2021 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure

Authors, Journal, Affiliations, Type, DOI

• Authors: Theresa A. McDonagh & Marco Metra (co-chairs); Task Force of the ESC Heart Failure Association
• Journal: European Heart Journal (2021) 42, 3599–3726
• Affiliations: King's College Hospital (London) & University of Brescia (Italy); pan-European multicentre
• Type: ESC Clinical Practice Guideline (replaces 2016 ESC HF Guideline)
• DOI: https://doi.org/10.1093/eurheartj/ehab368

Overview

The 2021 ESC Heart Failure Guidelines redefine the pharmacological and device management of heart failure across all ejection fraction categories. The most important advance is the introduction of SGLT2 inhibitors (dapagliflozin or empagliflozin) as a fourth foundational therapy alongside ACE-I/ARNI, beta-blockers, and MRA in HFrEF (Class I). The guideline formalises HFmrEF (LVEF 41–49%) as a distinct category and extensively updates management of comorbidities including atrial fibrillation, cardiomyopathies with genetic testing, diabetes, iron deficiency, and amyloidosis. It also updates cardiac rhythm management, advanced HF, and acute HF frameworks.

Keywords

Guidelines · heart failure · natriuretic peptides · ejection fraction · diagnosis · pharmacotherapy · neuro-hormonal antagonists · cardiac resynchronization therapy · mechanical circulatory support · transplantation · arrhythmias · comorbidities · hospitalization · multidisciplinary management · advanced heart failure · acute heart failure

Key Takeaways

Definition and Classification

• HF is a clinical syndrome of symptoms (dyspnoea, ankle swelling, fatigue) due to cardiac structural/functional abnormality causing elevated intracardiac pressures and/or inadequate cardiac output.
• Three phenotypes based on LVEF:
  • HFrEF: LVEF ≤40%
  • HFmrEF: LVEF 41–49% (renamed from "mid-range" to "mildly reduced")
  • HFpEF: LVEF ≥50% + objective evidence of diastolic dysfunction/raised filling pressures + elevated natriuretic peptides

Epidemiology and Prognosis

• HF affects ~1–2% of adults in developed countries, rising to >10% in those >70 years.
• ESC Long-Term Registry: 60% HFrEF, 24% HFmrEF, 16% HFpEF in outpatient setting.
• 1-year mortality ~20%, 5-year mortality ~53% (Olmsted County 2000–2010); 67% 5-year mortality in combined FHS/CHS cohort.
• HF hospitalizations: average once per year; 63% for non-CV causes. AF, higher BMI, high HbA1c, and low eGFR are strong predictors of HF hospitalizations.

HFrEF Pharmacotherapy — Four Pillars

• ACE-I (or ARNI as replacement): Class I — reduces mortality and HF hospitalisation. ARNI may now be considered as first-line instead of ACE-I.
• Beta-blocker: Class I — reduces mortality, HF hospitalisations, and symptoms.
• Mineralocorticoid receptor antagonist (MRA): Class I — reduces mortality and HF hospitalisation.
• SGLT2 inhibitors (dapagliflozin or empagliflozin): Class I (new recommendation) — reduces CV death and worsening HF regardless of diabetes status (EMPEROR-Reduced, DAPA-HF).
• Loop diuretics for fluid retention (symptom relief, Class I).

HFrEF Device Therapy

• ICD primary prevention: Class IIa (downgraded from Class I in 2016) for non-ischaemic DCM with LVEF ≤35% after ≥3 months OMT; Class I for ischaemic DCM.
• CRT: Class I for QRS ≥150 ms with LBBB morphology + LVEF ≤35%; Class IIa for QRS 130–149 ms with LBBB.

HFmrEF and HFpEF

• ACE-I, ARB, beta-blocker, MRA, and sacubitril/valsartan may each be considered for HFmrEF (Class IIb).
• HFpEF: no pharmacotherapy proven to reduce mortality; treatment focuses on screening and managing aetiologies and comorbidities (Class I).

