Heart failure with reduced ejection fraction

Overview and definition

Picture a 64-year-old with breathlessness on stairs and ankle swelling, whose echo shows an LVEF of 45%. Under the 2021 ESC scheme he would have had HFmrEF. Under the 2026 ESC guideline he has HFrEF, and he gets the same foundational therapy as a patient with an LVEF of 25%.^[1]

Heart failure is a clinical syndrome of signs and/or symptoms caused by structural and/or functional cardiac abnormalities. Those abnormalities raise intracardiac pressures and/or leave cardiac output inadequate, at rest or on exercise.^[1] People in the asymptomatic stages are not counted as having HF. They are at risk (stage A) or have pre-HF (stage B).^[1]

Why move the line? HFmrEF patients resemble HFrEF patients in aetiology, and their pathophysiology is reduced contractility and systolic dysfunction, closer to HFrEF than to the stiff, diastolic picture of HFpEF.^[1] Many patients with LVEF 41–49% may also see their LVEF deteriorate.^[1]

Classification

LVEF: one cut-point, used as guidance

^{[1] [2]}

The 2021 ESC scheme had three bands: HFrEF 40% or less, HFmrEF 41–49% and HFpEF 50% or more. That scheme is now history.^[1] The 2021 Universal Definition, endorsed by the Cardiac Society of Australia and New Zealand, also uses 40% or less for HFrEF.^[2][3] It defines HF with improved EF as symptomatic HF with a baseline LVEF of 40% or less, a rise of at least 10 points from baseline and a second LVEF above 40%.^[3]

^[1]

Treat the number with humility. A single LVEF cut-point is somewhat arbitrary, measurement varies with modality and interpreter, and LVEF may read falsely high in some situations, for example mitral regurgitation.^[1] LVEF is a continuous measure that may differ between methods and by sex, so a precise value is only guidance.^[1]

Stages A to D

• Stage A: at risk for HF, without signs, symptoms or cardiac abnormalities.^[1]
• Stage B: pre-HF, with cardiac abnormalities but no signs or symptoms.^[1]
• Stage C: symptomatic HF, with cardiac abnormalities and current or prior signs and/or symptoms.^[1]
• Stage D: advanced HF.^[1]

HF can also be labelled de novo or pre-existing, and chronic or decompensated.^[1] Decompensated HF (DHF) replaces the term acute HF in 2026.^[1]

NYHA class

^[1]

The new therapy vocabulary

^[1]

ESC 2026 also uses a new level-of-evidence system for the first time, which is why you will see levels such as B1 and B2.^[1]

Epidemiology and risk factors

^[1]

Coronary artery disease is the most common cause of HFrEF.^[1] Common causes of HF include ischaemic heart disease, hypertension and valvular heart disease, but many other causes and contributors exist, and often more than one possible cause may be present.^[1]

Some causes might be reversible, for example Takotsubo syndrome, arrhythmia-associated HF, myocarditis and HF caused by abnormal cardiac conduction.^[1] Cancer treatments may also cause HF, through direct cardiotoxic effects or indirectly.^[1] Arrhythmia-associated HF covers AF, atrial flutter, other supraventricular tachycardias, ventricular tachycardia and premature ventricular contractions.^[1] Suspect conduction-related HF when LV dysfunction comes with a QRS of 130 ms or more and no other cause.^[1]

Pathophysiology

^{[24] [25] [27] [1]}

Start with the injury. Cardiac output falls, and the body defends the circulation by activating the sympathetic nervous system and the renin–angiotensin–aldosterone system (RAAS).^[24] In the short term these changes in the heart, kidneys and vasculature are designed to maintain homeostasis.^[24] With chronic activation, the same responses cause haemodynamic stress and damage the heart and circulation.^[24]

That chain explains the drugs. Neurohormonal activation is one of the main drivers of progression, so antagonising it became the cornerstone of HF pharmacotherapy.^[24] Modulating the RAAS and the sympathetic nervous system, and SGLT2 inhibition, improve survival, reduce HF hospitalisation (HFH) and reduce symptoms in HFrEF.^[1] Beta-blockers act on the sympathetic side, reversing the neurohumoral effects of the sympathetic nervous system.^[27] ACE-Is, ARNIs, ARBs and MRAs are the RAAS inhibitors.^[1]

The natriuretic peptide system pushes the other way. It promotes diuresis and vasodilation and inhibits the RAAS.^[25] Neprilysin degrades natriuretic peptides, bradykinin, adrenomedullin and other vasoactive peptides. An ARNI pairs an ARB with a neprilysin inhibitor.^[1]

SGLT2 inhibitor benefit is unlikely to come from glucose lowering.^[26] Proposed mechanisms include early natriuresis with a fall in plasma volume, a rise in haematocrit, better vascular function, lower blood pressure and altered tissue sodium handling.^[26]

