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Medical
therapy

Chapter 04 / From mechanism to treatment

Follow each treatment from its molecular action to its effect on the heart, kidneys and circulation.

01 / Disease-modifying treatment

Treat the drivers
that sustain the disease.

Reduced cardiac performance activates responses that initially defend perfusion. Persistent neurohormonal activation can then increase vascular resistance, retain sodium and promote adverse remodelling. Disease-modifying treatment interrupts these processes and reduces future clinical events; improvement is not measured solely by today's urine output.

The classic four treatment families below underpin care for systolic heart failure. Much of their landmark evidence enrolled patients with LVEF ≤40%. Benefits and recommendations at higher EF vary by drug: the 2026 ESC guidance supports SGLT2 inhibitors and MRAs across EF ranges, with drug-specific evidence. A shared receptor target does not make different medicines interchangeable.

Angiotensin and natriuretic peptides

Reduce the harmful signal.
Preserve the counter-signal.

ACE inhibitors, ARBs and ARNI intervene at different points in the same regulatory system.

Explore the mechanism

Select a state to see where treatment acts.

Qualitative pathway diagram. Arrows describe biological relationships, not measured flow, dose response or a validated haemodynamic simulation.

ACE inhibitors: ramipril, enalapril

Renin initiates the conversion of angiotensinogen to angiotensin I. ACE then produces angiotensin II. Ramipril is converted to ramiprilat, which inhibits ACE: less angiotensin II means less vasoconstriction and less stimulation of aldosterone release.

ACE also breaks down bradykinin. Inhibiting that breakdown contributes to vasodilatation, but also explains cough and part of the risk of angioedema. Lower vascular resistance reduces the load against which the ventricle ejects.

ARBs: candesartan, valsartan

ARBs block the angiotensin II type-1 receptor (AT₁), rather than preventing angiotensin II formation. Angiotensin II may still circulate, but its principal vasoconstrictor and aldosterone-stimulating signal is blocked.

They do not inhibit ACE-mediated bradykinin breakdown, so cough is less common. ARBs can provide an alternative when ACE inhibition is not tolerated and ARNI is unsuitable. Routine combined ACE inhibitor–ARB therapy is avoided because renal dysfunction, hyperkalaemia and hypotension increase.

ARNI: why combine sacubitril with valsartan?

Sacubitril is a prodrug whose active metabolite inhibits neprilysin, an enzyme that degrades several vasoactive peptides. Preserving natriuretic-peptide signalling increases membrane guanylyl-cyclase activity and cGMP: this favours vasodilatation, sodium excretion and anti-remodelling effects.

Neprilysin also handles other substrates, including angiotensin II. Its inhibition therefore needs accompanying RAAS blockade; valsartan blocks AT₁. Sacubitril/valsartan combines enhancement of a compensatory pathway with inhibition of a maladaptive one.

Mechanism meets practice. ARNI replaces an ACE inhibitor or ARB. Never combine them; allow at least 36 hours between ACE inhibitor and ARNI in either direction because of angioedema risk. Check blood pressure, renal function and potassium. NT-proBNP is not a neprilysin substrate; BNP interpretation is affected by neprilysin inhibition.

Sources: Ramipril SmPC · Candesartan SmPC · Sacubitril/valsartan SmPC

Sympathetic activation

Protect the heart from
persistent adrenergic drive.

An immediate reduction in stimulation can produce a longer-term improvement in ventricular function.

Explore the mechanism

Select a state to see where treatment acts.

Qualitative pathway diagram. Arrows describe biological relationships, not measured flow, dose response or a validated haemodynamic simulation.

What happens at the receptor?

Noradrenaline activates cardiac β₁ receptors. These couple to Gs proteins, adenylyl cyclase and cAMP, activating protein kinase A. Changes in calcium handling increase contraction and accelerate relaxation; pacemaker activity also increases.

That response helps during a short-lived demand. Persistent stimulation raises energy requirements and promotes arrhythmia, cellular injury and adverse remodelling. Beta-blockade reduces this adrenergic input. Renal β₁ blockade also reduces renin release.

Why can EF improve later?

Heart rate and contractility may initially fall. Over time, reduced catecholamine exposure and workload can favour reverse remodelling. The benefit is therefore not explained simply by making each beat stronger or by slowing the pulse alone.

Start and increase treatment when clinically stable; initiation or escalation during shock or marked hypoperfusion can be harmful. Assess perfusion, congestion, pulse and conduction rather than reacting to one heart-rate measurement.

The individual drugs are not identical

Bisoprolol and metoprolol succinate prolonged-release predominantly block β₁ receptors. Evidence relates to the studied drug and formulation, not every beta-blocker. Carvedilol blocks β₁ and β₂ receptors and also α₁ receptors, producing additional peripheral vasodilatation; blood pressure can therefore limit titration.

