patients were included if they were NYHA class II-IV (70% class II), LVEF ≤ 40% (amended to ≤ 35%), had a BNP ≥ 150 pg/mL (or NT-proBNP ≥ 600 pg/mL), or hospitalization for HF in the past year and BNP ≥ 100 pg/mL (or NT-proBNP ≥ 400 pg/mL). The primary outcome was a composite of death from cardiovascular causes or hospitalization for HF. The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months. The primary outcome occurred in 914 patients (21.8%) in the sacubitril/valsartan group and 1117 patients (26.5%) in the enalapril group, a 20% relative reduction. There was also a decrease in all-cause mortality, cardiovascular mortality, HF hospitalization, and symptoms of HF. The sacubitril/valsartan group had a higher proportion of patients with hypotension but a smaller risk of renal impairment, hyperkalemia, and cough than the enalapril group. The type of patients and magnitude of effect were similar to other landmark trials in HFrEF including ACEis, β-blockers, and MRAs. This trial also closely reflects contemporary practice with high utilization of ACEis, β-blockers, and MRAs (100%, 92%, and 55%, respectively) at baseline and had an active gold standard comparator.
      • 33.
        We recommend that an ARNI be used in place of an ACEi or ARB, in patients with HFrEF, who remain symptomatic despite treatment with appropriate doses of GDMT to decrease cardiovascular death, HF hospitalizations, and symptoms (Strong Recommendation; High-Quality Evidence).
      Values and preferences. This recommendation places high value on medications proven in large trials to reduce mortality, HF re-hospitalization, and symptoms. It also considers the health economic implications of new medications.
      Practical tip. Drug tolerability, side effects, and laboratory monitoring with use of ARNIs is similar to that of ACEi or ARB noted previously.
      Practical tip. The PARADIGM-HF trial excluded patients with a serum potassium > 5.2 mmol/L, an eGFR < 30 mL/min, and symptomatic hypotension with a systolic BP of < 100 mm Hg.
      Practical tip. When switching between an ARNI and an ACEi, a washout period of at least 36 hours is required to decrease the risk of angioedema. No washout period is required for conversion between ARNIs and ARBs.
      Practical tip. ARNIs should not be used in anyone with a history of angioedema.
      Practical tip. Currently, there is only 1 ARNI, sacubitril-valsartan, available on the Canadian market. Initial dosing and rate of titration is dependent on pre-existing treatment and comorbidities and should be individualized (Table 14). When selecting a dose or titration schedule consideration should be given to the likelihood of tolerability and ultimately successful titration to doses shown to improve important HF outcomes.
      Table 14Potential valsartan/sacubitril dosing and titration
      ACEiARBInitial dose
      Health Canada labelled dose of 50 mg BID is 24.3 mg sacubitril/25.7 mg valsartan, 100 mg BID is 48.6 mg sacubitril/51.4 mg valsartan, and 200 mg is 97.2 mg sacubitril/102.8 mg valsartan.
      Titration
      Higher dose of RAAS inhibitor
       Enalapril ≥ 10 mg/dCandesartan ≥ 16 mg/d100 mg PO BIDOver 3-6 weeks, increase to target 200 mg PO BID
       Lisinopril ≥ 10 mg/dIrbesartan ≥ 150 mg/d
       Perindopril ≥ 4 mg/dLosartan ≥ 50 mg/d
       Ramipril ≥ 5 mg/dOlmesartan ≥ 10 mg/d
      Telmisartan ≥ 40 mg/d
      Valsartan ≥ 160 mg/d
      Lower dose of RAAS inhibitor50-100 mg PO BIDOver 6 weeks, increase to target 200 mg PO BID
      • Yusuf S.
      • Pitt B.
      • et al.
      SOLVD Investigators
      Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.
       Higher risk of hypotension (eg. low baseline SBP, poor renal function)50 mg PO BID
      ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; BID, twice per day; PO, orally; RAAS, renin-angiotensin-aldosterone system.
      Health Canada labelled dose of 50 mg BID is 24.3 mg sacubitril/25.7 mg valsartan, 100 mg BID is 48.6 mg sacubitril/51.4 mg valsartan, and 200 mg is 97.2 mg sacubitril/102.8 mg valsartan.