Atrial Fibrillation in Heart Failure

• AF is highly prevalent in HF; its proportion increases with age and HF severity. AF causing HF (tachycardiomyopathy) has a more favourable course than AF developing in pre-existing chronic HF.
• Anticoagulation: DOACs recommended in preference to VKAs for all HF patients with AF, except those with moderate/severe mitral stenosis or mechanical prosthetic valves (Class I). LA appendage closure may be considered if OAC is contraindicated (Class IIb).
• Rate control: Lenient rate control (resting HR <110 bpm) is an acceptable initial approach. Beta-blockers recommended first-line (Class IIa). Digoxin/digitoxin may be added when rate remains high or beta-blockers are contraindicated (Class IIa). i.v. amiodarone for NYHA class IV/haemodynamic instability. AV node ablation Class IIb if medical rate control fails.
• Rhythm control: Urgent electrical cardioversion recommended in haemodynamically unstable patients with rapid ventricular response (Class I). Amiodarone is the only safe antiarrhythmic in HFrEF — other agents (propafenone, flecainide, dronedarone) associated with worse outcomes.
• EAST-AFNET 4 evidence: Early rhythm control in early AF (28.6% had HF) significantly reduced composite CV death/stroke/HF hospitalisation/ACS (HR ~0.79); catheter ablation used in only 19.4% of rhythm control arm.
• Catheter ablation: When paroxysmal/persistent AF is clearly associated with worsening HF symptoms persisting despite medical therapy, catheter ablation should be considered (Class IIa). CASTLE-AF demonstrated catheter ablation reduced all-cause death/HF hospitalisation vs. medical therapy in HFrEF with AF (HR 0.62; 51 vs. 82 events; P=0.007), though this was a highly selected population.
• Anticoagulation threshold: Long-term OAC should be considered for stroke prevention in AF patients with CHA2DS2-VASc score of 1 in men or 2 in women (Class IIa — updated from prior recommendation).

Cardiomyopathies and Genetic Testing

• CMPs are a heterogeneous group, major causes of HF. Prevalence: DCM ~1:250–1:500; HCM ~1:500–1:5000; AC ~1:1000–1:5000.
• Gene mutations occur in up to 40% of DCM, 60% of HCM, and 15% in chemotherapy-induced/alcoholic/peripartum CMPs. Prevalence >10% even in non-familial DCM.
• Minimum genetic panel for DCM/HNDC (Class I for all patients): TTN, LMNA, MYH7 (MHC), TNNT, troponin-C, MYPC, RBM20, PLN, SCN5a, BAG3, actin alpha cardiac muscle, nexilin, tropomyosin-1, vinculin.
• First-degree relatives of confirmed DCM/HNDC patients with pathogenic mutation should have clinical evaluation (ECG, echo, CMR) repeated every 5 years or less if <50 years old.
• Gene-specific treatment implications:
  • LMNA: Higher risk of SCD; early primary prevention ICD should be considered, guided by risk factors: NSVT, LVEF <45% at first evaluation, male sex, and non-missense (insertion/deletion/truncation/splicing) mutations. Risk increases exponentially with number of risk factors (9% with 1 → 69% with 4 risk factors).
  • TTN: Higher rate of LV reverse remodeling (up to 70% improve), but higher risk of both atrial and ventricular tachyarrhythmias.
  • RBM20, PLN, FLN: Higher risk of SCD — early primary prevention ICD should be considered.
• CMR with LGE, T1 mapping, extracellular volume: identifies fibrosis/scar (subendocardial in ischaemic disease; mid-wall in DCM), and enables tissue characterisation of myocarditis, amyloidosis, sarcoidosis, Chagas, Fabry, LV non-compaction, haemochromatosis, and AC.
• Endomyocardial biopsy: Gold standard for cardiac inflammation; minimum 5–7 samples; specific indications include giant cell myocarditis, eosinophilic myocarditis, sarcoidosis, vasculitis, SLE.
• TRED-HF pilot: Relapse of non-ischaemic DCM within 6 months in 44% of patients who had achieved partial/complete LVEF recovery (>40%) after withdrawal of medical treatment — supports continued therapy even after EF normalisation.
• Mavacamten (EXPLORER-HCM): Phase 3 RCT demonstrated improved exercise capacity, LVOT obstruction, NYHA class, and health status in obstructive HCM — first disease-specific treatment for inherited CMP.
• Amyloidosis: Tafamidis Class I for both hTTR-CA (NYHA I–II) and wtTTR-CA (NYHA I–II) to reduce symptoms, CV hospitalisation, and mortality.