β₁ selectivity is relative, not an assurance that bronchospasm cannot occur. Bradycardia and atrioventricular block are predictable consequences of excessive nodal inhibition.

Sources: Bisoprolol SmPC · Carvedilol SmPC · β-adrenergic signalling

Mineralocorticoid signalling

Block aldosterone's
effects beyond salt retention.

MRAs act at an intracellular receptor that regulates gene expression.

Explore the mechanism

Select a state to see where treatment acts.

Qualitative pathway diagram. Arrows describe biological relationships, not measured flow, dose response or a validated haemodynamic simulation.

At the kidney

Aldosterone activates the mineralocorticoid receptor in the distal nephron. Its transcriptional effects favour sodium reabsorption through epithelial sodium channels and the sodium–potassium pump. Potassium secretion is promoted in the process.

Blocking this signal reduces sodium retention and reduces potassium excretion. This explains the potassium-sparing effect and the risk of hyperkalaemia. The natriuresis is not equivalent to the rapid decongestion achieved by a loop diuretic.

In the heart and vessels

Excess mineralocorticoid-receptor activation also promotes inflammatory and fibrotic pathways. Blocking it can limit adverse tissue remodelling. Upstream ACE inhibition or an ARB does not reliably abolish aldosterone activity, so an MRA adds a distinct site of action.

The clinical value is established by outcome trials, not by how much urine the patient produces after a dose.

Spironolactone, eplerenone and finerenone

Spironolactone is a steroidal competitive antagonist with effects at other steroid receptors; gynaecomastia and sexual adverse effects can limit treatment. Eplerenone is more selective for the mineralocorticoid receptor, with fewer sex-hormone effects. Both have established systolic-HF outcome evidence.

Finerenone is a selective, non-steroidal MRA. Its receptor complex inhibits recruitment of transcriptional coactivators involved in inflammatory and fibrotic signalling. Its HF evidence includes patients with LVEF ≥40%, and the current UK product information includes that indication. It is not an automatic substitute for a steroidal MRA in every phenotype, and two MRAs should not be combined.

The predictable trade-off: potassium can rise, especially with impaired renal function or other potassium-raising drugs. Check potassium and eGFR before treatment and after initiation or dose changes, using the drug-specific monitoring protocol.

Sources: Spironolactone SmPC · Eplerenone SmPC · Finerenone SmPC

Renal sodium–glucose transport

A renal target.
A cardiovascular benefit.

Dapagliflozin and empagliflozin improve HF outcomes even without diabetes.

Explore the mechanism

Select a state to see where treatment acts.

Qualitative pathway diagram. Arrows describe biological relationships, not measured flow, dose response or a validated haemodynamic simulation.

The established target

SGLT2 sits on the luminal surface of proximal tubular cells and reabsorbs filtered glucose together with sodium. Inhibition leaves more glucose in the tubular fluid and reduces proximal sodium reabsorption. Glucose in the urine produces osmotic diuresis.

Greater sodium delivery to the macula densa alters tubuloglomerular feedback, helping reduce intraglomerular pressure. An early, modest eGFR dip can reflect this haemodynamic change; it must still be interpreted alongside volume status and the clinical picture.

Why the benefit exceeds glucose lowering

Dapagliflozin and empagliflozin have shown benefit in HF populations with and without diabetes, across a broad EF range. Their glucose-lowering effect depends on filtered glucose and renal function; cardiovascular benefit cannot be reduced to a fall in HbA1c.

Changes in renal haemodynamics, volume distribution and cardiac loading likely contribute. Effects on energetics, cellular stress and other pathways remain under investigation. No single proposed mechanism fully explains the outcome benefit.

What the mechanism predicts in practice

Glycosuria increases susceptibility to genital fungal infection. Osmotic diuresis can contribute to volume depletion, particularly alongside other diuretics. Hypoglycaemia is uncommon with an SGLT2 inhibitor alone, but concomitant insulin or a sulfonylurea changes that risk.

Ketoacidosis can occur with only modestly elevated glucose. Give sick-day advice and interrupt treatment during major surgery or acute serious illness according to current guidance; reassess before restarting. SGLT2 inhibitors are not a substitute for loop diuretics when substantial congestion needs treatment.

Sources: Dapagliflozin SmPC · Empagliflozin SmPC

Clinical framework

2026 ESC heart failure guidelines. Mechanisms are supported by the linked product information. Drug choice, licensing, eligibility and monitoring remain phenotype- and patient-specific. This first section covers the foundational treatment families; selected additional therapies will be developed with the phenotype-specific section.

Content reviewed: 30 October 2026.

02 / Decongestion and haemodynamics

Diuretics reduce renal sodium reabsorption so that sodium and water leave the body. The aim is to relieve pulmonary and systemic congestion while maintaining perfusion. A larger urine volume is useful only when it moves the patient towards that goal.

Fluid accumulation

Sustained sodium retention expands extracellular volume. Removing sodium and water can reduce venous pressures, oedema and breathlessness. Loop diuretics are the main pharmacological starting point for significant fluid overload.

