Drugs for Heart Failure

1. Diuretics (Symptomatic Relief)

Loop Diuretics

• Furosemide, Bumetanide, Torasemide
• First-line for volume overload; cause rapid, intense diuresis
• Used at all stages; IV form used when oral absorption is impaired (gut edema)
• In severe/stage D HF, loop diuretics can be combined with a thiazide (e.g., hydrochlorothiazide, metolazone) to block different nephron segments synergistically
• The carbonic anhydrase inhibitor acetazolamide can be added acutely to augment decongestion
• Diuretics alone do not reduce mortality - disease-modifying agents must be added

Thiazide / Thiazide-like Diuretics

• Used in milder HF or in combination with loop diuretics in resistant cases
• Combination requires close monitoring of electrolytes (hyponatremia, hypo/hyperkalemia) and renal function

⚠️ Diuretics relieve symptoms but do not slow structural progression or reduce premature death on their own.

• Goldman-Cecil Medicine, p. 482

2. The "Four Pillars" of HFrEF Disease Modification

Pillar 1 - ARNI (or ACE Inhibitor / ARB)

• Combines angiotensin receptor blockade (valsartan) with neprilysin inhibition (sacubitril)
• Neprilysin inhibition increases natriuretic peptides (ANP, BNP), promoting vasodilation and natriuresis
• Reduces mortality and hospitalization more than ACE inhibitor (PARADIGM-HF trial)
• Key caution: Never combine with ACE inhibitor (risk of angioedema); must have 36-hour washout from ACE inhibitor before starting

• Inhibit conversion of Ang I → Ang II; reduce harmful neurohormonal activation
• Indicated in all patients with left ventricular systolic dysfunction regardless of symptoms or etiology
• Common side effect: dry cough (due to bradykinin accumulation) → switch to ARB
• Contraindicated in bilateral renal artery stenosis, pregnancy, history of angioedema

• Block angiotensin II at the AT1 receptor directly
• Do not cause cough; used when ACE inhibitor is not tolerated

Pillar 2 - Beta-Blockers

• Block the harmful effects of chronic sympathetic activation (catecholamine toxicity, remodeling)
• Reduce mortality, sudden cardiac death, and hospitalizations
• Must be started at low dose and up-titrated slowly over weeks
• Do NOT start during acute decompensated HF; start only when patient is euvolemic/stable
• Side effects: bradycardia, hypotension, fatigue, worsening dyspnea initially
• If heart rate <50 bpm with worsening symptoms: halve the dose; rarely need to stop entirely

Pillar 3 - Mineralocorticoid Receptor Antagonists (MRAs)

• Block aldosterone receptors → reduce sodium retention, fibrosis, myocardial remodeling
• Added to standard therapy (diuretic + ACE inhibitor/ARB/ARNI + beta-blocker) in NYHA class II-IV
• Both increase survival and reduce hospitalizations
• Key risks: Hyperkalemia (monitor K⁺ closely), gynecomastia (spironolactone > eplerenone), renal impairment
• Contraindicated if eGFR <30 mL/min or K⁺ >5.0 mmol/L

Pillar 4 - SGLT2 Inhibitors

• Originally antidiabetic drugs; now proven to reduce HF hospitalization and cardiovascular death in both diabetic and non-diabetic HF patients
• Mechanism in HF: osmotic diuresis, natriuresis, reduced preload/afterload, metabolic effects (ketone body utilization), anti-inflammatory and anti-fibrotic effects
• Benefit seen in HFrEF and HFmrEF/HFpEF (dapagliflozin, empagliflozin)
• Side effects: genital mycotic infections (5-10%), urinary tract infections, rare euglycemic diabetic ketoacidosis (especially in type 1 DM / insulin users)
• Sick day rule: Stop SGLT2 inhibitor when acutely unwell or 3 days before surgery
• Goldman-Cecil Medicine, p. 482

Recent meta-analysis (PMID 39993464): GLP-1 receptor agonists (e.g., semaglutide) also show benefit in HF with mildly reduced or preserved EF - an emerging area.

3. Additional / Adjunct Drugs

Ivabradine

• Inhibits the If ("funny") current in the SA node → reduces heart rate without affecting contractility or blood pressure
• Indicated when heart rate remains ≥70 bpm on maximum tolerated beta-blocker (or when beta-blocker is not tolerated) in sinus rhythm
• Reduces HF hospitalization (SHIFT trial)
• Not for patients with atrial fibrillation

Digoxin

• Cardiac glycoside; inhibits Na⁺/K⁺-ATPase → increases intracellular Ca²⁺ → positive inotropy
• Also has vagotonic effects (slows AV conduction - useful in AF with rapid ventricular rate)
• In sinus rhythm: added when HF remains symptomatic despite ARNI/ACE-I/ARB + beta-blocker + MRA + SGLT2i
• Does not reduce mortality, but reduces hospitalizations
• Narrow therapeutic window; target serum level 0.5-0.9 ng/mL
• Loading dose: 10-15 μg/kg lean body weight in 3 divided doses; maintenance = 1/3 loading dose
• Reduce dose in elderly, renal impairment, low body mass
• Blood levels checked ≥6 hours post-dose (ideally 8-12 hours)
• Toxicity: bradycardia, heart block, visual disturbances (yellow-green halos), nausea/vomiting

Hydralazine + Isosorbide Dinitrate (H-ISDN)

• Combination vasodilator (arterial + venous)
• Alternative when ACE inhibitor/ARB/ARNI is contraindicated (e.g., renal failure, angioedema)
• Particularly beneficial in Black patients with HFrEF (A-HeFT trial)
• Side effects: headache, reflex tachycardia, lupus-like syndrome (hydralazine)

Vericiguat

• Soluble guanylate cyclase (sGC) stimulator
• Increases cGMP → vasodilation
• For high-risk HFrEF patients recently hospitalized for worsening HF
• Used on top of optimal medical therapy

4. HFpEF (Preserved EF) - Specific Notes

• SGLT2 inhibitors (empagliflozin, dapagliflozin) - now have evidence for HFpEF
• Diuretics - for symptom control
• Spironolactone - may reduce hospitalizations
• Blood pressure control remains key
• ACE inhibitors and beta-blockers have not consistently shown mortality benefit in HFpEF

Quick Reference Summary Table

• Goldman-Cecil Medicine International Edition - Heart Failure chapter, pp. 479-490
• Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine
• Textbook of Family Medicine, 9th Edition
• Recent evidence: GLP-1 RA meta-analysis in HFpEF/HFmrEF (J Card Fail, 2025); SGLT2i kidney outcomes meta-analysis (JAMA, 2026)