Which treatment is indicated for which heart failure type?
The four pillars of guideline-directed medical therapy (GDMT) are mortality-modifying treatments. Indication depends on heart failure type classified by LVEF.
| Heart failure type | ACE inhibitor / ARB / ARNI | Beta-blocker | Mineralocorticoid receptor antagonist | SGLT2 inhibitor |
|---|
| HFrEF <40% | ✓ Indicated | ✓ Indicated | ✓ NYHA II–IV | ✓ Indicated |
| HFmrEF 40–49% | Consider | Consider | Consider | ✓ Primary |
| HFpEF ≥50% | Not for EF | Not for EF | Not for EF | ✓ Primary |
ACE inhibitor, beta-blocker and mineralocorticoid receptor antagonist are not indicated for improving ejection fraction in HFpEF. They may still be used for co-existing conditions (e.g. hypertension, AF), but should not be labelled as heart failure GDMT in that context.
Pillar 1 — ACE inhibitor / Angiotensin receptor blocker (ARB) / ARNI
| Drug | Full name | Starting dose | Target dose | Interval |
|---|
| Ramipril | ACE inhibitor | 1.25–2.5mg od | 10mg od | 1–2 wks |
| Lisinopril | ACE inhibitor | 2.5mg od | 20–30mg od | 1–2 wks |
| Enalapril | ACE inhibitor | 2.5mg bd | 10–20mg bd | 1–2 wks |
| Candesartan | Angiotensin receptor blocker | 2mg od | 32mg od | 1–2 wks |
| Losartan | Angiotensin receptor blocker | 12.5mg od | 150mg od | 1–2 wks |
| Sacubitril/Valsartan | Angiotensin receptor–neprilysin inhibitor (ARNI) | 24/26mg bd | 97/103mg bd | 4 wks |
Pillar 2 — Beta-blocker
Only bisoprolol, carvedilol and nebivolol are licensed for heart failure. Do not use atenolol, metoprolol (standard release) or other beta-blockers for the HF indication.
| Drug | Starting dose | Target dose | Interval | Notes |
|---|
| Bisoprolol | 1.25mg od | 10mg od | 2 wks | First-line preferred; heart rate target ~60 bpm |
| Carvedilol | 3.125mg bd | 25mg bd (50mg bd if >85kg) | 2 wks | Non-selective beta-blocker with alpha-blocking properties |
| Nebivolol | 1.25mg od | 10mg od | 2 wks | Licensed for heart failure in patients ≥70 years (SENIORS trial) |
Pillar 3 — Mineralocorticoid receptor antagonist (MRA)
| Drug | Starting dose | Target dose | Notes |
|---|
| Spironolactone | 25mg od | 50mg od | ~10% of males develop gynaecomastia — switch to eplerenone if this occurs |
| Eplerenone | 25mg od | 50mg od | Less androgenic; licensed specifically for post-MI HF |
Pillar 4 — SGLT2 inhibitor (Sodium-glucose cotransporter-2 inhibitor)
| Drug | Dose | Indication | Notes |
|---|
| Dapagliflozin (Forxiga) | 10mg od — fixed, no titration | HFrEF + HFpEF (NICE TA652) | Contraindicated T1DM; discuss with renal physician if eGFR <30 |
| Empagliflozin (Jardiance) | 10mg od — fixed, no titration | HFrEF + HFpEF (NICE TA773) | EMPEROR-Preserved trial for HFpEF; same renal cautions apply |
Furosemide Dose Ladder
20–40mg od
Starting dose for new or mild fluid retention
↓
80mg od
First escalation — weight gain ≥1kg sustained >2 days; check U&E within 1 week
↓
80mg morn + 40mg lunchtime
Further escalation; U&E within 1 week
↓
80mg twice daily
High dose — mandatory U&E within 1 week; watch for over-diuresis
↓
>80mg twice daily
Seek cardiology or hospital physician input before further escalation
Patient self-escalation: Patient may independently increase furosemide by 40mg (one step) for up to 3 days without GP contact if weight gain ≥1kg on 2 consecutive days with symptoms.
