Heart Failure Pharmacology

HF Classification (ACC/AHA Staging)

Drug Classes

1. Diuretics

• Loop diuretics (furosemide, bumetanide, torsemide): First-line for congestion/edema. Furosemide IV in acute decompensation. Cause secondary K+ and Mg2+ loss - monitor closely.
• Thiazides (hydrochlorothiazide, metolazone): Used for mild HF or added to loop diuretics for diuretic resistance.
• SGLT2 inhibitors (below) also exert natriuresis and partially substitute for traditional diuretics.

2. RAAS Inhibitors

ACE Inhibitors (ACEi)

• Reduce preload and afterload; slow ventricular remodeling; reduce mortality in all NYHA classes.
• This is a class effect - all ACEi appear effective.
• Common agents and target doses:

• Contraindications: History of angioedema, bilateral renal artery stenosis, K+ >5.0 mmol/L, creatinine >2.5 mg/dL, SBP <90 mmHg.
• Do not combine with ARNI (angioedema risk).

ARBs (Angiotensin Receptor Blockers)

• Similar hemodynamic benefit to ACEi. Reserve as ACEi alternatives (usually due to cough).
• Candesartan and valsartan have mortality/hospitalization data in HF.
• When used alone, ARBs are less preferred than ARNI.

ARNI - Sacubitril/Valsartan (Entresto)

• Combines neprilysin inhibitor (sacubitril) + ARB. Neprilysin inhibition elevates natriuretic peptides (ANP, BNP), promoting vasodilation and natriuresis.
• Preferred first-line over ACEi/ARB in HFrEF (NYHA II-IV). Can be initiated even during hospitalization for decompensated HF.
• Also reduces NT-proBNP and symptoms in HFpEF.
• Never combine with ACEi (angioedema risk); wash out ACEi for 36 hours before starting.

3. Beta-Blockers

• Based on antagonizing excess catecholamine-mediated harm (tachycardia, myocardial injury, remodeling).
• Start low, titrate slowly (no faster than every 2 weeks). Effects may take 3-6 months to manifest.
• Only these four beta-blockers have mortality benefit in HFrEF:

• Carvedilol additionally blocks alpha-1 receptors (vasodilation) and has antioxidant properties.
• Do not initiate during acute decompensation or in unstable/IV-diuretic-dependent patients. Halve dose if worsening congestion occurs.
• Calcium channel blockers (amlodipine excepted) are generally avoided - their negative inotropy can worsen HF.

4. Mineralocorticoid Receptor Antagonists (MRAs)

• Spironolactone and eplerenone: Reduce morbidity and mortality in moderate-to-severe HFrEF.
• Block aldosterone-mediated fibrosis and sodium retention.
• Eplerenone is preferred post-MI and in patients who develop gynecomastia on spironolactone.
• Monitor K+ and renal function closely; avoid if K+ >5.5 mmol/L or eGFR <30.
• A 2024 Lancet individual patient meta-analysis (PMID 39232490) confirmed benefit of MRAs across HF with reduced and mildly reduced EF.

5. SGLT2 Inhibitors (Gliflozins)

• Dapagliflozin (Farxiga) and empagliflozin (Jardiance): Reduce HF hospitalizations and cardiovascular death in both HFrEF and HFpEF (regardless of diabetes status).
• Mechanisms: natriuresis, osmotic diuresis, reduced inflammation/fibrosis, improved cardiac energetics.
• SGLT2i are now first-line in HFpEF (alongside BP/HR control).
• Benefit also seen for stages A and B (prevention).

6. Ivabradine (I_f Channel Blocker)

• Blocks the funny current (I_f) in the SA node, reducing heart rate without affecting contractility.
• Indicated in HFrEF with resting HR ≥70 bpm on maximal beta-blocker (or beta-blocker intolerant), LVEF ≤35%, NYHA II-III.
• Reduces HF hospitalizations.

7. Hydralazine + Isosorbide Dinitrate (H-ISDN)

• Venous (nitrate) + arteriolar (hydralazine) vasodilation.
• BiDil (fixed combination) is recommended specifically for Black patients with HFrEF who cannot tolerate RAAS blockade, or as add-on therapy.
• Also useful when ACEi/ARB/ARNI are contraindicated (e.g., renal failure).

8. Digoxin

• Inhibits Na+/K+-ATPase → increased intracellular Ca2+ → positive inotropy. Also slows AV conduction (useful in AF).
• Indications: HF + atrial fibrillation; persistent symptoms despite optimized quadruple therapy.
• Narrow therapeutic index; toxicity risk (nausea, visual changes, arrhythmias) - especially with hypokalemia.
• Only ~50% of HFrEF patients in sinus rhythm benefit.
• Does not reduce mortality but reduces hospitalizations and symptoms.

9. Vericiguat (sGC Stimulator)

• Stimulates soluble guanylate cyclase, increasing cGMP and causing vasodilation.
• Approved for worsening chronic HFrEF (NYHA II-IV) despite optimized therapy.
• Reduces cardiovascular death/HF hospitalizations in high-risk patients.

Acute Decompensated HF (ADHF)

HFpEF (EF ≥50%) - Special Considerations

Drugs to Avoid in HF

• NSAIDs: Sodium retention, worsen renal function, blunt diuretic effect
• Most CCBs: Negative inotropy (except amlodipine/felodipine, which are safe)
• Class I antiarrhythmics (flecainide, etc.): Pro-arrhythmic
• Thiazolidinediones (rosiglitazone, pioglitazone): Fluid retention
• Tricyclic antidepressants: Negative inotropy

Recent Evidence Updates

• MRAs (Lancet, 2024, PMID 39232490): Individual patient meta-analysis confirmed mortality and hospitalization benefit across HFrEF and HFmrEF.
• GLP-1 Receptor Agonists (J Card Fail, 2025, PMID 39993464): Systematic review/meta-analysis showing efficacy in HFpEF and HFmrEF - an emerging role for semaglutide/tirzepatide in HF with obesity.