      7.1.1.6 Ivabradine

      Resting heart rate independently predicts CVD events, including HF hospitalization.
      • Diaz A.
      • Bourassa M.G.
      • Guertin M.C.
      • Tardif J.C.
      Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease.
      • Fox K.
      • Ford I.
      • Steg P.G.
      • et al.
      Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial.
      Systematic reviews have shown that a major contributor to the benefits of β-blocker therapy might be their rate-lowering effect.
      • McAlister F.A.
      • Wiebe N.
      • Ezekowitz J.A.
      • Leung A.A.
      • Armstrong P.W.
      Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure.
      • Komajda M.
      • Hanon O.
      • Hochadel M.
      • et al.
      Contemporary management of octogenarians hospitalized for heart failure in Europe: Euro Heart Failure Survey II.
      • Flannery G.
      • Gehrig-Mills R.
      • Billah B.
      • Krum H.
      Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving beta-blockers.
      Despite their benefits, β-blockers are generally underused and underdosed.
      • Komajda M.
      • Hanon O.
      • Hochadel M.
      • et al.
      Contemporary management of octogenarians hospitalized for heart failure in Europe: Euro Heart Failure Survey II.
      • Flannery G.
      • Gehrig-Mills R.
      • Billah B.
      • Krum H.
      Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving beta-blockers.
      • Komajda M.
      • Follath F.
      • Swedberg K.
      • et al.
      The EuroHeart Failure Survey programme–a survey on the quality of care among patients with heart failure in Europe. Part 2: treatment.
      Ivabradine is approved for the treatment of HF by Health Canada. The latter drug selectively inhibits the depolarizing If current in the sinus node. It thus requires sinus rhythm to provide its pharmacological effect. In contrast to β-blockers, ivabradine does so without lowering BP or myocardial contractility.
      • DiFrancesco D.
      • Borer J.S.
      The funny current: cellular basis for the control of heart rate.
      • Colin P.
      • Ghaleh B.
      • Monnet X.
      • et al.
      Contributions of heart rate and contractility to myocardial oxygen balance during exercise.
      The first trial to assess ivabradine in CAD was the Morbidity-Mortality Evaluation of the If Inhibitor Ivabradine in Patients With Coronary Disease and Left-Ventricular Dysfunction (BEAUTIFUL) trial.
      • Fox K.
      • Ford I.
      • Steg P.G.
      • et al.
      Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial.
      In this trial the effect of ivabradine 7.5 mg twice daily was evaluated in patients with CAD and LVEF < 40% in sinus rhythm with a heart rate > 60 bpm in > 10,000 patients. Although ivabradine did not reduce the primary composite end point of cardiovascular death, hospitalization for MI, or new-onset or worsening HF, it did reduce the incidence of the secondary end point of fatal and nonfatal MI in patients with a baseline heart rate ≥ 70 bpm.
      The Systolic Heart Failure Treatment With the If Inhibitor Ivabradine Trial (SHIFT) trial was the key trial to address the use of ivabradine in symptomatic HF.
      • Swedberg K.
      • Komajda M.
      • Bohm M.
      • et al.
      Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.
      Inclusion criteria were NYHA class II-IV, sinus rhythm, resting heart rate ≥ 70 bpm, LVEF ≤ 35%, and HF admission within 12 months. Patients were randomized to a target dose of ivabradine 7.5 mg twice daily vs placebo. The primary end point was a composite of cardiovascular death or HF admission. Ninety percent of patients were receiving a β-blocker, and 56% were receiving > 50% of target doses. Heart rate was 8 bpm lower in the ivabradine group at the end of the study. There was an 18% decrease in the primary outcome, which was largely driven by hospital admission for worsening HF (RRR, 26%). Treatment effect was consistent across prespecified subgroups, although the difference between treatment groups did not reach statistical significance in the subgroup with a baseline heart rate lower than the median of 77 bpm. Additionally, in those receiving > 50% of the target dose of a β-blocker, the overall trial results were similar. Ivabradine did not reduce all-cause or cardiovascular mortality. There were more withdrawals (21% vs 19%) and bradycardia in the ivabradine group (10% vs 2%). Only 1% of patients withdrew from the study as a consequence of bradycardia. Visual symptoms specific to ivabradine occurred rarely (3% vs 1% with placebo; P < 0.0001 and led to withdrawal in 1% of cases).
      • 34.
        We recommend that ivabradine be considered in patients with HFrEF, who remain symptomatic despite treatment with appropriate doses of GDMT, with a resting heart rate > 70 beats per minute (bpm), in sinus rhythm, and a previous HF hospitalization within 12 months, for the prevention of cardiovascular death and HF hospitalization (Strong Recommendation; Moderate-Quality Evidence).
      Values and preferences. High value is placed on the improvement of cardiovascular death and HF hospitalizations as adjunctive therapy to standard HF medication treatments in a selected HF population. The health economic implications are unknown. Differing criteria for heart rate eligibility have been approved by various regulatory authorities ranging from 70 to 77 bpm with the trial entry criteria of 70 bpm.
      Practical tip. Every effort should be made to achieve target or maximally tolerated doses of β-blockers before initiation of ivabradine.
      Practical tip. Ivabradine has no effect on BP or myocardial contractility.