Bumetanide
Bumetanide 1mg is approximately equivalent to furosemide 40mg. Dose range 0.5–3mg once daily. Apply the same monitoring principles as furosemide. Some patients prefer bumetanide due to more predictable gastrointestinal absorption.
Metolazone — Use with Extreme Caution
Metolazone combined with a loop diuretic is extremely potent. Initiation usually requires specialist input. Mandatory U&E at 24–48hrs after starting and weekly for 4 weeks if stable; monthly thereafter. Risk of severe hyponatraemia, hypokalaemia, dehydration and pre-renal failure.
Often prescribed every other day or three times per week rather than daily. If Na⁺ falls below 130 mmol/L — seek specialist advice immediately and withhold dose.
Diuretic Biochemistry — When to Act
| Parameter | Threshold | Action |
|---|
| Urea rising | >20 mmol/L or rise >10 mmol/L | Reduce diuretic (if no congestion); seek advice |
| Creatinine rising | >300 µmol/L or rise >100 µmol/L | Reduce diuretic; seek cardiology advice |
| Potassium low | <3.5 mmol/L | Reduce diuretic; consider increasing ACE inhibitor dose; or add mineralocorticoid receptor antagonist |
| Potassium rising on MRA | ≥5.5 mmol/L | Stop mineralocorticoid receptor antagonist — see ACE inhibitor tab for full potassium ladder |
| Sodium | Na⁺ <130 mmol/L | Careful fluid balance assessment before any diuretic change; seek specialist advice |
When to seek specialist advice before starting ACE inhibitor in primary care
Seek specialist advice if any of the following are present before initiating ACE inhibitor: creatinine >170 µmol/L or eGFR <30 · K⁺ >5.0 mmol/L · Na⁺ <130 mmol/L · SBP <90 mmHg · furosemide >80mg daily · known or suspected renal artery stenosis or significant aortic stenosis · personal history of angioedema
Potassium Management — ACE inhibitor / ARB / ARNI / Mineralocorticoid receptor antagonist
| K⁺ level | Context | Action |
|---|
| <5.0 mmol/L | Any | Acceptable — continue and proceed with uptitration |
| 5.0–5.5 mmol/L | Stable doses | Acceptable at stable doses — monitor; no immediate action required |
| 5.5–5.9 mmol/L | During uptitration | Recheck within 24hrs. If persists — reduce or temporarily hold ACE inhibitor/ARNI |
| ≥6.0 mmol/L | On ACE inhibitor / ARB | Stop immediately. Check sample not haemolysed. Seek GP or cardiology advice urgently. |
| ≥6.0 mmol/L | On ARNI (sacubitril/valsartan) | Immediately discontinue ARNI and mineralocorticoid receptor antagonist. Urgently evaluate and treat. |
| >5.5 mmol/L | On mineralocorticoid receptor antagonist | Stop mineralocorticoid receptor antagonist. Seek advice if potassium persists elevated. |
Acceptable Renal Function Changes on ACE Inhibitor / ARNI Uptitration
| Change | ACE inhibitor / ARB | Sacubitril/Valsartan (ARNI) |
|---|
| Small, stable rise | Urea <5 mmol/L / creatinine <50 µmol/L — monitor, no action if stable | eGFR decrease <25% AND eGFR ≥30 — no action needed |
| Moderate rise | Creatinine rise 50–100 µmol/L — check every 2 days; seek GP advice | eGFR decrease 25–40% — halve dose; recheck in 5–7 days |
| Significant rise | Creatinine >300 µmol/L or rise >100 µmol/L — STOP; seek specialist advice | eGFR decrease >40% — STOP ARNI; weekly recheck; aim to restart |
Some creatinine rise is expected and acceptable. Worsening renal function is often due to over-diuresis — check hydration and diuretic dose before attributing to ACE inhibitor.
ARB use in HF — when to choose over ACE inhibitor
Angiotensin receptor blockers (ARBs) such as candesartan or losartan are used as an alternative to ACE inhibitors when the patient is intolerant due to a persistent dry cough (the most common reason) or angioedema not caused by the bradykinin pathway. They are not superior to ACE inhibitors and should not be routinely combined with them in HF.
Do not combine ACE inhibitor + ARB in heart failure — increased risk of hyperkalaemia and renal impairment without additional mortality benefit.