Treatment can reverse remodelling and lift LVEF.^[1] In most patients LV function and structural abnormalities do not fully normalise, and symptoms or biomarker abnormalities may persist or recur.^[1]

Clinical presentation

^[1]

Less specific findings include peripheral oedema (ankle, sacral, scrotal), and confusion is a less typical symptom, especially in the elderly.^[1] Older patients may present atypically.^[1] Bendopnoea means breathlessness on bending forward.^[1]

Differential diagnosis and natriuretic peptides

Natriuretic peptides help, but they move with many other conditions. Read them against the patient in front of you.^[1]

^{[1] [1]}

The 2021 ESC guideline used a single rule-out threshold of NT-proBNP below 125 pg/mL. More than 75% of healthy people over 80 years exceed it.^[1] The HFA-ESC consensus statement on NT-proBNP testing recommends age-related thresholds, and ESC 2026 points to these age-adjusted outpatient cut-offs.^[1] In suspected decompensated HF the rule-out threshold is not age-adjusted: NT-proBNP below 300 pg/mL. If clinical suspicion remains despite values below the rule-out threshold, specialist assessment and echocardiography should be sought.^[1] NT-proBNP is unaffected by ARNI therapy, whereas ARNIs affect BNP degradation.^[1]

Investigations

All of these are Class I, level C in suspected HF: a laboratory screen, natriuretic peptides, a 12-lead ECG, a chest X-ray and a transthoracic echocardiogram.^[1] The laboratory screen is full blood count, eGFR and UACR, electrolytes, liver and thyroid function, HbA1c, lipids, and iron status (TSAT and ferritin).^[1]

In primary care data from England, patients with HF and NT-proBNP above 2000 pg/mL had a two-fold risk of early HFH. Expedited specialist assessment of this group is warranted.^[1]

^[1]

Late gadolinium enhancement on CMR helps separate ischaemic from non-ischaemic damage.^[1] Evidence that viability testing selects patients for revascularisation is lacking.^[1]

Management: foundational medical therapy

^[1]

The recommendations with class and level

^[1]

Table footnote: no large prospective RCT has tested beta-blockers or ACE-I/ARNI/ARB exclusively at LVEF 41–49%.^[1]

Loop diuretics are additional medical therapy, not FMT. Dynamic individualised loop diuretic dosing for signs and/or symptoms of congestion is Class I, level A. That level A is a Task Force judgement of clear clinical effectiveness; no adequately powered RCTs have been done or are likely, for ethical reasons.^[1]

The HFrEF evidence for MRAs comes from steroidal MRAs, spironolactone and eplerenone.^[1] SGLT2 inhibitors reduced CV mortality as an individual endpoint only in HFrEF.^[1]

How to start

There is no evidence favouring any sequence. By consensus, FMT can be commenced together as soon as HFrEF is diagnosed, with individual variations based on clinical assessment.^[1] Composite event rates were lower at target doses than at lower doses in dose-response trials.^[1] If targets cannot be reached, use the maximal tolerated dose.^[1]

AHA/ACC/HFSA 2022 allows its step 1 medications to start simultaneously at low doses, or sequentially without reaching target before adding the next.^[2]

Doses (selected agents, ESC 2026 Table 11)

^[1]

For lisinopril, a higher dose reduced morbidity/mortality compared with a lower dose, but there is no substantive placebo-controlled trial and the optimal dose is uncertain.^[1] Sacubitril–valsartan has an optional 24/26 mg twice-daily start for a history of symptomatic hypotension, ACE-I-naive patients and eGFR 30–60 mL/min/1.73 m².^[1] Carvedilol may go to 50 mg twice daily above 85 kg. Spironolactone can start at 12.5 mg when kidney function or potassium warrants caution.^[1]

ACE-I, ARNI and ARB

PARADIGM-HF randomised 8442 patients with NYHA II–IV HF and LVEF 40% or less to sacubitril–valsartan 200 mg twice daily or enalapril 10 mg twice daily.^[4][2] The primary composite of cardiovascular death or HF hospitalisation occurred in 21.8% with sacubitril–valsartan versus 26.5% with enalapril (HR 0.80); death from any cause occurred in 17.0% versus 19.8% (HR 0.84).^[4][2] Hypotension and non-serious angioedema were more frequent with ARNI; renal impairment, hyperkalaemia and cough were less frequent.^[4]

ESC states that an ARNI may be efficacious as de novo treatment in symptomatic chronic HFrEF, to simplify management and maintain eGFR and QoL.^[1] Pre- and post-discharge starts show similar efficacy and safety, with larger NT-proBNP falls than ACE-I in ACE-I/ARB-naive patients.^[1] Use ACE-Is and ARNIs cautiously with systolic pressure below 100 mmHg, eGFR below 30 mL/min/1.73 m² or potassium above 5.2 mEq/L, and avoid abrupt withdrawal.^[1]