      7.1.1.7 Hydralazine and isosorbide dinitrate

      Three RCTs inform the use of H-ISDN in HFrEF. The Vasodilator in Heart Failure Trial (V-HeFT) trial, the first RCT, compared the effect of H-ISDN, prazosin and placebo in HFrEF on mortality (n = 642).
      • Cohn J.N.
      • Archibald D.G.
      • Ziesche S.
      • et al.
      Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study.
      After a mean follow-up of 2.3 years, there was no difference in mortality for the entire follow-up period (primary outcome), but showed a 66% relative improvement in survival in the H-ISDN group at 2 years. This trial predated the era of ACEis and β-blockers. The second trial to evaluate H-ISDN (300 mg and 160 mg) compared with enalapril (20 mg daily) in HFrEF on the outcome of mortality (n = 804).
      • Cohn J.N.
      • Johnson G.
      • Ziesche S.
      • et al.
      A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure.
      There was a reduction in mortality in the enalapril arm after a mean of 2.5 years (32.8% vs 38.2%; P = 0.016) and no difference in hospitalizations. Neither of these trials provide an insight into the role of H-ISDN in the face of contemporary therapy. The third trial was the African-American Heart Failure Trial (A-HeFT) trial, in which H-ISDN was investigated in additional to optimal therapy (ACEi/ARB, β-blocker, MRA) in self-identified black patients with NYHA class III/IV HFrEF.
      • Taylor A.L.
      • Ziesche S.
      • Yancy C.
      • et al.
      Combination of isosorbide dinitrate and hydralazine in blacks with heart failure.
      Black patients were specifically evaluated in this trial because it had been noted that this population has a less active renin-angiotensin system and seemed to respond better to H-ISDN. In this trial H-ISDN (225 mg or 120 mg) was evaluated vs placebo (in addition to standard therapy) on the outcome of all-cause mortality, first hospitalization for HF, and quality of life. A total of 1050 black patients were enrolled and followed for a mean of 10 months. The study was terminated early secondary to higher mortality in the placebo group. The primary outcome was a weighted score, but individual components of the outcome showed a difference favouring H-ISDN for all-cause mortality, first hospitalization for HF, and change in quality of life score. It is unclear if these results can be extrapolated to other groups.
      • 35.
        We recommend the combination of hydralazine and isosorbide dinitrate (H-ISDN) be considered in addition to standard GDMT at appropriate doses for black patients with HFrEF and advanced symptoms (Strong Recommendation; Moderate-Quality Evidence).
      • 36.
        We recommend that H-ISDN be considered in patients with HFrEF who are unable to tolerate an ACEi, ARB, or ARNI because of hyperkalemia or renal dysfunction (Strong Recommendation; Low-Quality Evidence).
      Values and preferences. There is limited high-quality clinical trial evidence in the modern era from which to base an H-ISDN recommendation without considering the tolerability and adverse effects. Adverse effects related to H-ISDN are frequent, limit uptitration, and result in discontinuation in a significant proportion of patients. Every effort should be made to use ACEi/ARB/ARNI therapy including a low dose and/or rechallenge therapy before changing to H-ISDN.
      Practical tip. Renal dysfunction warranting a trial of H-ISDN includes those who have a significant change in creatinine from baseline with ACEi/ARB/ARNI therapy that persists despite modification of dose, rechallenge, and/or removal of other potentially nephrotoxic agents. It may also be considered in those with a serum creatinine (Scr) > 220 μmol/L who experience significant worsening in renal function with the use of ACEi/ARB/ARNI therapy, or in a trial of these agents (eg, potential worsened renal function requiring renal replacement therapy) is thought to outweigh benefits.
      Practical tip. Hyperkalemia warranting a trial of H-ISDN includes those with persistent hyperkalemia (K > 5.5 mmol/L) despite dietary intervention, dosage reduction of ACEi/ARB/ARNI, and removal of other agents known to increase potassium levels.
      Practical tip. Nitrates alone might be useful to relieve orthopnea, paroxysmal nocturnal dyspnea, exercise-induced dyspnea, or angina in patients when used as tablet, spray, or transdermal patch, but continuous (ie, around the clock) use should generally be avoided because most patients will develop tolerance.