What is Sacubitril/Valsartan (Entresto)?
Sacubitril/Valsartan is an angiotensin receptor–neprilysin inhibitor (ARNI). It combines two mechanisms: valsartan (an angiotensin receptor blocker) blocks the RAAS pathway; sacubitril inhibits neprilysin, an enzyme that breaks down natriuretic peptides (BNP, ANP). The result is reduced cardiac workload, vasodilation and enhanced diuresis beyond what ACE inhibitors or ARBs achieve alone.
The PARADIGM-HF trial showed a 20% relative risk reduction in cardiovascular death and HF hospitalisation compared to enalapril in patients with HFrEF.
Eligibility (NICE TA388)
| Criterion | Detail |
|---|
| HF type | HFrEF — LVEF <40% |
| Symptoms | NYHA class II–IV — symptomatic despite optimal ACE inhibitor or ARB |
| Prior therapy | Must be established on ACE inhibitor or ARB (ARNI is an upgrade, not de-novo initiation) |
| SBP minimum | ≥100 mmHg (see titration guidance) |
| eGFR minimum | ≥30 mL/min (discuss with renal physician if borderline) |
| Initiation | Discuss with consultant cardiologist before starting — GP prescribes ongoing after cardiology input |
⚠ 48-Hour ACE Inhibitor Washout — Critical Safety Requirement
ACE inhibitor MUST be stopped for a minimum of 48 hours before starting sacubitril/valsartan. Concurrent use carries a significant risk of angioedema — a potentially life-threatening reaction. This is a hard clinical rule. Special care required for patients on dosette boxes or with cognitive impairment where inadvertent overlap may occur.
If patient is on an ARB (e.g. candesartan), no washout is required — switch directly.
Titration Ladder
Starting dose depends on prior ACE inhibitor dose. Uptitrate every 4 weeks as tolerated. Target is 97/103mg twice daily — or maximum tolerated dose.
24/26mg bd
Starting dose for patients on low-dose ACE inhibitor (e.g. enalapril ≤10mg/day) or if de-escalating from higher dose due to tolerability
Starting
↓ titrate after 4 weeks if tolerated
49/51mg bd
Intermediate dose — also the starting dose for patients previously on enalapril 10–20mg daily or equivalent. Check BP, renal function and potassium before uptitrating.
Intermediate
↓ titrate after 4 weeks if tolerated
97/103mg bd
Target dose — proven in PARADIGM-HF. If not tolerated due to hypotension or renal deterioration, step back to 49/51mg and document as maximum tolerated dose.
Target dose
Drug Interactions
| Drug | Interaction | Action |
|---|
| ACE inhibitor (any) | Angioedema risk — NEVER co-prescribe | 48-hour washout mandatory before starting |
| Atorvastatin | ARNI increases atorvastatin peak plasma concentration by ~2-fold | If on atorvastatin 80mg — consider reducing to 40mg; monitor LFTs |
| Lithium | Sacubitril/valsartan may increase lithium levels | Combination not recommended; if unavoidable, close lithium level monitoring essential |
| Aliskiren | Dual RAAS blockade — risk of hypotension, hyperkalaemia and renal failure | Contraindicated in combination |
| Potassium-sparing diuretics / potassium supplements | Additive hyperkalaemia risk with mineralocorticoid receptor antagonist | Monitor potassium closely |
Contraindications
- Concomitant ACE inhibitor use
- Personal history of angioedema associated with ACE inhibitor or ARB therapy
- Hereditary or idiopathic angioedema
- Concomitant aliskiren use in patients with diabetes mellitus or renal impairment (eGFR <60)
- Severe hepatic impairment, biliary cirrhosis or cholestasis (Child–Pugh C)
- Pregnancy — teratogenic; do not use in women of childbearing potential without contraception
- SBP <100 mmHg at initiation
Monitoring after Initiation
| Timepoint | Check |
|---|
| Baseline (before starting) | BP, U&E, creatinine, potassium, LFTs, eGFR |
| 1–2 weeks after each dose step | BP, U&E, creatinine, potassium |
| Stable on target dose | 3–6 monthly U&E, creatinine, potassium |
| On atorvastatin 80mg | LFTs at baseline and 1 month after starting |
What are SGLT2 inhibitors and why do they work in heart failure?