ARBs do not inhibit kininases, so cough and angio-oedema are much rarer.^[1] No ARB has reduced all-cause mortality in any trial, and adding an ARB to an ACE-I increases adverse effects.^[1]

Beta-blockers

Bisoprolol, metoprolol succinate and carvedilol reduce death in HFrEF; nebivolol reduced only the combined endpoint of death and CV hospitalisation.^[1] Start early in clinically stable patients at low dose and uptitrate gradually to the highest tolerated dose. After admission with DHF, start cautiously in hospital once haemodynamically stable.^[1] Keep going even if symptoms do not improve.^[1]

• MERIT-HF: 3991 patients, NYHA II–IV, EF 0.40 or less; metoprolol CR/XL target 200 mg once daily; all-cause mortality RR 0.66, sudden death 0.59.^[9]
• CIBIS-II: 2647 patients, NYHA III–IV, LVEF 35% or less; bisoprolol mortality HR 0.66, sudden death HR 0.56.^[10]
• Carvedilol in severe chronic HF (Packer 2001): euvolaemic patients with EF below 25% and symptoms at rest or minimal exertion; carvedilol cut the risk of death by 35%.^[11][2]

MRAs

• RALES: severe HF, LVEF 35% or less, spironolactone 25 mg daily; death 35% with spironolactone versus 46% with placebo (RR 0.70); gynaecomastia or breast pain in 10% of men on spironolactone versus 1% on placebo.^[12][2]
• EMPHASIS-HF: NYHA II, EF 35% or less, eplerenone up to 50 mg daily; primary outcome (cardiovascular death or HF hospitalisation) HR 0.63; death 12.5% versus 15.5% (HR 0.76); potassium above 5.5 mmol/L in 11.8% versus 7.2%.^[13][2]

Eplerenone and finerenone cause less gynaecomastia because they are more receptor-specific.^[1] Start MRAs with caution in impaired kidney function (they are untested below eGFR 25 mL/min/1.73 m²) and at potassium 5.0 mmol/L or more.^[1] AHA/ACC/HFSA 2022 calls eGFR 30 or less, or potassium 5.0 mEq/L or more, contraindications to starting an MRA.^[2]

SGLT2 inhibitors

• DAPA-HF: 4744 patients, NYHA II–IV, EF 40% or less, dapagliflozin 10 mg daily; primary outcome (worsening HF or cardiovascular death) 16.3% versus 21.2% (HR 0.74); death from any cause HR 0.83; benefit regardless of diabetes.^[5]
• EMPEROR-Reduced: 3730 patients, empagliflozin 10 mg daily; primary outcome (cardiovascular death or HF hospitalisation) 19.4% versus 24.7% (HR 0.75); slower eGFR decline (−0.55 versus −2.28 mL/min/1.73 m² per year).^[6]

Expect genital and urinary infections and a mild early dip in eGFR; long-term kidney function improves.^[1] In people with established cardiovascular disease, a network meta-analysis found high-certainty evidence that SGLT2 inhibitors reduce HF hospitalisation.^[8]

LVEF 41–49%: now inside HFrEF

This is the group the 2026 reclassification moved. Be honest about the evidence: no large prospective RCT has been performed exclusively in LVEF 41–49%.^[1] These patients appear to respond to FMT like those with LVEF below 40%.^[1]

• An individual-patient meta-analysis of beta-blocker trials suggested similar mortality reductions with LVEF below 40% and 40–50% in sinus rhythm.^[1]
• A PEACE subgroup showed lower mortality with trandolapril at LVEF 40–50%.^[1]
• CHARM-Preserved was neutral on its primary endpoint, but a retrospective analysis found fewer HF hospitalisations with candesartan at LVEF 40–49%.^[1]

The table footnote states it directly: no large prospective RCT tested beta-blockers or ACE-I/ARNI/ARB exclusively at LVEF 41–49%.^[1] The SGLT2 inhibitor and MRA recommendations already cover symptomatic HF at any LVEF.^[1]

Additional medical therapy (AMT)

^[1]

Table 11 doses: digoxin 62.5 µg to 250 µg o.d., digitoxin 0.07 mg to 0.1 mg o.d., ivabradine 5 mg to 7.5 mg b.i.d., vericiguat 2.5 mg to 10 mg o.d., and hydralazine/isosorbide dinitrate 37.5/20 mg to 75/40 mg t.i.d.^[1] Titrate glycosides to plasma levels, aiming for a digoxin concentration below 1.2 ng/mL.^[1]