      7.1.1.8 Digoxin

      The effect of digoxin on mortality and morbidity in patient with heart failure (Digitalis Investigation Group [DIG-trial])
      Digitalis Investigation Group
      The effect of digoxin on mortality and morbidity in patients with heart failure.
      enrolled 6800 patients with HF and a LVEF ≤ 45% and were randomized to digoxin (median dose 0.25 mg/d) or placebo. The primary outcome was mortality over a mean follow-up of 37 months. Fifty-four percent were NYHA class II and 94% of patients were receiving an ACEi. There was no difference in all-cause mortality. There was a decrease in HF-related deaths but an increase in “other cardiac deaths,” which has led to speculation that it might be due to arrhythmic death and led to an overall neutral effect on mortality. There were fewer patients hospitalized for HF in the digoxin group. Suspected digoxin toxicity was higher in the digoxin group (11.9% vs 7.9%). A systematic review included 13 studies (n = 7896, 88% of participants from the DIG-trial) showed similar results.
      • Hood Jr., W.B.
      • Dans A.L.
      • Guyatt G.H.
      • Jaeschke R.
      • McMurray J.J.
      Digitalis for treatment of heart failure in patients in sinus rhythm.
      None of these studies provide much insight into the relative benefit or harm of digoxin in light of contemporary therapy with β-blockers and MRAs, however, many landmark trials of these agents had a substantial background therapy of digoxin with no apparent change in the overall results if a patient was or was not receiving digoxin.
      • 37.
        We suggest digoxin be considered in patients with HFrEF in sinus rhythm who continue to have moderate to severe symptoms, despite appropriate doses of GDMT to relieve symptoms and reduce hospitalizations (Weak Recommendation; Moderate-Quality Evidence).
      Values and preferences. These recommendations place a high value on the understanding that the use of cardiac glycosides in HFrEF remains controversial in light of contemporary therapy, and digoxin had no effect on mortality, cardiovascular hospitalizations, exercise, or the primary end point in DIG-trial. Digoxin can cause atrial and ventricular arrhythmias particularly in the presence of hypokalemia or in the presence of worsening of renal function (with increased digoxin levels).
      Practical tip. In patients receiving digoxin, serum potassium and creatinine should be measured with increases in digoxin or diuretic dose, the addition or discontinuation of an interacting drug, or during a dehydrating illness, to reduce the risk of digoxin toxicity. Patients with reduced or fluctuating renal function, elderly patients, those with low body weight, and women are at increased risk of digoxin toxicity and might require more frequent monitoring including digoxin levels.
      Practical tip. Routine digoxin levels are not required other than to assess for digoxin toxicity. Digoxin levels should not be used to guide chronic therapy. Titration to digoxin levels has not been tested in clinical trials.