Fluid redistribution

Acute pulmonary oedema can also reflect a rapid shift of blood into the central circulation, with little change in total body water. Blood pressure, afterload and respiratory support matter alongside diuresis. Hypoperfusion or shock requires urgent haemodynamic assessment rather than automatic diuretic escalation.

Interactive nephron / Sites of action

Choose a drug or a combination. The highlighted segments show which sodium-reabsorbing pathways are targeted.

Glomerular filtrate

↓

Proximal tubule
Carbonic anhydrase

↓

Descending limb

↓

Thick ascending limb
NKCC2

↓

Distal convoluted tubule
NCC

↓

Collecting duct → urine

Qualitative teaching schematic, not anatomical scale or a validated renal simulation. Highlighting indicates a drug target, not complete transport inhibition or a predicted urine output. Distal-blockade examples use either metolazone or hydrochlorothiazide, not both.

01 / Furosemide — inhibit sodium transport in the loop

Furosemide reaches the tubular lumen through proximal tubular secretion and inhibits NKCC2, the sodium–potassium–2 chloride cotransporter in the thick ascending limb. This reduces sodium chloride reclamation and disrupts the medullary concentration gradient, promoting natriuresis and diuresis.

More sodium reaches downstream segments, increasing potassium loss. Magnesium and calcium excretion also increase. Volume contraction and enhanced distal sodium delivery can contribute to hypokalaemic metabolic alkalosis.

The response depends on enough drug reaching its luminal target. Oral absorption can be variable; gut congestion, reduced renal delivery and competing organic anions can limit response. Intravenous administration bypasses absorption, but does not remove renal causes of resistance. Assess the effect of the administered dose before escalating.

02 / Bumetanide — the same target, different delivery

Bumetanide also inhibits loop NKCC2. It is more potent per milligram, with oral bioavailability reported at approximately 80–95%, making absorption more predictable than with furosemide. The relevant comparison is an equivalent diuretic exposure, not an equal milligram dose.

Switching can help when oral delivery is unreliable; it does not provide a second nephron target. Combining furosemide and bumetanide is therefore not sequential nephron blockade. Bumetanide shares the risks of volume depletion, hypokalaemia, hypomagnesaemia and renal-function changes. Dose conversion must account for route and response using the local protocol.

03 / Metolazone — reduce downstream sodium recovery

Metolazone is a thiazide-like diuretic, usually taught as distal sodium–chloride cotransporter (NCC) blockade. Its predominant cortical diluting-site action limits sodium recovery downstream from the loop; additional proximal effects have also been described.

With repeated loop exposure, downstream sodium reabsorption can compensate for the blocked loop segment. Adding metolazone can interrupt that compensation and produce a substantial diuresis, including in patients with low GFR. Its prolonged effect means losses can continue after the initial response.

Combination treatment needs close assessment of sodium, potassium, renal function and volume status. Metolazone preparations are not automatically interchangeable: the MHRA warns of formulation-dependent absorption and bioavailability. Prescribe and review the specific preparation.

04 / Hydrochlorothiazide — distal blockade with trial evidence

Hydrochlorothiazide inhibits NCC in the early distal convoluted tubule, reducing sodium chloride reabsorption. Combined with a loop, it limits downstream compensation. More sodium reaching later nephron segments can increase potassium and hydrogen-ion secretion, contributing to hypokalaemia and alkalosis; hyponatraemia is another important risk.

Hydrochlorothiazide and metolazone occupy a similar therapeutic role here. Use a selected distal agent rather than assuming that combining both adds a complementary mechanism. Hydrochlorothiazide's evidence in acute HF comes from addition to intravenous loop treatment, not replacement of the loop.

05 / Acetazolamide — reduce proximal bicarbonate reclamation

Carbonic anhydrase enables the reactions that support bicarbonate reabsorption in the proximal tubule. Inhibiting it with acetazolamide reduces sodium bicarbonate recovery, increasing delivery of sodium and bicarbonate to downstream segments. When paired with a loop diuretic, this targets an additional, upstream site.

Urinary bicarbonate loss lowers plasma bicarbonate. This can be useful when congestion coexists with metabolic alkalosis, but can cause or worsen metabolic acidosis. Acetazolamide is not a potassium-sparing drug. Check bicarbonate, potassium and renal function, as well as the clinical response.

The contemporary acute-HF trial evidence concerns a short course of intravenous acetazolamide. Do not automatically extrapolate it to long-term oral treatment or severe renal dysfunction outside the studied population.

What the 2026 ESC recommendation actually covers

For patients with fluid overload already treated with loop diuretics, short-term addition of intravenous acetazolamide or oral hydrochlorothiazide should be considered to improve decongestion: Class IIa, level B1. This supports combination treatment in an appropriate monitored setting; it does not establish a mortality benefit or require both add-on drugs together.