Advanced Heart Failure

• Definition includes: ≥2 episodes of congestion or low output requiring IV diuretics/vasoactive agents in 12 months, severe and persistent HF symptoms (NYHA III–IV), severe cardiac dysfunction (any of: LVEF ≤30%, isolated RV failure, non-operable valve disease with LVEF <50%, pVO2 <12 mL/kg/min), ≥1 hospitalisation in prior 6 months.
• Heart transplantation: Class I for advanced HF refractory to medical/device therapy without absolute contraindications.
• Long-term LVAD (destination therapy): viable alternative when transplant is not an option.

Acute Heart Failure

• Modified classification: acutely decompensated HF, acute pulmonary oedema, isolated right ventricular failure, cardiogenic shock.
• Cardiogenic shock management: short-term MCS (IABP, Impella, ECMO) as bridge to recovery (BTR), bridge to decision (BTD), or bridge to bridge (BTB) — Class IIa.
• Vasodilators (i.v.) may be considered as initial therapy if SBP >110 mmHg (Class IIb — downgraded from IIa in 2016).
• Routine opiates NOT recommended (Class III — downgraded from IIb in 2016).

Other Comorbidities

• Diabetes: SGLT2 inhibitors recommended regardless of HF phenotype (Class I for T2DM at CV risk). DPP-4 inhibitor saxagliptin not recommended in HF (Class III).
• Iron deficiency: Screen all HF patients with FBC + ferritin + TSAT. IV ferric carboxymaltose Class IIa (serum ferritin <100 ng/mL or 100–299 ng/mL with TSAT <20%) in symptomatic HF recently hospitalised with LVEF ≤50%.
• Cancer/cardio-oncology: CV assessment before cardiotoxic therapy for at-risk patients (Class I); ACE-I + carvedilol should be considered if LVEF drops ≥10% to <50% during anthracycline therapy (Class IIa).

Limitations of the Document

• Guideline scope focuses on diagnosis and treatment of established HF; prevention of HF (including AF, hypertension, and asymptomatic LV dysfunction management) is addressed only briefly.
• Device therapy evidence base (ICD, CRT) remains predominantly from ischaemic DCM populations; non-ischaemic DCM recommendations rely more on subset analyses.
• HFpEF treatment section acknowledges near-absence of mortality-reducing pharmacotherapy evidence.
• CASTLE-AF (catheter ablation in HF + AF) enrolled a highly selected population; generalisability is limited.
• Genetic testing recommendations are anchored to the current state of the gene-disease knowledge base, which evolves rapidly; the minimum gene panel will need ongoing revision.

Key Concepts Mentioned

• concepts/CHA2DS2-VA — anticoagulation threshold in HF + AF (CHA2DS2-VASc score referenced throughout)
• concepts/Late-Gadolinium-Enhancement — CMR fibrosis characterisation in all CMP subtypes
• concepts/VA-Risk-Stratification-DCM — gene-specific risk stratification for ICD in DCM
• concepts/Catheter-Ablation-AF — CASTLE-AF evidence base for ablation in HFrEF
• concepts/Phenotypic-Approach-to-Cardiomyopathy — diagnostic workup framework
• concepts/Genetic-Testing-in-AF — minimum gene panel and testing indications

Key Entities Mentioned

• entities/Atrial-Fibrillation — management in HF; rate/rhythm control; catheter ablation; anticoagulation
• entities/LMNA — DCM high-risk genotype; ICD risk stratification with specific risk factors
• entities/TTN — most common DCM gene; LV reverse remodeling; atrial/ventricular arrhythmia risk
• entities/PKP2 — mentioned in AC context within cardiomyopathy table
• entities/DCM — genetic testing minimum panel; TRED-HF evidence; gene-specific outcomes
• entities/HCM — mavacamten (EXPLORER-HCM); genetic testing 60% yield
• entities/ATTR-Amyloidosis — tafamidis Class I recommendation (both hTTR and wtTTR)
• sources/EAST-AFNET4-NEJM-2020 — cited for early rhythm control in HF + AF context

Wiki Pages Updated

• wiki/sources/HF-ESC-2021.md (created)
• wiki/wikiindex.md (updated)
• wiki/entities/Atrial-Fibrillation.md (updated — HF+AF management, CASTLE-AF)
• wiki/entities/LMNA.md (updated — ESC 2021 ICD risk factors)
• wiki/entities/TTN.md (updated — LV reverse remodeling + arrhythmia risk)
• wiki/entities/DCM.md (updated — ESC 2021 genetic panel)
• wiki/concepts/Genetic-Testing-in-AF.md (updated — DCM minimum gene panel context)
• wiki/log.md (appended)