      7.1.1.9 Omega-3 polyunsaturated fatty acid

      The Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza cardiaca-Heart Failure (GISSI-HF) study was an RCT designed to assess the effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in HF.
      • Tavazzi L.
      • Maggioni A.P.
      • Marchioli R.
      • et al.
      Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.
      More than 4600 patients with NYHA class II to IV HF, irrespective of etiology or EF, were randomly assigned to a fish-based n-3 PUFA (daily 850 mg to 882 mg eicosapentaenoic acid and docosahexaenoic acid as ethyl esters in the average ratio of 1:1.2) or placebo. The primary end points were time to death, and time to death or admission to hospital for cardiovascular reasons. After a median 3.9-year follow-up, there was a decrease in both primary outcomes favouring n-3 PUFA (9% relative reduction in all-cause death and an 8% relative reduction in death or admission to hospital). The therapy was well tolerated with primarily gastrointestinal side effects, and fewer than 10% of patients required study drug withdrawal.
      Current sources of n-3 PUFA in Canada are food supplements, therefore, are not subject to the regulatory review (including predefined tolerances for drug content) that is required for any drug approval. As such, it is difficult to be certain of the amount of n-3 PUFA present in any given commercial preparation. Indeed, evidence suggests a large degree of variability between different available forms of n-3 PUFA.
      • Tatarczyk T.
      • Engl J.
      • Ciardi C.
      • et al.
      Analysis of long-chain omega-3 fatty acid content in fish-oil supplements.
      Patients and caregivers who wish to use n-3 PUFA are therefore referred to a local medical practitioner, pharmacy, or other reputable source of information to determine their best source of n-3 PUFA. Reports of excessive bleeding have been associated with doses < 3 g/d, but this remains controversial.
      • Villani A.M.
      • Crotty M.
      • Cleland L.G.
      • et al.
      Fish oil administration in older adults: is there potential for adverse events? A systematic review of the literature.
      • Kris-Etherton P.M.
      • Hill A.M.
      N-3 fatty acids: food or supplements?.
      • 38.
        We suggest n-3 PUFA therapy at a dose of 1 g/d be considered for reduction in morbidity and cardiovascular mortality in patients with HFrEF (Weak Recommendation; Moderate-Quality Evidence).
      Values and preferences. Although there is an effect of fish oils on important HF outcomes, this recommendation also considers the modest effect size and issues surrounding the lack of standardization of commercial preparations in Canada.
      Practical tip. With most data, the dose of n-3 PUFA is 1 g/d. It is unknown whether higher or lower doses would confer clinical benefit and they are therefore not suggested. Doses greater than 3 g/d are associated with excessive bleeding.
      Practical tip. n-3 PUFA therapy might affect measures of anticoagulation. Close monitoring of the international normalized ratio (INR) in patients receiving warfarin after institution of n-3 PUFA is suggested.
      Practical tip. There is evidence of significant variability in the content of n-3 PUFA. Patients considering n-3 PUFA should consult with their pharmacist to select a reliable supplement brand that most closely matches formulations shown to be effective in clinical trials.

      7.1.1.10 3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins)

      Many patients with HF have coexistent ischemic heart disease; however, these patients were systematically excluded from many of the early landmark statin trials. Two RCTs give insight into the benefit of statins specifically in patient with HF.
      The Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) study was an RCT of 5011 patients with HF that compared rosuvastatin 10 mg/d with placebo.
      • Kjekshus J.
      • Apetrei E.
      • Barrios V.
      • et al.
      Rosuvastatin in older patients with systolic heart failure.
      There was no difference in the primary end point of cardiovascular mortality, nonfatal MI, or nonfatal stroke. There was an 8% relative reduction in the secondary outcome of cardiovascular hospitalizations, but not HF hospitalizations. Rosuvastatin was well tolerated, with fewer withdrawals from therapy than with placebo. Despite achieving the expected low-density lipoprotein cholesterol-lowering of rosuvastatin, there was little benefit in this cohort of patients with CAD.
      • van der Harst P.
      • Voors A.A.
      • van Gilst W.H.
      • Bohm M.
      • van Veldhuisen D.J.
      Statins in the treatment of chronic heart failure: a systematic review.
      The second trial was the GISSI-HF study; 4574 patients with chronic HF, NYHA class II-IV, irrespective of cause and LVEF, were randomly assigned to rosuvastatin 10 mg/d or placebo, and followed for a median of 3.9 years.
      • Tavazzi L.
      • Maggioni A.P.
      • Marchioli R.
      • et al.
      Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.
      There was no difference in the primary end points of time to death, and time to death or admission to hospital for cardiovascular reasons. There was no difference in any other outcomes or subgroups.
      • 39.
        We recommend against statins used solely for the indication of HF in the absence of other indications for their use. Statin treatment should be in accordance with primary and secondary prevention guidelines for CVD (Strong Recommendation; High-Quality Evidence).
      Practical tip. Routine statin therapy is unlikely to provide clinical benefit for patients with HF due to nonischemic causes and in the absence of a very high risk of vascular events (such as recent MI, diabetes, and known vascular disease).
      Practical tip. In those already receiving statin therapy, it is reasonable to consider statin withdrawal in patients with advanced HF, in polypharmacy where risks outweighs benefits, or when palliative care is an overriding concern.