ADVOR / 519 patients

Acetazolamide: more successful early decongestion

IV acetazolamide 500 mg once daily was added to standardised IV loop treatment. Successful decongestion within three days occurred in 42.2% versus 30.5% with placebo. This was an early decongestion endpoint, not evidence of improved survival.

Patients with eGFR below 20 mL/min/1.73 m², systolic BP below 90 mmHg or concurrent SGLT2-inhibitor treatment were excluded. A subsequent renal analysis found more transient worsening renal function during treatment, emphasising the need to interpret creatinine alongside achieved decongestion.

CLOROTIC / 230 patients

Hydrochlorothiazide: more weight loss, more renal dysfunction

Oral hydrochlorothiazide, with dose determined by eGFR, was added to IV furosemide. Weight loss at 72 hours was greater: 2.3 versus 1.5 kg. Patient-reported breathlessness did not significantly improve compared with placebo.

The prespecified renal impairment endpoint occurred in 46.5% versus 17.2%. The trial stopped early because recruitment was slow and did not establish a mortality or rehospitalisation benefit. Increased fluid loss must be balanced against renal and electrolyte effects.

When the response is disappointing

01 / Reassess

Is congestion still present?

Review JVP, oedema, pulmonary findings, symptoms and perfusion. Persistent breathlessness alone does not prove that more fluid should be removed.

02 / Delivery

Has the loop reached its target?

Review route, dose, timing, urine output, sodium intake and interfering medicines such as NSAIDs. In acute care, an early spot urine sodium can help assess natriuretic response alongside urine volume.

03 / Complement

Target another segment if needed

After reviewing loop exposure, consider a proximal or distal add-on. Choose according to renal function, bicarbonate, electrolytes and the clinical setting, then reassess rather than leaving combination therapy unreviewed.

Monitor the patient, not one number

Follow weight and fluid balance alongside congestion, blood pressure and perfusion. Check sodium, potassium, magnesium, bicarbonate and renal function; hospital combination treatment commonly needs at least daily blood tests and more frequent checks when unstable. A creatinine rise during effective decongestion can be functional, but hypotension, oliguria, progressive renal dysfunction or electrolyte disturbance require prompt review. Once euvolaemia is reached, reassess the add-on and use the lowest maintenance diuretic exposure that prevents recurrent congestion.

Sources: 2026 ESC HF guidance · HFA diuretic position statement · Furosemide · Bumetanide · Metolazone pharmacology · MHRA metolazone advice · Hydrochlorothiazide · Acetazolamide · ADVOR · ADVOR renal analysis · CLOROTIC

Reviewed 30 October 2026. Trial doses describe the evidence; they are not an individual prescribing protocol.

03 / Phenotype-specific strategies

Which feature changes
the treatment?

Start with foundational therapy and control congestion. Then ask what remains treatable: iron deficiency, persistent symptoms with reduced EF, obesity-related HFpEF, rhythm or the underlying cause. These features can coexist; choosing one does not exclude the others.

Iron deficiency: treat the deficit, not just the haemoglobin

Iron supports oxygen transport and mitochondrial energy production in cardiac and skeletal muscle. A normal haemoglobin does not exclude iron deficiency. Replacing iron can improve functional status without being an anaemia treatment alone.

Iron availability is reducedConsider iron indices even when haemoglobin is normal

↓

Intravenous iron replacementFerric carboxymaltose or ferric derisomaltose: evidence-based preparations

↓

Replenish iron available to tissuesAssess symptoms, function and iron status again

Conceptual pathway, not a quantitative prediction of response.

Identify the phenotype

Check haemoglobin, ferritin and transferrin saturation (TSAT), and investigate the cause of deficiency, including blood loss. Ferritin rises with inflammation and can obscure limited iron availability.

The 2026 ESC guidance favours TSAT <20%. Older trials generally used ferritin <100 µg/L, or 100–299 µg/L with TSAT <20%; these definitions identify overlapping but different populations.

What is recommended?

For symptomatic HFrEF with iron deficiency, IV iron is recommended for symptoms and quality of life (I, B1) and should be considered to reduce HF hospitalisation (IIa, B1). Mortality benefit remains unproven; evidence in HFpEF is limited.

How to interpret the evidence and deliver treatment

FAIR-HF and CONFIRM-HF established improvements in symptoms and functional outcomes. Later event trials have produced mixed primary results; the hospitalisation signal should not be presented as established survival benefit. The evidence relates to intravenous replacement: oral iron is not an equivalent evidence-based HF intervention.

Use preparation-specific dosing and infusion precautions. Consider hypersensitivity, iron overload and hypophosphataemia, particularly with repeated ferric carboxymaltose. Recheck iron status after an appropriate interval rather than immediately after infusion, and look for recurrent losses.