• Glycosides: DIG showed no mortality effect (34.8% versus 35.1%; RR 0.99) but fewer worsening-HF admissions (26.8% versus 34.7%; RR 0.72).^[16][1] DIGIT-HF enrolled chronic symptomatic HFrEF (LVEF 40% or less with NYHA III/IV, or LVEF 30% or less with NYHA II). Digitoxin reduced death or HFH (39.5% versus 44.1%; HR 0.82), without a significant reduction in death alone or HFH alone.^[1] Digoxin is primarily eliminated through the kidneys, whereas digitoxin undergoes hepatic elimination.^[1]
• Ivabradine: SHIFT enrolled symptomatic HF with LVEF 35% or lower, sinus rhythm at 70 beats/min or more, and a heart failure admission within the previous year. The primary endpoint fell from 29% to 24% (HR 0.82), driven mainly by HF admissions.^[17] ESC notes that only 25% of SHIFT patients were on optimal beta-blocker doses; because beta-blockers have well-proven morbidity and mortality benefits, they should be uptitrated to target first.^[1]
• Vericiguat: VICTORIA (EF below 45%, recent worsening) reduced CV death or first HFH (35.5% versus 38.5%; HR 0.90) without a significant CV death reduction.^[18][1] VICTOR, in ambulatory patients without recent worsening, was neutral on its primary endpoint (HR 0.93).^[1]
• Omecamtiv mecarbil modestly reduced HF events in GALACTIC-HF without a significant mortality benefit and is not approved for clinical use.^[1]

Devices (GDIT)

ICD

Arrhythmic sudden death caused about 30–60% of deaths in early HF trials.^[1] Antiarrhythmic drugs reduce ventricular arrhythmias but do not prolong survival and may shorten it.^[1]

^[1]

SCD-HeFT randomised 2521 patients with NYHA II–III and LVEF 35% or less. ICD versus placebo cut death by 23% (HR 0.77) with a 7.2-point absolute five-year benefit; amiodarone did no better than placebo (HR 1.06).^[14][1][2] MADIT-II enrolled 1232 post-MI patients with EF 0.30 or less; the ICD hazard ratio for death was 0.69.^[15][1]

Wait for FMT, but not for ever. A 3-month period after uptitration of FMT before considering ICD implantation is reasonable, while delay carries a sudden death risk of 2–4% by 6 months and about 7% by 1 year.^[1] Non-ischaemic patients may gain less than ischaemic patients, although a meta-analysis of RCTs still showed an overall survival benefit in non-ischaemic HF.^[1] Aetiology therefore changes device eligibility: a primary-prevention ICD is Class I, level B1 in ischaemic HFrEF but Class IIa, level B1 in non-ischaemic HFrEF.^[1]

CRT

^{[1] [1]}

Implanting CRT early, ideally before a first HFH, may benefit those most likely to respond (LVEF 35% or less, LBBB, QRS 150 ms or more).^[1] Conduction system pacing has no RCT with patient-centred outcomes in HFrEF, so ESC 2026 makes no recommendation.^[1]

Decompensation: what changes for chronic HFrEF

The acute topic covers DHF in depth. For the chronic HFrEF patient, four points matter.^[1]

1. Keep FMT going. Continue or rapidly reintroduce FMT; stop it only for clear hypoperfusion or a specific indication.^[1]
2. Decongest. IV loop diuretics are Class I, level A for DHF with fluid overload; again, the Task Force assigns level A for clear clinical benefit, and no adequately powered RCT has been or is likely to be done, for ethical reasons. Diuretic-naive patients usually respond to 40 mg IV furosemide; for patients already on loop diuretics, an IV dose of twice the usual oral dose should be considered.^[1] DOSE enrolled patients with chronic HF already taking 80–240 mg/day of oral furosemide (or equivalent), comparing a high IV dose (2.5 times the previous oral dose) with a low dose (equal to it). It found no significant difference in its co-primary endpoints (patients' global symptom assessment over 72 hours; change in creatinine at 72 hours) between bolus and infusion or between high and low dose. High dose showed a nonsignificant trend to better symptoms (P=0.06) and greater diuresis, but also transient worsening of renal function. Its authors note the findings may not apply to newly diagnosed HF or to patients with more modest diuretic requirements.^[19]
3. Start the SGLT2 inhibitor in hospital after initial stabilisation (Class I, level B1).^[1]
4. Read the blood pressure. IV vasodilators may be considered as initial therapy in DHF when systolic pressure is above 110 mmHg (IIb, C). Inotropes may be considered at systolic pressure below 90 mmHg with hypoperfusion that does not respond to standard treatment, including a fluid challenge (IIb, C).^[1]