SGLT2 inhibitors (sodium-glucose cotransporter-2 inhibitors) were originally developed as glucose-lowering agents for type 2 diabetes. Their benefit in heart failure is independent of glucose lowering and occurs through several mechanisms:
- Osmotic diuresis — reduces cardiac preload and congestion
- Natriuresis — reduces blood pressure and ventricular wall stress
- Reduced cardiac inflammation and fibrosis
- Improved cardiac energetics (ketone body utilisation)
- Cardiorenal protection — slows CKD progression
These drugs are effective across the full spectrum of heart failure — HFrEF and HFpEF — making them uniquely indicated for all patients regardless of ejection fraction.
Dapagliflozin (Forxiga) vs Empagliflozin (Jardiance)
| Dapagliflozin 10mg | Empagliflozin 10mg |
|---|
| HFrEF indication | ✓ NICE TA652 (DAPA-HF trial) | ✓ NICE TA652 (EMPEROR-Reduced trial) |
| HFpEF indication | ✓ NICE TA652 (DELIVER trial) | ✓ NICE TA773 (EMPEROR-Preserved trial) |
| Dose | 10mg once daily — no titration | 10mg once daily — no titration |
| eGFR threshold | Discuss with renal physician if <30; currently not recommended <20 | Same cautions apply |
| Type 2 diabetes benefit | Dual benefit — improves HbA1c and reduces HF hospitalisation | Dual benefit — similar profile |
| Cost (indicative) | ~£35–40/month | ~£35–40/month |
Practical prescribing points
- No titration required — start at 10mg once daily and continue
- Expect an initial eGFR dip — a fall of 5–15% in the first weeks is expected and should stabilise; do not stop based on initial dip unless eGFR falls below 20 mL/min
- Type 1 diabetes — contraindicated in all indications due to risk of diabetic ketoacidosis
- Sick day rules — advise patients to hold SGLT2 inhibitor during acute illness with dehydration, vomiting, diarrhoea, or fasting (surgical procedures)
- Genital mycotic infections — increased frequency; patient counselling at initiation
- Urinary frequency — transient in the first weeks; reassure patient
- Do not combine with loop diuretic escalation simultaneously — osmotic diuresis is additive; risk of over-diuresis
Contraindications and cautions
| Situation | Recommendation |
|---|
| Type 1 diabetes mellitus | Contraindicated — risk of diabetic ketoacidosis |
| eGFR <30 mL/min | Discuss with renal physician before initiating |
| eGFR <20 mL/min | Currently not recommended |
| Recurrent urinary tract infections | Caution — SGLT2 inhibitors increase UTI frequency |
| Acute illness / dehydration / surgery | Temporarily stop (sick day rule) |
| Pregnancy or breastfeeding | Avoid |
Reading the Echo Report — Key Parameters
LVEF (%)
Normal ≥55%
<40% = HFrEF; 40–49% = HFmrEF; ≥50% = HFpEF. Determines the entire GDMT pathway.
LV end-diastolic diameter (LVEDD)
Normal <56mm
Dilated LV (>56mm) = dilated cardiomyopathy pattern. Helps distinguish ischaemic from idiopathic aetiology.
Wall thickness (IVSd)
Normal 6–11mm
>12mm = left ventricular hypertrophy. >15mm asymmetric = consider hypertrophic cardiomyopathy.
LA volume index
Normal <34 mL/m²
Elevated = chronic diastolic pressure overload. Key marker in HFpEF assessment alongside E/e'.
E/e' ratio
Normal <8
>15 = raised LV filling pressures (elevated LVEDP). Key diastolic dysfunction marker in HFpEF.
Wall motion abnormality (WMA)
Normal: none
Regional WMA = ischaemic aetiology. Anterior = LAD territory; inferior/posterior = RCA/LCx territory.
TAPSE (RV function)
Normal >17mm
<17mm = RV dysfunction. <12mm with symptoms = advanced HF, poor prognosis.
Valvular disease
None significant
Significant AS, MR or AR may be the primary cause of HF — refer urgently if newly identified significant lesion.