Obesity-related HFpEF: target a contributor to the syndrome

Excess adiposity can contribute to exercise limitation, inflammation and abnormal cardiac loading. Weight-directed treatment belongs alongside management of congestion, blood pressure, AF, sleep-disordered breathing and established HF therapies.

The 2026 ESC guidance says semaglutide or tirzepatide should be considered in symptomatic HF with LVEF ≥45% and BMI ≥30 kg/m², with or without diabetes, for weight reduction, exercise capacity and quality of life (IIa, B1).

Semaglutide · GLP-1 receptor agonist

Semaglutide increases satiety and reduces energy intake; its insulin and glucagon effects are glucose-dependent. In STEP-HFpEF, weekly semaglutide 2.4 mg improved symptoms, physical limitations, exercise function and weight in obesity-related HF with EF ≥45%.

The pooled STEP-HFpEF and STEP-HFpEF DM programme included 1,145 participants. At 52 weeks, the between-group differences favoured semaglutide by 7.5 KCCQ points, 8.4 percentage points of body-weight reduction and 17.1 metres in six-minute walk distance. KCCQ is a patient-reported measure of HF symptoms and limitations.

These are persuasive health-status findings. The programme was not a definitive mortality trial, and HF-event analyses should be read in that context.

Tirzepatide · GIP/GLP-1 receptor agonist

Tirzepatide activates both glucose-dependent insulinotropic polypeptide and GLP-1 receptors, affecting appetite and metabolic regulation. SUMMIT enrolled 731 people with EF ≥50% and BMI ≥30, testing weekly tirzepatide titrated up to 15 mg against placebo.

Cardiovascular death or worsening HF occurred in 9.9% versus 15.3% (HR 0.62, 95% CI 0.41–0.95). The difference was driven by fewer worsening-HF events; cardiovascular death alone was not reduced. KCCQ improved by 6.9 points more than placebo at 52 weeks.

This provides direct randomised HF-event evidence, as well as symptom benefit, for this particular phenotype. It does not establish a survival benefit or justify extrapolation to all HF patients.

Match the patient to the evidence

The trial populations were selected for obesity and higher EF; these results do not establish routine use as HFrEF treatment or in non-obese HFpEF. Gastrointestinal intolerance can limit treatment. Review hydration, diuretic requirements, nutritional intake and preservation of muscle mass during weight loss. Use gradual, product-specific titration and check current UK licensing and local access criteria. Trial target doses are not starting doses.

Weight loss, reduced inflammatory burden and changes in cardiac loading are plausible contributors. Their relative contribution to benefit is not fully resolved; these drugs should not be described as proven direct myocardial repair treatments.

Cardiac amyloidosis: identify the protein, then target its supply

Amyloid deposits make the myocardium stiff and impair filling; ejection fraction may remain preserved despite substantial disease. Treatment depends on the precursor protein: transthyretin (ATTR) or immunoglobulin light chains (AL). Tafamidis treats ATTR cardiomyopathy, not AL amyloidosis.

Establish the type before choosing treatment

Arrange serum free light chains and serum and urine immunofixation to assess for a monoclonal protein. Bone scintigraphy can support a non-biopsy ATTR diagnosis in the appropriate clinical setting only after AL has been excluded; a positive scan alone is insufficient. Suspected AL warrants urgent specialist assessment. Confirmed ATTR should prompt genetic testing and counselling to distinguish hereditary from wild-type disease.

ATTR / Where treatment acts

Liver produces transthyretinVutrisiran reduces production by silencing TTR messenger RNA

↓

TTR circulates as a tetramerTafamidis and acoramidis stabilise this four-part protein, reducing its dissociation

↓

Unstable subunits misfold and form amyloidLess precursor available for further deposition; these drugs do not directly remove existing deposits

Qualitative mechanism diagram, not a validated simulation or a prediction of individual response.

Tafamidis · stabilise the precursor

Tafamidis binds the thyroxine-binding sites of the TTR tetramer. It slows separation into individual subunits, the key early step before misfolding and aggregation. It stabilises both wild-type and variant TTR.

In ATTR-ACT, 441 participants were followed for 30 months. Mortality was 29.5% with pooled tafamidis versus 42.9% with placebo (HR 0.70, 95% CI 0.51–0.96), with fewer cardiovascular hospitalisations and slower decline in walking distance and health status. This is disease-modifying treatment, not immediate relief of congestion.

ATTR-ACT · NICE TA984

Acoramidis · another TTR stabiliser

Acoramidis also binds TTR and strengthens the interactions that keep its tetramer together. It is an oral alternative stabiliser, rather than a second treatment to add to tafamidis.

ATTRibute-CM favoured acoramidis over placebo at 30 months using a hierarchical endpoint of death, cardiovascular hospitalisation, NT-proBNP and six-minute walk distance: win ratio 1.8 (95% CI 1.4–2.2). A win ratio compares ranked outcomes between patient pairs; it is not an 80% reduction in mortality.

