Heart Failure Pharmacotherapy

Heart failure pharmacotherapy combines drugs that relieve congestion with drugs that block harmful neurohormonal activation and improve survival. In heart failure with reduced ejection fraction (LVEF 40% or under), four drug groups reduce death and hospitalisation: an angiotensin receptor neprilysin inhibitor (or ACE inhibitor or angiotensin receptor blocker), a beta blocker, a mineralocorticoid receptor antagonist and an SGLT2 inhibitor.

Phenotypes. Reduced ejection fraction (LVEF 40% or under), mildly reduced (41% to 49%) and preserved (50% or over). Treatment evidence is strongest for the reduced group. For the others, an SGLT2 inhibitor and diuretic for congestion are the base, with an MRA or angiotensin receptor neprilysin inhibitor considered where LVEF is below normal.

Regional pattern. Registries in sub-Saharan Africa show heart failure at younger ages than in high-income settings, most often from hypertension, rheumatic valve disease, cardiomyopathies (dilated, peripartum, endomyocardial fibrosis), pericardial disease and, in some areas, HIV and Chagas-like causes. Treatment must address the cause as well as the syndrome.

Mechanism. Sympathetic and renin-angiotensin-aldosterone activation raises preload and afterload, remodels the ventricle and promotes sodium retention and arrhythmia. Drug classes interrupt these loops. Diuretics treat the resulting congestion.

Drug groups. Prognostic: sacubitril-valsartan, ACE inhibitors, angiotensin receptor blockers, bisoprolol, carvedilol, metoprolol succinate, nebivolol, spironolactone, eplerenone, dapagliflozin, empagliflozin. Symptomatic or selected: loop diuretics, ivabradine, digoxin, hydralazine with isosorbide dinitrate, vericiguat, intravenous iron.

• Loop diuretics: relieve congestion, no survival effect. Dose to the lowest that keeps euvolaemia.
• Sacubitril-valsartan: preferred over ACE inhibitor in reduced ejection fraction.
• ACE inhibitor or angiotensin receptor blocker: when sacubitril-valsartan is not available or tolerated.
• Beta blockers: bisoprolol, carvedilol, metoprolol succinate, nebivolol.
• MRAs: spironolactone, eplerenone, and finerenone in mildly reduced or preserved ejection fraction.
• SGLT2 inhibitors: dapagliflozin and empagliflozin 10 mg daily, benefit across ejection fraction.
• Ivabradine: lowers sinus rate without negative inotropy.
• Vericiguat: soluble guanylate cyclase stimulator for worsening heart failure.
• Digoxin: symptomatic benefit and fewer hospitalisations, no mortality effect.
• Hydralazine with isosorbide dinitrate: for patients of African ancestry in NYHA class III to IV, or when renin-angiotensin blockade is not tolerated.

• Reduced ejection fraction, initiation: start all four prognostic groups early, in low doses and in any order that blood pressure, heart rate, potassium and kidney function allow, and titrate every 2 to 4 weeks to target or maximum tolerated dose. Do not wait to reach full dose of one group before starting another.
• Target doses: sacubitril-valsartan 97/103 mg twice daily; enalapril 10 to 20 mg twice daily; ramipril 5 mg twice daily; bisoprolol 10 mg daily; carvedilol 25 mg twice daily (50 mg twice daily over 85 kg); metoprolol succinate 200 mg daily; spironolactone 25 to 50 mg daily; eplerenone 50 mg daily; dapagliflozin or empagliflozin 10 mg daily.
• Congestion: furosemide 20 to 80 mg daily or twice daily, torasemide 5 to 20 mg daily or bumetanide 0.5 to 2 mg daily, adjusted to weight and symptoms.
• Ivabradine: sinus rhythm with resting rate 70 beats/minute or over despite maximum tolerated beta blocker. 5 mg twice daily (2.5 mg twice daily if over 75 years), then 7.5 mg twice daily to a target rate of 50 to 60 beats/minute.
• Vericiguat: after a worsening event on therapy, 2.5 mg daily, doubled every 2 weeks to 10 mg daily. Contraindicated in pregnancy and with long-acting nitrates or phosphodiesterase 5 inhibitors.
• Iron deficiency: intravenous iron (ferric carboxymaltose or derisomaltose) when ferritin is under 100 micrograms/L, or 100 to 299 micrograms/L with transferrin saturation under 20%, to improve symptoms and reduce hospitalisation.
• Mildly reduced or preserved ejection fraction: SGLT2 inhibitor, loop diuretic for congestion, then MRA or sacubitril-valsartan. Treat hypertension, atrial fibrillation and obesity.
• Device and referral: implantable defibrillator if LVEF stays 35% or under after 3 months of optimal therapy, and resynchronisation for left bundle branch block with QRS 150 ms or over. Refer for advanced heart failure assessment when symptoms persist despite therapy.
• Acute decompensation: intravenous loop diuretic, oxygen if hypoxic, vasodilator if blood pressure is high, inotrope or vasopressor for shock, and start or resume prognostic drugs before discharge.

Drugs to avoid. NSAIDs, verapamil and diltiazem (reduced ejection fraction), thiazolidinediones, class I antiarrhythmics, dronedarone, cilostazol, and saxagliptin.

Adverse effects by group. Hypotension and kidney injury with renin-angiotensin blockade, hyperkalaemia with MRAs and renin-angiotensin blockers, bradycardia and fatigue with beta blockers, genital infection and volume depletion with SGLT2 inhibitors, electrolyte disturbance with diuretics.

Monitoring. Weight daily, blood pressure, heart rate, potassium and creatinine 1 to 2 weeks after each renin-angiotensin blocker or MRA change, NT-proBNP, electrolytes, and echocardiography after 3 months of optimal therapy.

Sick day rule. Withhold diuretics, renin-angiotensin blockers, MRAs and SGLT2 inhibitors during dehydrating illness and restart after recovery.

Referral and escalation. Worsening dyspnoea, weight gain over 2 kg in 3 days, syncope or low blood pressure with poor perfusion needs urgent review.

Special groups. Pregnancy: avoid renin-angiotensin blockers, MRAs and SGLT2 inhibitors; use hydralazine with nitrate, metoprolol or labetalol, and diuretics, with specialist input. Peripartum cardiomyopathy: specialist use of bromocriptine may be considered. Older adults: start low and monitor falls. Kidney disease: monitor potassium and creatinine closely. Rheumatic valve disease: treat the valve lesion and anticoagulate atrial fibrillation with warfarin.