Echo findings needing urgent action
The following findings should prompt same-day or urgent review rather than routine follow-up: · LVEF <20% with symptoms → same-day cardiology contact · Significant pericardial effusion → urgent review (exclude tamponade) · Severe aortic stenosis with symptoms → urgent cardiology · New regional WMA → possible acute ischaemic event · TAPSE <12mm with symptoms → advanced HF, urgent referral
Which GDMT is indicated? — Quick reference by echo finding
| Echo finding | ACE inhibitor / ARB / ARNI | Beta-blocker | Mineralocorticoid receptor antagonist | SGLT2 inhibitor |
|---|
| EF <40% (HFrEF) — dilated or regional WMA | ✓ First-line | ✓ First-line | ✓ NYHA II–IV | ✓ First-line |
| EF 40–49% (HFmrEF) | Consider | Consider | Consider | ✓ Best evidence |
| EF ≥50%, LVH/LA dilatation (HFpEF) | Not for EF | Not for EF | Not for EF | ✓ First-line |
| Asymmetric LVH ≥15mm (HCM suspected) | ⚠ May worsen LVOTO | ✓ First-line for LVOTO | Avoid | Discuss specialist |
Dilated Cardiomyopathy (DCM)
Echo: Dilated LV (LVEDD >56mm), global systolic impairment, thin walls, LVEF typically <40%.
Treatment: Full four-pillar GDMT — ACE inhibitor/ARB/ARNI + beta-blocker + mineralocorticoid receptor antagonist + SGLT2 inhibitor.
Exclude reversible causes before assuming idiopathic: alcohol (ask specifically), thyroid disease, tachycardia-induced cardiomyopathy (rate?), haemochromatosis (ferritin), peripartum onset. Offer first-degree relative screening for genetic DCM — 20–35% have identifiable genetic cause.
Hypertrophic Cardiomyopathy (HCM) ⚠
Echo: IVS ≥15mm (asymmetric), usually preserved or hyperdynamic EF, possible left ventricular outflow tract (LVOT) obstruction with gradient >30 mmHg.
🛑 CRITICAL: HCM does NOT follow standard HFrEF GDMT. Vasodilators — ACE inhibitors, ARBs, nitrates and large-dose diuretics — can WORSEN LVOT obstruction and cause haemodynamic collapse. Beta-blocker is first-line for obstructive HCM. Do NOT start ARNI without specialist input. SGLT2 inhibitor: discuss with HCM specialist before use. Refer to dedicated HCM service. Family screening required. Consider driving restrictions, sport recommendations and sudden cardiac death risk stratification.
Hypertensive Heart Disease / Left Ventricular Hypertrophy
Echo: Concentric wall thickening (IVSd >12mm), preserved EF, LA dilatation, grade II–III diastolic dysfunction — the typical HFpEF phenotype.
Treatment: SGLT2 inhibitor (NICE TA773); diuretics for symptom control. Blood pressure control is the foundational treatment.
Amlodipine and felodipine are safe calcium channel blockers in left ventricular systolic dysfunction. Verapamil and diltiazem are contraindicated when EF is reduced. ACE inhibitor or ARB appropriate if co-existing hypertension requiring treatment, not as GDMT.
Ischaemic Cardiomyopathy
Echo: Regional wall motion abnormality (RWMA); thinned or scarred segments in a coronary artery territory; anterior (LAD), inferior/posterior (RCA/LCx).
Treatment: Full four-pillar HFrEF GDMT + antiplatelet therapy + statin (secondary prevention).
Revascularisation assessment is important — hibernating myocardium may recover function after PCI or CABG. Lower ICD threshold in ischaemic aetiology (higher sudden cardiac death risk). Refer for coronary angiography if revascularisation not already assessed.
Takotsubo / Stress Cardiomyopathy
Echo: Apical ballooning with basal hyperkinesis; typically precipitated by emotional or physical stress; most commonly affects post-menopausal women.
Usually reversible — repeat echo at 4–8 weeks before committing to long-term heart failure therapy. Acute-phase mortality is real: arrhythmia, LVOTO, cardiogenic shock. Avoid catecholamines in acute phase. If EF normalises on repeat echo, GDMT may be weaned with specialist guidance.