STRONG-HF uptitrated to 100% of recommended doses within 2 weeks of discharge, with four visits over 2 months.^[22] HF readmission or all-cause death by day 180 occurred in 15.2% with high-intensity care versus 23.3% with usual care (RR 0.66).^[22] More adverse events by 90 days occurred with high-intensity care (41% versus 29%), but serious adverse events were similar (16% with high-intensity care versus 17% with usual care).^[22] ESC reports that the trial has been criticised for its highly selected population, suboptimal control-arm treatment and lack of SGLT2 inhibitors.^[1]

PIONEER-HF started sacubitril–valsartan after stabilisation: the time-averaged NT-proBNP reduction (weeks 4 and 8 versus baseline) was 46.7% with sacubitril–valsartan versus 25.3% with enalapril, with no significant difference in worsening renal function, hyperkalaemia, symptomatic hypotension or angioedema.^[20] TRANSITION's primary endpoint was the proportion reaching the 97/103 mg twice-daily target at 10 weeks: 45.4% with pre-discharge and 50.7% with post-discharge starts (RR 0.90), which the authors call comparable.^[21] AHA/ACC/HFSA 2022 recommends ARNi de novo before discharge in hospitalised acute HF.^[2]

Complications and pitfalls

Kidney function and potassium

• Misreading kidney function changes is a leading cause of under-dosing and inappropriate stopping.^[1]
• On an MRA with potassium above 5.5 mEq/L: recheck potassium first; there might then be an indication for dose reduction or temporary discontinuation, and the MRA is restarted if hyperkalaemia resolves.^[1]
• Severe hyperkalaemia (potassium above 5.5 or above 6 mmol/L) warrants temporary down-titration or discontinuation of MRAs and/or ARNI/ACE-I/ARB. AKI with eGFR below 15 may need a temporary pause of MRAs, ARNI/ACE-I/ARB and SGLT2 inhibitors.^[1]
• Potassium binders get no recommendation in 2026 because clinical benefit is unproven.^[1]

When to continue and when to pause FMT

In general, intercurrent illness or infection without haemodynamic compromise should not lead to down-titration or discontinuation of FMT. Asymptomatic or tolerable hypotension should not lead to down-titration or discontinuation of FMT, but may require re-evaluation of diuretic use.^[1] Temporary discontinuation of beta-blockers and ARNI/ACE-I/ARB is advised in severe haemodynamic instability. After a pause under 14 days, restarting at the previously tolerated dose is usually safe in stable patients.^[1]

Drugs to avoid

• Non-dihydropyridine calcium channel blockers (e.g. verapamil, diltiazem) and central sympathetic agonists (e.g. moxonidine) are contraindicated in HFrEF; if more antihypertensive treatment is needed, amlodipine or felodipine may be considered provided the patient is euvolaemic.^[1]
• Saxagliptin and glitazones are contraindicated in HF.^[1]
• Propafenone, flecainide and dronedarone are associated with poorer outcomes in HFrEF and should be avoided; amiodarone is recommended when pharmacological cardioversion is needed.^[1]
• Chronic thiazide use in stable patients should be avoided.^[1]

Improved LVEF: remission

TRED-HF, a small open-label trial, used phased withdrawal of FMT in patients with HFrEF and DCM whose LVEF had improved from below 40% to at least 50%, whose LV volume had normalised and whose NT-proBNP had fallen below 250 ng/L. HFrEF relapsed in 40% within 6 months.^[1] The small open-label CATHEDRAL-HF pilot (60 patients) found no higher relapse rate with phased withdrawal of FMT other than carvedilol, which was continued, compared with continued FMT. ESC still concludes that improvement is remission, which requires FMT to be maintained.^[1] Gradual discontinuation under frequent clinical, laboratory and imaging surveillance may be considered only in highly selected asymptomatic patients with complete normalisation of LV function, LV volume and natriuretic peptides after specific treatment of a reversible cause, to accommodate patient preference (Class IIb, level C).^[1]

AHA/ACC/HFSA 2022 labels a previous LVEF of 40% or less with a follow-up LVEF above 40% as HFimpEF (with no 10-point criterion). It says improvement does not mean full myocardial recovery, and that EF can decrease after drugs are withdrawn in many patients whose EF had improved to the normal range.^[2]

Special populations and scenarios

Atrial fibrillation. Beta-blockers are first-line rate control in stable HFrEF with AF (Class I, level C). In stable patients, digoxin should be considered if the rate stays high despite beta-blockers, or if beta-blockers are contraindicated or not tolerated (IIa, C).^[1] AV node ablation with CRT should be considered (IIa, B1) for severely symptomatic permanent AF with poor rate control despite medical therapy and at least one HFH.^[1] Catheter ablation should be considered (IIa, C) in selected patients with symptomatic AF and HFrEF; all of high AF burden, less than 1 year of continuous persistent AF, and a clear cause–effect link between AF and HF are required.^[1] Oral anticoagulation is recommended for clinical AF at elevated thromboembolic risk by CHA₂DS₂-VA score (I, A). Urgent cardioversion is recommended in DHF with rapid ventricular rates and haemodynamic instability (I, C); IV amiodarone or digoxin may be considered in haemodynamically unstable HFrEF with AF for acute rate control (IIb, C). DOACs are recommended in preference to VKAs (I, B1), except in moderate or severe mitral stenosis and mechanical prosthetic valves, where VKAs are recommended.^[1]