Diarrhoea and gout are recognised adverse effects. An early, generally non-progressive fall in estimated GFR can occur; interpret renal results alongside volume status and the clinical picture.

ATTRibute-CM · Acoramidis SmPC · NICE TA1121

Vutrisiran: reduce production upstream

Vutrisiran is a small interfering RNA delivered to hepatocytes. It directs breakdown of TTR messenger RNA, reducing liver production of both variant and wild-type transthyretin. Unlike a stabiliser, it reduces the amount of precursor entering the circulation. It is administered subcutaneously every three months.

In HELIOS-B, vutrisiran reduced the composite of all-cause death and recurrent cardiovascular events versus placebo (HR 0.72, 95% CI 0.56–0.93). Some participants were already taking tafamidis. This was not a direct comparison against tafamidis and does not establish routine combination treatment as the best strategy for every patient.

TTR carries retinol-binding protein, so lowering TTR also lowers circulating vitamin A. Prescribed vitamin A supplementation is required; new night blindness or other ocular symptoms need assessment. Follow the product-specific precautions, including those concerning pregnancy.

HELIOS-B · Vutrisiran SmPC · NICE TA1115

AL amyloidosis: suppress the abnormal plasma-cell clone

In AL, the precursor is an immunoglobulin light chain produced by a clonal plasma-cell population. Urgent haematology-led treatment aims to stop this supply before further organ injury. A common first-line approach is daratumumab with bortezomib, cyclophosphamide and dexamethasone, adapted to cardiac stage and tolerability.

Daratumumab targets CD38 on plasma cells; bortezomib inhibits the proteasome; cyclophosphamide damages DNA; dexamethasone contributes anti-plasma-cell activity. Selected patients may be considered for autologous stem-cell transplantation. Advanced cardiac involvement requires particularly careful regimen selection and supportive care.

ACC multidisciplinary consensus: diagnosis and AL management

Match treatment to disease stage and the person

NICE recommends tafamidis, acoramidis and vutrisiran as options for adults with wild-type or hereditary ATTR cardiomyopathy, subject to their commercial arrangements. The newer appraisals advise choosing the least expensive suitable option after discussing advantages and disadvantages. These are NHS England recommendations; access elsewhere follows the relevant national and local pathway.

There is no direct head-to-head trial establishing which of these agents is best. Specialist selection considers cardiac stage, neuropathy, comorbidity, administration and patient preference. Evidence is less secure in very advanced disease. Patisiran, inotersen and eplontersen should not be assumed interchangeable with these cardiomyopathy treatments merely because they also lower TTR.

Congestion still needs careful diuresis. Restrictive physiology and autonomic dysfunction can make hypotension or excessive preload reduction poorly tolerated. Individualise conventional HF drugs rather than automatically applying the four-drug HFrEF framework to every amyloid phenotype.

Sources reviewed 31 October 2026. Treatment selection belongs within a specialist amyloidosis pathway.

Read the phenotype and the endpoint together.

EF is one treatment dimension. Rhythm, renal function, blood pressure, iron status, adiposity and aetiology also matter. Persistent symptoms should prompt reassessment of congestion, diagnosis and foundational treatment before adding another drug.

Sources: 2026 ESC guidance · Digoxin SmPC · DIGIT-HF · STEP-HFpEF · Pooled STEP programme · SUMMIT

Reviewed 30 October 2026.

04 / Optimisation in practice

A prescription starts
a monitoring pathway.

Most ongoing titration and surveillance happens in the community. Community heart failure nurses, working with GPs, pharmacists and specialist teams, assess symptoms, arrange blood tests, chase results, support patients and coordinate dose changes. This is a substantial clinical workload, not an administrative footnote.

Finerenone does not automatically mean more frequent tests

Spironolactone has an earlier, intensive initial SPS schedule. Finerenone has a four-week product-specific checkpoint and additional monitoring according to risk. Its indication-specific adjustment rules add complexity, but the frequency depends on the patient, concurrent treatment and local protocol. Use the schedule below to make those differences visible.

How to use this table: U&Es means sodium, potassium, urea and renal-function testing; explicitly request magnesium, calcium or bicarbonate when needed. These are reference schedules for stable adult HF, not permission to defer tests in an unwell patient. Local specialist protocols and individual risk can require earlier review. Where no fixed national interval exists, the table says so.