Cardiac Amyloidosis
Echo: Thickened walls (concentric), granular sparkling texture, small cavity, bi-atrial dilatation, diastolic dysfunction, low voltage on ECG (voltage:mass mismatch).
Types: AL amyloidosis (plasma cell dyscrasia) and ATTR amyloidosis (transthyretin — wild-type in elderly men, or hereditary variant).
ATTR amyloidosis is increasingly recognised in elderly patients presenting with heart failure. Specific therapy (tafamidis, NICE TA655 for TTRv) is available. Referral to specialist amyloid centre is essential. Standard HFrEF GDMT is generally not appropriate — ACE inhibitors and beta-blockers are often poorly tolerated. Digoxin is contraindicated (binds amyloid fibrils causing toxicity).
Monitoring Timeline — Stable Heart Failure in Primary Care
| Timepoint | Check | Trigger |
|---|
| Before initiation | U&E, creatinine, potassium, BP, HR, FBC, TFT, glucose, ECG, CXR, BNP/NT-proBNP | New diagnosis |
| 1 week post change | U&E, creatinine, potassium, BP, HR | Any dose change to ACE inhibitor/ARB/ARNI/MRA/loop diuretic |
| 2 weeks | U&E, potassium | After mineralocorticoid receptor antagonist initiation; borderline results at 1 week |
| 4 weeks | U&E, potassium | After mineralocorticoid receptor antagonist initiation; ARNI titration steps |
| 3-monthly × 1 year (MRA) | U&E, potassium, creatinine | All patients on mineralocorticoid receptor antagonist for first 12 months |
| 3–6 monthly (stable) | U&E, creatinine, potassium | Stable on ACE inhibitor/ARNI without mineralocorticoid receptor antagonist |
| 6-monthly (stable >1yr on MRA) | U&E, potassium, creatinine | Once stable for >1 year on mineralocorticoid receptor antagonist |
| Every review | BP, HR, symptoms, weight, oedema | All reviews |
| Annual | U&E, FBC, glucose, flu immunisation, full medication review | All heart failure patients |
| Echo repeat | Repeat echocardiogram | If EF changes or clinical deterioration — NOT routinely for stable patients |
Device Therapy — Referral Thresholds (NICE TA314)
Optimal medical therapy should be established before device referral where possible. Age is not a barrier — physiological status is more relevant than chronological age.
| Device | Full name | Key criteria | Notes |
|---|
| ICD | Implantable Cardioverter Defibrillator | LVEF ≤35%, NYHA I–III on optimal medical therapy | NYHA IV generally not indicated. Ischaemic aetiology carries higher sudden cardiac death risk. |
| CRT-P | Cardiac Resynchronisation Therapy Pacemaker | LVEF ≤40%, QRS ≥120ms, NYHA II–IV on optimal medical therapy | Greatest benefit: left bundle branch block + QRS ≥150ms. Non-LBBB: benefit present but smaller. |
| CRT-D | Cardiac Resynchronisation Therapy Defibrillator | Patient meets criteria for both CRT and ICD | Combined resynchronisation + defibrillation. |
Daily Weight Monitoring
Weigh every morning at the same time, before eating, after voiding. Record the result. If weight increases by more than 2kg in 2 consecutive days with symptoms of breathlessness or ankle swelling:
- Patient may independently increase furosemide by 40mg for up to 3 days without contacting the practice
- If weight does not return to baseline within 3 days — contact the practice
- If already on furosemide >80mg twice daily — contact practice before self-escalating
ICD / CRT-D Deactivation at End of Life
For patients with declining functional status and an ICD or CRT-D, a compassionate discussion about device deactivation is part of good end-of-life care. This is a patient-led conversation — not a clinical decision imposed on the patient.
- British Heart Rhythm Society guidance supports device deactivation at end of life as ethically appropriate
- Refer to the patient's cardiology team or heart failure nurse specialist to facilitate the conversation if helpful
- Document discussion and any resulting decision clearly — share with out-of-hours services and ambulance service
- Important: deactivating the defibrillator function in CRT-D does not affect the pacing function — the patient will not lose pacing support
- The Scottish Ambulance Service should be notified if a DNACPR is in place alongside a device