7.3 Heart Failure Drugs
Heart failure treatment aims to improve symptoms, reduce hospitalizations, and prolong survival. Drugs target neurohormonal activation (RAAS, SNS) and hemodynamic abnormalities.
ACE Inhibitors
Mechanism in Heart Failure
↓ Angiotensin II → ↓ afterload (vasodilation), ↓ preload (↓ aldosterone → ↓ volume)
↓ Cardiac remodeling (↓ fibrosis, ↓ hypertrophy)
↓ Sympathetic activation
Evidence & Benefits
HFrEF (reduced EF <40%): First-line therapy
Mortality reduction: ~20-30% (landmark trials: SOLVD, CONSENSUS)
↓ Hospitalizations, ↑ exercise tolerance, ↑ quality of life
Start low, titrate up to target or max tolerated dose
Common Agents
Enalapril, lisinopril, ramipril, captopril
Monitor: BP, renal function, K⁺ (especially with MRA or in CKD)
ARBs (Angiotensin Receptor Blockers)
Role in Heart Failure
Alternative to ACE inhibitors if intolerant (cough, angioedema)
Similar mortality benefit in HFrEF
Valsartan, losartan, candesartan
ACEI + ARB Combination
Generally NOT recommended—↑ adverse effects (hyperkalemia, hypotension, renal dysfunction)
No additional mortality benefit vs. monotherapy (ONTARGET trial)
Exception: Replaced by ARNI (see below)
ARNI - Angiotensin Receptor-Neprilysin Inhibitor
Sacubitril/Valsartan (Entresto)
Combination drug: sacubitril (neprilysin inhibitor) + valsartan (ARB)
Neprilysin: Enzyme that degrades natriuretic peptides (ANP, BNP), bradykinin
Inhibition → ↑ natriuretic peptides → natriuresis, vasodilation, ↓ fibrosis
Clinical Benefits
PARADIGM-HF trial: 20% ↓ CV death + HF hospitalization vs. enalapril
Now preferred over ACEI/ARB alone in HFrEF (Class I recommendation)
Requires 36-hour washout from ACEI before starting (angioedema risk)
Side Effects
Hypotension, hyperkalemia, renal dysfunction (similar to ACEI/ARB)
Angioedema (higher risk than ARB alone—neprilysin also degrades bradykinin)
Beta-Blockers
Mechanism in Heart Failure
Counter chronic sympathetic activation (harmful in HF)
↓ HR → ↑ diastolic filling time, ↓ O₂ demand
↓ Arrhythmias, ↓ cardiac remodeling, ↑ EF over time
Evidence-Based Beta-Blockers
Carvedilol: Non-selective β + α₁ blockade, additional antioxidant effects
Metoprolol succinate (extended-release): β₁-selective
Bisoprolol: β₁-selective, widely used in Europe
Mortality reduction ~35% in HFrEF (COPERNICUS, MERIT-HF, CIBIS-II)
Initiation & Titration
Start LOW dose when stable (euvolemic, not acutely decompensated)
Uptitrate slowly every 2-4 weeks to target or max tolerated
May worsen symptoms initially—educate patient, don't stop abruptly
Contraindications: Decompensated HF, cardiogenic shock, severe bradycardia/AV block
Mineralocorticoid Receptor Antagonists (MRAs)
Mechanism
Aldosterone antagonists (competitive inhibition at receptor)
↓ Na⁺/H₂O retention, ↓ K⁺ excretion, ↓ cardiac fibrosis
Aldosterone escape phenomenon: ACEI/ARB incompletely suppress aldosterone
Spironolactone & Eplerenone
Spironolactone: Non-selective (also binds androgen/progesterone receptors)
RALES trial: 30% ↓ mortality in severe HFrEF (NYHA III-IV)
Eplerenone: Selective MRA, fewer hormonal side effects
EMPHASIS-HF: mortality benefit in mild-moderate HFrEF
Clinical Use & Monitoring
Add to ACEI/ARB + β-blocker in HFrEF with symptoms (NYHA II-IV)
Post-MI with LV dysfunction
Major risk: Hyperkalemia (especially with ACEI/ARB, CKD)
Monitor K⁺ and creatinine closely—K⁺ >5.5 or Cr >2.5 = contraindication
Spironolactone side effects: Gynecomastia, breast tenderness (10-20%)
Diuretics
Loop Diuretics - Symptom Relief
Furosemide, bumetanide, torsemide
↓ Preload, relieve congestion (dyspnea, edema)
NO mortality benefit—symptomatic treatment only
Titrate to lowest effective dose (↓ neurohormonal activation)
Practical Considerations
IV for acute decompensation: rapid symptom relief
Oral for chronic management: adjust based on daily weights, symptoms
Diuretic resistance: ↑ dose, switch to torsemide (better bioavailability), add thiazide
Monitor: K⁺, Mg²⁺, renal function, volume status
Digoxin
Mechanism
Na⁺/K⁺-ATPase inhibitor → ↑ intracellular Na⁺ → ↓ Na⁺/Ca²⁺ exchanger → ↑ intracellular Ca²⁺
Positive inotrope (↑ contractility)
↑ Vagal tone → ↓ AV conduction (useful in AFib with HF)
Evidence in Heart Failure
DIG trial: NO mortality benefit, but ↓ hospitalizations
Symptom improvement in HFrEF with persistent symptoms despite ACEI/β-blocker
Also for AFib rate control in HF patients
Dosing & Toxicity
Low-dose (0.125 mg/day) preferred—narrow therapeutic window
Target level: 0.5-0.9 ng/mL (levels >1.2 associated with ↑ mortality)
Toxicity: GI upset, visual changes, arrhythmias (any type)
Risk factors: Hypokalemia, hypomagnesemia, renal insufficiency, elderly
Treatment of toxicity: Digoxin-specific Fab antibodies (severe cases)
Newer Agents
SGLT2 Inhibitors
Dapagliflozin, empagliflozin (originally diabetes drugs)
↓ CV death + HF hospitalization in HFrEF (DAPA-HF, EMPEROR-Reduced)
Also benefit HFpEF (preserved EF)—unique among HF drugs
Mechanisms: Natriuresis, ↓ preload/afterload, metabolic effects
Now recommended for all HFrEF patients (Class I)
Ivabradine
If (funny current) inhibitor in SA node
Selective HR reduction (no ↓ BP or contractility)
HFrEF with sinus rhythm, HR ≥70 despite β-blocker
SHIFT trial: ↓ HF hospitalizations
Side effects: Visual disturbances (phosphenes), bradycardia
Hydralazine + Isosorbide Dinitrate
Combination vasodilators (arterial + venous)
Alternative if intolerant to ACEI/ARB/ARNI
Mortality benefit in African American patients (A-HeFT trial)
Add-on to standard therapy in this population
Vericiguat
Soluble guanylate cyclase (sGC) stimulator
↑ cGMP → vasodilation, ↓ fibrosis
VICTORIA trial: modest ↓ CV death + HF hospitalization
For worsening HFrEF despite guideline-directed therapy
Guideline-Directed Medical Therapy (GDMT) Summary
Core Four for HFrEF (All with Mortality Benefit)
1. ARNI (or ACEI/ARB if ARNI not available/tolerated)
2. Beta-blocker (carvedilol, metoprolol succinate, or bisoprolol)
3. MRA (spironolactone or eplerenone)
4. SGLT2 inhibitor (dapagliflozin or empagliflozin)
Add as needed: Loop diuretic (symptoms), digoxin (persistent symptoms/AFib), ivabradine (HR ≥70)
Goal: Optimize all four pillars to target or max tolerated dose