Coronary disease. Revascularisation for HF with obstructive CAD and persistent angina despite FMT and antianginal drugs is Class I, level C. If revascularisation is planned after Heart Team assessment, CABG should be considered as the preferred strategy with LVEF 35% or less and multivessel CAD suitable for surgery (IIa, B1).^[1]

Secondary mitral regurgitation. Mitral TEER is Class I, level B1 for stable symptomatic HFrEF with persistent severe secondary MR despite optimised FMT and CRT if indicated, in patients who fulfil specific clinical and echocardiographic criteria.^[1]

Diabetes. There is no evidence that type 2 diabetes alters the efficacy of FMT, and SGLT2 inhibitors are recommended regardless of HbA1c or other glucose-lowering drugs.^[1] In DAPA-HF, dapagliflozin helped whatever the background glucose-lowering therapy.^[7] SGLT2 inhibitors are not indicated in type 1 diabetes because of ketoacidosis risk.^[1]

Chronic kidney disease. No statistically significant interaction has been found between CKD and the effect of each FMT component on its trial's primary endpoint, and absolute benefit is larger because baseline risk is higher.^[1] Severe CKD remains an evidence gap.^[1]

Iron deficiency. The older definition, used in almost all recent IV iron trials, was ferritin below 100 ng/mL, or ferritin 100–299 ng/mL with TSAT below 20%. ESC 2026 supports the newer definition of TSAT below 20%.^[1] In symptomatic HFrEF with iron deficiency, IV iron is Class I, level B1 for symptoms and QoL, and IIa, B1 to reduce HFH.^[1] In IRONOUT-HF, oral iron polysaccharide 150 mg twice daily for 16 weeks left 76% still iron deficient (24% responded), and the post hoc analysis does not support routine use in symptomatic HFrEF with iron deficiency.^[23]

Cancer therapy. FMT is recommended for symptomatic HF that develops during cancer therapy, regardless of LVEF. FMT for HFrEF is also recommended for asymptomatic moderate-to-severe cancer therapy-related cardiac dysfunction, and should be considered in asymptomatic mild presentations.^[1]

Pregnancy. ACE-Is, ARBs, ARNIs, MRAs, ivabradine and SGLT2-Is are not recommended in pregnancy (Class III, level C). Switch non-selective beta-blockers to metoprolol or bisoprolol with close monitoring (I, C).^[1] Pre-conception counselling is recommended (I, C).^[1]

Older and frail patients. In patients with HF, frailty is particularly prevalent in older adults; when it is suspected or identified, a multidisciplinary approach to individualised management is warranted.^[1]

Stage B. In stage B HF, an ACE-I (or an ARB if ACE-I is not tolerated) is recommended with LVEF 40% or less (I, A), and a beta-blocker with LVEF below 50% (I, B1).^[1]

Prognosis and disposition

Medically treated advanced HF carries a 1-year mortality above 40%.^[1] Advanced HF needs all four ESC criteria despite FMT, AMT and GDIT. Criterion 1 is severe, persistent NYHA III–IV symptoms. Criterion 2 is severe cardiac dysfunction defined by at least one of: LVEF 30% or less; isolated RV failure (e.g. ARVC); or non-operable severe valve or congenital abnormalities. A further qualifying option is persistently high (or increasing) BNP or NT-proBNP with severe LV diastolic dysfunction or structural abnormalities (i.e. HFpEF, hypertrophic or restrictive cardiomyopathies). Criterion 3 is congestion needing high-dose IV diuretics (or diuretic combinations), or malignant arrhythmias, causing 2 or more unplanned visits or admissions in 12 months, or 1 or more low-output episodes needing inotropes or vasoactive drugs. Criterion 4 is severe impairment of exercise capacity estimated to be of cardiac origin: inability to exercise, a 6-min walk under 300 m, or peak VO₂ below 12–14 mL/kg/min (12 on a beta-blocker) or below 50% predicted.^[1]

ESC 2026 Table 15 lists a second set, the "rule of three", where at least one criterion also indicates high risk of advanced HF. These are HFH (2 or more, or 1 needing inotropes, within the last year), diuretic resistance, and intolerance of neurohormonal drugs with onset of cardiorenal syndrome.^[1] Systematic assessment with either set is essential for timely referral to an advanced HF centre.^[1]