      7.1.1.11 Anticoagulation and antiplatelet therapy

      There are no RCTs that evaluate the role of ASA in comparison with placebo in patients with HF. A meta-analysis showed a reduction in serious vascular events, stroke, and coronary events with ASA therapy in secondary prevention trials.
      • Baigent C.
      • Blackwell L.
      • et al.
      Antithrombotic Trialists' (ATT) Collaboration
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      The 2 largest RCTs both compared warfarin with ASA (with or without clopidogrel) rather than placebo. The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial compared warfarin (INR, 2.5-3), ASA (162 mg) and clopidogrel (75 mg) in patients with HFrEF in sinus rhythm. A total of 1587 patients were followed for a mean of 1.9 years.
      • Massie B.M.
      • Collins J.F.
      • Ammon S.E.
      • et al.
      Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial.
      The study was stopped early secondary to poor recruitment. There was no difference in the primary end point of all-cause mortality, nonfatal MI, or nonfatal stroke in any of the groups. However, there was a reduction in stroke in the warfarin arm compared with the antiplatelet arms, but there was also a higher risk of bleeding in the warfarin group compared with the clopidogrel group. The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial, the largest trial to date, had similar results with a single comparison arm of ASA 325 mg daily vs warfarin (INR, 2-3.5). A total of 2305 patients were enrolled with a mean follow-up of 42 months.
      • Homma S.
      • Thompson J.L.
      • Pullicino P.M.
      • et al.
      Warfarin and aspirin in patients with heart failure and sinus rhythm.
      There was no difference in the primary outcome of ischemic stroke, intracerebral hemorrhage, or all-cause mortality, but there was a decrease in ischemic stroke and an increase in major hemorrhage for patients who received warfarin. In a meta-analysis of the 4 main RCTs, there was no difference in all-cause mortality, HF-related hospitalization, or nonfatal MI.
      • Hopper I.
      • Skiba M.
      • Krum H.
      Updated meta-analysis on antithrombotic therapy in patients with heart failure and sinus rhythm.
      There was a decrease in all cause stroke and ischemic stroke and an increase in major bleeding for patients who received warfarin.
      • Kumar G.
      • Goyal M.K.
      Warfarin versus aspirin for prevention of stroke in heart failure: a meta-analysis of randomized controlled clinical trials.
      The ongoing A Randomized, Double-blind, Event-driven, Multicenter Study Comparing the Efficacy and Safety of Rivaroxaban With Placebo for Reducing the Risk of Death, Myocardial Infarction or Stroke in Subjects With Heart Failure and Significant Coronary Artery Disease Following an Episode of Decompensated Heart Failure (COMMANDER-HF) trial is testing the additional use of rivaroxaban vs placebo in patients with sinus rhythm, HFrEF, and a recent hospital admission (NCT01877915).
      • 40.
        We recommend acetylsalicylic acid (ASA) at a dose of between 75 and 162 mg be considered only in patients with HFrEF with clear indications for secondary prevention of atherosclerotic cardiovascular events (Strong Recommendation; High-Quality Evidence).
      • 41.
        We recommend against routine anticoagulation use in patients with HFrEF who are in sinus rhythm and have no other indication for anticoagulation (Strong Recommendation; High-Quality Evidence).
      Anterior ST-elevation myocardial infarction (STEMI) and LV dysfunction has been associated with increased rates of LV thrombus and subsequent thrombotic complications. The rate of LV thrombus associated with anterior STEMI has decreased with more contemporary reperfusion strategies and DAPT. Historical rates range from 3% to 27%, depending on LV function.
      • Solheim S.
      • Seljeflot I.
      • Lunde K.
      • et al.
      Frequency of left ventricular thrombus in patients with anterior wall acute myocardial infarction treated with percutaneous coronary intervention and dual antiplatelet therapy.