Medication	Before starting	After starting / changing	Once stable	Adverse effects and cautions
ACE inhibitors / ARBsRamipril, enalapril; candesartan, valsartanSource ↗	U&Es, creatinine/eGFR; BP.	Repeat bloods 1–2 weeks after starting or each dose increase; 5–7 days if high risk (e.g. CKD, older age, diabetes, combined diuretic/MRA).	Every 3–6 months; sooner with acute illness or renal risk.	Hypotension, hyperkalaemia, renal-function change; ACE-inhibitor cough. Angioedema is uncommon but urgent.
ARNISacubitril/valsartanSource ↗	U&Es, creatinine/eGFR; BP and volume status.	Bloods 1–2 weeks after starting and each increment; earlier review if high risk. Check BP before and after increments.	Every 3–6 months once optimised, plus illness-triggered checks.	Hypotension, hyperkalaemia, renal impairment. Observe the 36-hour ACE-inhibitor washout; angioedema needs urgent care.
SpironolactoneSteroidal MRASource ↗	U&Es and creatinine/eGFR, including potassium; BP.	SPS: 1 week after starting/change; monthly for first 3 months, then every 3 months for one year.	Every 6 months when stable; closer surveillance with CKD, high potassium or illness.	Hyperkalaemia, renal dysfunction, gynaecomastia/breast tenderness and sexual adverse effects.
EplerenoneSteroidal MRASource ↗	U&Es and creatinine/eGFR; BP.	1 week after starting/change, then monthly for first 3 months.	Every 6 months if stable; more often with renal/electrolyte risk.	Hyperkalaemia, renal dysfunction, dizziness/hypotension; fewer sex-hormone effects than spironolactone.
FinerenoneNon-steroidal MRASource ↗	Potassium and eGFR; check indication, interacting drugs and BP.	SmPC: potassium/eGFR at 4 weeks after initiation, restart or dose adjustment. NICE general MRA advice also supports a 1–2-week check; reconcile these in the agreed local plan, with earlier checks for high-risk patients.	SmPC says periodic, risk-based checks rather than a universal fixed interval. Document a schedule; 3–6-monthly stable HF review is a framework, not a substitute for closer monitoring when needed.	Hyperkalaemia, worsening renal function, hypotension. HF and diabetic-CKD dose/withholding rules differ. Do not combine with another MRA.
Beta-blockersBisoprolol, carvedilol, metoprolol succinateSource ↗	Pulse, BP, ECG/conduction and congestion; no dedicated routine blood panel solely for beta-blockade.	Pulse, BP and clinical status at every increment; commonly reviewed at 1–2-week titration contacts. ECG if symptomatic bradycardia.	Clinical review with routine HF follow-up; bloods follow other medicines/comorbidities.	Fatigue, bradycardia, dizziness/hypotension, cold extremities; worsening congestion during titration. Bronchospasm/conduction block require assessment.
SGLT2 inhibitorsDapagliflozin, empagliflozinSource ↗	Renal function and volume status; glucose/HbA1c as appropriate for diabetes.	No routine extra early renal/potassium test solely for SGLT2 initiation in a stable patient. Arrange earlier clinical/blood review if frail, hypovolaemic, on intensive diuresis or otherwise high risk.	Routine HF/CKD schedule. Test ketones urgently if ketoacidosis is suspected, even with near-normal glucose.	Genital fungal infection, polyuria, volume depletion. Rare ketoacidosis: provide sick-day and perioperative advice.
Loop diureticsFurosemide; bumetanideSource ↗	U&Es, creatinine/eGFR; BP, weight and volume status. Consider magnesium.	Furosemide SPS: 1–2 weeks after start/change, or 5–7 days if high risk. Apply a comparable risk-based plan to bumetanide; acute/intensive diuresis needs earlier checks.	Usually 6-monthly bloods if stable; repeat promptly after escalation, dehydration or clinical deterioration.	Hypokalaemia, hyponatraemia, hypomagnesaemia, dehydration, postural hypotension, gout; renal-function changes.
Distal add-on diureticsMetolazone, hydrochlorothiazideSource ↗	U&Es, creatinine/eGFR, magnesium and bicarbonate; weight/BP/volume assessment.	No single national community interval fits all regimens. Agree bloods within days of addition/change—often 48–72 hours in high-risk combination treatment—and review before further doses where appropriate. This is a proposed safety plan, subject to local specialist protocol.	Daily or more frequent bloods during unstable inpatient combination treatment. Outpatient frequency depends on dosing and response; do not wait months after adding an intermittent agent.	Marked sodium/potassium depletion, dehydration, alkalosis, renal dysfunction, gout. Metolazone effects may be prolonged; preparations differ.
AcetazolamideUsually short-course IV add-on in acute HFSource ↗	U&Es, bicarbonate, creatinine/eGFR; consider magnesium.	During acute inpatient combination therapy, check at least daily and more often if unstable; reassess clinical response each day.	No routine chronic community HF schedule: continuation outside acute care needs a specific specialist plan.	Bicarbonate loss/metabolic acidosis, hypokalaemia, paraesthesia, GI upset and renal/electrolyte disturbance.
DigoxinCardiac glycosideSource ↗	Renal function, potassium, magnesium, calcium, thyroid function; pulse/ECG.	Routine serum levels are not required. If indicated after a dose change: around 7 days with normal renal function, longer with impairment. Take at least 6 hours after a dose, ideally 8–12 hours. Check sooner for suspected toxicity.	SPS: annual renal function/electrolytes including calcium/magnesium, more often in older people or renal impairment. Other HF drugs usually require more frequent bloods. Levels for toxicity, interactions, renal deterioration or adherence concerns.	Nausea, poor appetite, dizziness; confusion, visual disturbance, bradycardia or arrhythmia may signal toxicity, not an acceptable titration effect.
Intravenous ironFerric carboxymaltose / ferric derisomaltoseSource ↗	FBC, ferritin, TSAT; consider phosphate and deficiency risk.	Reassess haemoglobin no earlier than 4 weeks after the final infusion. Plan ferritin/TSAT review around 3 months rather than immediately after infusion. Phosphate checks for repeated/high-dose carboxymaltose or risk factors, and if symptoms suggest deficiency.	Reassess iron status at routine HF reviews and when symptoms/anaemia recur; replacement depends on results and formulation.	Infusion reactions, headache, nausea; hypophosphataemia particularly with carboxymaltose. Observe for hypersensitivity during and at least 30 minutes after infusion.
Semaglutide / tirzepatideWeight-directed therapySource ↗	Weight/BMI, nutritional status, renal function; HbA1c if diabetes.	Review tolerance, hydration, intake and weight at dose-escalation contacts (typically at least 4 weeks between increments, product-specific). No routine additional renal panel solely for initiation; check promptly with persistent vomiting/diarrhoea or dehydration.	Diabetes blood monitoring as indicated; routine HF/CKD surveillance. Reassess diuretic/antihypertensive requirements as weight falls.	Nausea, vomiting, diarrhoea, constipation; dehydration. Severe persistent abdominal pain requires assessment for pancreatitis/gallbladder disease.