Early consultation with an advanced HF centre (one performing LVAD implantation and/or heart transplantation) to evaluate candidacy is Class I, level A for patients with, or at risk of, advanced HF who are motivated and have no absolute contraindication to heart transplantation or durable MCS. The Task Force assigns level A for clear clinical effectiveness.^[1] In advanced HF, any down-titration of FMT should prompt that contact, if there are no absolute contraindications to MCS or transplantation.^[1] Integrated palliative care is recommended in advanced HF (I, B2).^[1]

For all patients with HF, a multidisciplinary HF programme is recommended (I, B1), and personalised exercise training within exercise-based cardiac rehabilitation is recommended for all stable patients without specific contraindications (I, B1).^[1] Remote PA pressure monitoring should be considered in symptomatic patients in NYHA III with an HFH in the past 12 months (IIa, B1).^[1] Trials of BNP- or NT-proBNP-guided therapy in HFrEF gave inconsistent results, and routine biomarker measurement to guide diuretic therapy is not supported.^[1] At follow-up, an ECG looks for QRS prolongation that may qualify for CRT, and echocardiography should be performed if there is clinical deterioration or if otherwise deemed relevant.^[1]

Evidence, guidelines and regional differences

What 2026 changed from 2021/2023.

• HFrEF expanded to LVEF below 50%; HFmrEF removed; decompensated HF replaces acute HF.^[1]
• MRA moved from an HFrEF-only Class I to Class I, A for symptomatic HF at any LVEF.^[1]
• Digoxin rose from IIb, B to a glycoside (digoxin or digitoxin) recommendation at IIa, B1 for symptomatic HFrEF with LVEF 40% or less despite optimal FMT.^[1]
• CRT instead of RV pacing for AV block moved from I, A to IIa, B1.^[1]
• Vericiguat stayed Class IIb but was rewritten: 2021 covered NYHA II–IV with worsening HF on ACE-I (or ARNI), beta-blocker and MRA (IIb, B); 2026 covers symptomatic HFrEF with LVEF below 45% despite optimal FMT (IIb, B1).^[1]
• Beta-blockers for AF rate control rose from IIa, B (patients with HF and AF) to I, C (stable HFrEF with AF, first-line).^[1]
• Uptitration of FMT at least every 1–2 weeks, and continuation of FMT at the highest tolerated doses (including after LVEF improves), became new Class I, level C recommendations.^[1]

ESC 2026 versus AHA/ACC/HFSA 2022.

• LVEF cut-off: below 50% (ESC) versus 40% or less, with HFmrEF at 41–49% plus raised filling pressures, and HFimpEF (US).^[1][2]
• MRA thresholds: caution with impaired kidney function (MRAs untested below eGFR 25) and potassium 5.0 mmol/L or more (ESC) versus contraindications to starting an MRA at eGFR 30 or less or potassium 5.0 mEq/L or more (US).^[1][2]
• Both require at least 36 hours between the last ACE-I dose and the first ARNI dose.^[1][2]

Australia and New Zealand (NHFA/CSANZ 2018)

The National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand (NHFA/CSANZ) published their Guidelines for the Prevention, Detection, and Management of Heart Failure in Australia in 2018; they were intended to replace the 2011 update.^[28] This section draws on the full guideline text published in Heart, Lung and Circulation, which gives guidance on the clinical care of adult patients with heart failure in Australia.^[28] Its recommendations were formulated with GRADE methodology, which gives the strength of a recommendation for or against an intervention; each row of the NHFA/CSANZ 2018 recommendation tables below condenses one selected recommendation and keeps its printed strength and quality of evidence.^[28] For topics with a limited evidence base, or where the impact of interventions on clinical outcomes was considered modest, the guideline includes comments in its practice advice sections.^[28] The guideline received final approval in June 2018, so it predates the AHA/ACC/HFSA 2022 and ESC 2026 guidelines used in the rest of this topic.^[28] Comparison rows set selected 2018 rows beside the matching ESC 2026 rows; any 2018 row that differs from a newer recommendation elsewhere in this topic should be read as history rather than current practice.^[28]

Classification and diagnosis

NHFA/CSANZ 2018 defines HFrEF as clinical symptoms with or without signs of heart failure and a measured LVEF below 50%.^[28] If the LVEF is only mildly reduced (41–49%), additional criteria are required, for example signs of heart failure, or diastolic dysfunction with high filling pressure demonstrated invasively, by echocardiography or by biomarker testing.^[28] The writing committee chose the 50% cut-off mainly for therapeutic reasons and did not recommend a separate mid-range (HFmrEF) category at that time.^[28] HFrEF in which the EF has improved to more than 50% with treatment should generally be considered and treated like HFrEF, because the pathophysiology is not believed to have changed in most cases.^[28] ESC 2026 defines HFrEF as LVEF below 50% with symptoms and/or signs of HF and has removed HFmrEF, whereas AHA/ACC/HFSA 2022 defines HFrEF as LVEF 40% or less and HFmrEF as LVEF 41–49% with evidence of spontaneous or provokable raised LV filling pressures.^[1][2]