      • Nikolsky E.
      • Mehran R.
      • Dangas G.D.
      • et al.
      Outcomes of patients treated with triple antithrombotic therapy after primary percutaneous coronary intervention for ST-elevation myocardial infarction (from the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI] trial).
      • Schwalm J.D.
      • Ahmad M.
      • Salehian O.
      • Eikelboom J.W.
      • Natarajan M.K.
      Warfarin after anterior myocardial infarction in current era of dual antiplatelet therapy: a randomized feasibility trial.
      However, rates of embolization are much more difficult to quantify. There are no prospective RCTs that address the role of anticoagulation in MI with low EF.
      A retrospective study of 460 patients done in 2015 evaluated the role of warfarin after primary PCI for anterior STEMI.
      • Le May M.R.
      • Acharya S.
      • Wells G.A.
      • et al.
      Prophylactic warfarin therapy after primary percutaneous coronary intervention for anterior ST-segment elevation myocardial infarction.
      Warfarin use was at the discretion of the attending physician and 131 patients were discharged receiving warfarin; 99% were discharged receiving DAPT. The rate of death, stroke, need for transfusion, and major bleeding was higher in the warfarin group. Other cohorts have shown similar results.
      • Udell J.A.
      • Wang J.T.
      • Gladstone D.J.
      • Tu J.V.
      Anticoagulation after anterior myocardial infarction and the risk of stroke.
      These data should be placed in context with emerging evidence for the use of DAPT as well as non-vitamin K antagonist oral anticoagulants in the setting of an ACS.
      • 42.
        We recommend against routine anticoagulation after large anterior MI and low EF, in the absence of intracardiac thrombus or other indications for anticoagulation (Weak Recommendation; Low-Quality Evidence).
      Values and preferences. High value is placed on the paucity of compelling evidence supporting efficacy and the potential for harm from bleeding according to the contemporary treatment recommendations with dual antiplatelet therapy (DAPT) post-MI, the emerging efficacy of direct oral anticoagulants after percutaneous coronary intervention (PCI), and the lack of high-quality trial evidence for anticoagulation with warfarin post-MI.
      Practical tips. Anticoagulation may be considered in those with an LV thrombus.
      Practical tip. If anticoagulation is used, a duration of 3 months before re-evaluating is reasonable.
      Practical tip. Either warfarin or a direct oral anticoagulant could be used for LV thrombus on the basis of the lack of trial evidence and mechanism of action.

      7.1.1.12 Anti-inflammatory medications

      Several studies have shown that nonsteroidal anti-inflammatory drugs increase the risk of HF. This includes new-onset HF as well as worsening HF outcomes such as hospitalizations and even mortality. There are inconsistent data regarding the safety of individual agents in HF, however most have been associated with negative cardiovascular effects.
      • Page J.
      • Henry D.
      Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem.
      • Heerdink E.R.
      • Leufkens H.G.
      • Herings R.M.
      • et al.
      NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics.
      • Mamdani M.
      • Juurlink D.N.
      • Lee D.S.
      • et al.
      Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study.
      • Gislason G.H.
      • Rasmussen J.N.
      • Abildstrom S.Z.
      • et al.
      Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure.
      • Hudson M.
      • Richard H.
      • Pilote L.
      Differences in outcomes of patients with congestive heart failure prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs: population based study.
      • Feenstra J.
      • Heerdink E.R.
      • Grobbee D.E.
      • Stricker B.H.
      Association of nonsteroidal anti-inflammatory drugs with first occurrence of heart failure and with relapsing heart failure: the Rotterdam Study.