Make the work visible—and assign it.

Before the dose changes

Agree who prescribes, orders bloods and contacts the patient. Record the dose, test date and review date. Confirm that the patient can attend, or arrange community phlebotomy/home assessment.

Close the results loop

A blood test is not complete care until someone reviews it, acts on it and explains the plan. Name the responsible clinician/team, an escalation route and cover for absence. Chase missed tests and unread results.

Plan capacity

Each titration can generate calls, visits, prescriptions, blood requests and repeat checks. Coordinate compatible tests to reduce visits, without delaying the earliest safety check. Protected nursing time and reliable result access are part of safe optimisation.

Recheck when the situation changes

Intercurrent illness, poor intake, vomiting/diarrhoea, altered diuretic doses, NSAIDs or potassium-raising medicines can invalidate a previously safe schedule. New symptomatic hypotension, bradycardia, oliguria or significant electrolyte abnormalities need timely clinical assessment. Follow drug-specific and local escalation thresholds rather than one universal stop rule.

Reference framework: NHS SPS medicine-monitoring guidance, NICE NG106, UK Kidney Association guidance and current product information. Proposed combination-diuretic timings are explicitly labelled. Reviewed 30 October 2026.

Medicaltherapy

Treat the driversthat sustain the disease.

Reduce the harmful signal.Preserve the counter-signal.

ACE inhibitors: ramipril, enalapril

ARBs: candesartan, valsartan

Protect the heart frompersistent adrenergic drive.

What happens at the receptor?

Why can EF improve later?

Block aldosterone'seffects beyond salt retention.

At the kidney

In the heart and vessels

A renal target.A cardiovascular benefit.

The established target

Why the benefit exceeds glucose lowering

Fluid accumulation

Fluid redistribution

What the 2026 ESC recommendation actually covers

Acetazolamide: more successful early decongestion

Hydrochlorothiazide: more weight loss, more renal dysfunction

When the response is disappointing

Is congestion still present?

Has the loop reached its target?

Target another segment if needed

Monitor the patient, not one number

Which feature changesthe treatment?

Iron deficiency: treat the deficit, not just the haemoglobin

Identify the phenotype

What is recommended?

Digoxin: an additional option, not a replacement for foundational treatment

Myocardial mechanism

A narrow therapeutic margin

Obesity-related HFpEF: target a contributor to the syndrome

Semaglutide · GLP-1 receptor agonist

Tirzepatide · GIP/GLP-1 receptor agonist

Match the patient to the evidence

Cardiac amyloidosis: identify the protein, then target its supply

Establish the type before choosing treatment

Tafamidis · stabilise the precursor

Acoramidis · another TTR stabiliser

Match treatment to disease stage and the person

A prescription startsa monitoring pathway.

Finerenone does not automatically mean more frequent tests

Make the work visible—and assign it.

Before the dose changes

Close the results loop

Plan capacity

Recheck when the situation changes

Medical
therapy

Treat the drivers
that sustain the disease.

Reduce the harmful signal.
Preserve the counter-signal.

Protect the heart from
persistent adrenergic drive.

Block aldosterone's
effects beyond salt retention.

A renal target.
A cardiovascular benefit.

Which feature changes
the treatment?

A prescription starts
a monitoring pathway.