^[28]

Pharmacotherapy

The ACE inhibitor, beta blocker, MRA and ARB rows each separate a moderate or severe reduction in LVEF (40% or less) from a mild reduction (41–49%), and the rows for the mild reduction are weak recommendations.^[28] A row worded "should be considered" can still carry a strong recommendation (ivabradine is an example), so read the strength column as well as the verb.^[28]

^[28]

Beside the 2018 rows for LVEF 41–49%, the 2022 Australian consensus statement (which calls this range HFmrEF) gives three new recommendations:^[29]

^[29]

ESC 2026 counts LVEF 41–49% as HFrEF; its rows for these drugs are set beside the 2018 rows in the comparison table below (LVEF 41–49%, SGLT2 inhibitors and intravenous iron rows).^[1]

Devices

^[28]

Multidisciplinary care

^[28]

Where ESC 2026 differs

Where the 2026 ESC guideline gives a different recommendation, the table sets the two side by side; read the 2018 column as history.^[28][1]

^{[28] [1]}

On starting therapy, the 2022 Australian consensus statement describes the 2018 HFrEF treatment algorithm as encouraging a step-wise approach after starting an ACE inhibitor, beta blocker and MRA.^[29] ESC 2026 instead states a consensus that FMT can be commenced together as soon as HFrEF is diagnosed, with individual variations based on clinical assessment.^[1]

Later Australian consensus statement (2022)

The 2022 consensus statement says the 2018 NHFA/CSANZ heart failure guidelines were not scheduled for review.^[29] Given this and high clinician interest, an academic group (Evidence to Practice) facilitated a working group of clinicians with expertise in the diagnosis and management of heart failure in Australia to develop a consensus statement on drug studies published since the 2018 guidelines.^[29] The 2022 statement uses HFrEF for LVEF 40% or less and HFmrEF for LVEF 41–49%, so its acronyms differ from the 2018 guideline.^[29][28] Its new HFrEF recommendations, with the strength and quality of evidence it prints, are:^[29]

^[29]

Beside the first three 2022 rows, ESC 2026 recommends an ACE-I or ARNI in symptomatic HFrEF (I, A), switching from an ACE-I or ARB to an ARNI in symptomatic HFrEF (I, B1), and dapagliflozin or empagliflozin in symptomatic HF independent of LVEF (I, A).^[1] ESC 2026 gives vericiguat Class IIb, level B1 in symptomatic HFrEF with LVEF below 45% despite optimal FMT, and says omecamtiv mecarbil is not currently approved for clinical use in HF.^[1] For intravenous iron, ESC 2026 recommends it in symptomatic HFrEF with iron deficiency to alleviate HF symptoms and improve QoL (I, B1), and says it should be considered to reduce the risk of HFH (IIa, B1).^[1]

Exam pearls

• HFrEF in 2026: LVEF below 50% plus symptoms and/or signs; US and Universal Definition still use 40% or less.^[1][2][3]
• FMT: beta-blocker, ACE-I/ARNI/ARB, MRA, SGLT2-I; SGLT2-I and MRA for symptomatic HF at any LVEF.^[1]
• Pace: uptitrate at least every 1–2 weeks; after HFH, rapid initiation and uptitration of FMT before discharge and at frequent follow-up visits in the first 6 weeks after an HFH.^[1]
• ICD (primary prevention): symptomatic NYHA II/III, LVEF 35% or less despite 3 months or more of optimal FMT, expected survival above 1 year with good functional status; ischaemic I, B1 (not within 40 days of MI); non-ischaemic IIa, B1.^[1]
• CRT: symptomatic HFrEF, LVEF 35% or less despite optimal FMT, sinus rhythm, LBBB with QRS 150 ms or more is I, A; QRS below 130 ms without a high-degree AV block pacing indication is III, A.^[1]
• Washout: at least 36 hours from ACE-I to ARNI.^[1][2]
• Ivabradine: symptomatic HFrEF, sinus rhythm, resting heart rate above 70 b.p.m., LVEF 35% or less, on the highest tolerated FMT including the beta-blocker.^[1]
• Trials: PARADIGM-HF HR 0.80; DAPA-HF HR 0.74; EMPEROR-Reduced HR 0.75; SCD-HeFT ICD HR 0.77; STRONG-HF RR 0.66.^{[4][5][6][14][22][1][2]}

References29ShowHide

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