PharmacologyTier 1Medical Sciences concept

Evidence-based pharmacotherapy in heart failure with reduced ejection fraction (ACEi, beta-blockers, MRA, ARNI)

Core concept

Every mortality-benefit drug in HFrEF interrupts neurohormonal activation
- RAAS, SNS, aldosterone-driven fibrosis, natriuretic peptide degradation
- Inotropes improve haemodynamics without interrupting it -> better symptoms, shorter life
Four pillars, all Class I, all started early and up-titrated together - not sequenced

Pillar	Agents	Mechanism
1. RAS	ARNI (sacubitril/valsartan) preferred, else ACEi or ARB	dec Ang II, inc natriuretic peptides
2. Beta-blocker	Bisoprolol, carvedilol, metoprolol succinate, nebivolol	dec SNS, dec arrhythmia, reverse remodelling
3. MRA	Spironolactone, eplerenone; finerenone	dec aldosterone-driven fibrosis and hypokalaemia
4. SGLT2 inhibitor	Dapagliflozin, empagliflozin	dec HF hospitalisation, dec CV death; independent of diabetes

Loop diuretics relieve congestion but have never shown a mortality benefit - symptom therapy, titrated to euvolaemia

Key detail

ESC 2026 changes worth knowing
- MRA is Class I in chronic heart failure across the whole EF spectrum, not just HFrEF
- ARNI and SGLT2 inhibitor are Class I in HFrEF
- Digoxin/digitoxin upgraded in chronic heart failure in selected patients
- Upgraded recommendations for durable mechanical circulatory support and M-TEER
- Classification moved to HFrEF / HFimpEF (improved) / HFpEF, away from rigid EF cutoffs
STRONG-HF changed the tempo, not the drug list
- Rapid up-titration to full dose within ~2 weeks of discharge, with close follow-up (day 1, 2, 3, 6 weeks) -> dec 180-day readmission and death
- Start low doses of all four early rather than maximising one before adding the next
- Benefit persists across the EF spectrum
Practical up-titration
- Accept an eGFR fall up to ~30% and a creatinine rise up to ~50% on RAS blockade
- Accept K up to 5.5 with monitoring; use a potassium binder rather than abandoning the MRA
- Beta-blockers are started when euvolaemic, and continued (dose-reduced) during decompensation unless in cardiogenic shock
- 36-hour ACEi washout before an ARNI
Additional agents by indication
- Vericiguat (sGC stimulator) after a worsening HF event
- Ivabradine if sinus rhythm and HR >=70 on maximal beta-blockade
- Hydralazine/isosorbide dinitrate - self-identified Black patients, or where RAS blockade is not tolerated
- IV ferric carboxymaltose for iron deficiency (ferritin <100, or 100-299 with TSAT <20%) - improves symptoms and reduces hospitalisation
- Digoxin for rate control in AF, and symptom benefit in sinus rhythm
Avoid: NSAIDs, non-dihydropyridine calcium channel blockers, thiazolidinediones, class Ic antiarrhythmics, saxagliptin

Clinical relevance

The commonest error is a patient on a "full dose" of one pillar and none of the other three - four low doses beat one high dose
Reassess EF after 3 months of optimal therapy before ICD/CRT decisions - many recover (HFimpEF)
- Continue therapy in HFimpEF - withdrawal causes relapse (TRED-HF)
Devices: ICD for EF <=35% despite optimal therapy; CRT for EF <=35% with LBBB and QRS >=150 ms
Always establish the aetiology - ischaemia, valve disease, cardiac amyloidosis (tafamidis), sarcoid, myocarditis, peripartum, chemotherapy, tachycardia-mediated
Monitor U&E, BP and weight at every titration step; educate on daily weights and fluid/salt
Cardiac rehabilitation and multidisciplinary HF nurse follow-up are Class I and reduce readmission

Correlations

Neprilysin inhibition mechanism; BNP physiology
SGLT2 inhibitor metabolic effects
Renin-angiotensin-aldosterone system
Determinants of blood pressure and cardiac output; preload-independent contractility
Vasopressor mechanisms - the drugs that help haemodynamics without helping survival

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