2.2 Heart Failure & Antiarrhythmic Drugs

Pharmacologic Foundations of HFrEF

Modern management of heart failure with reduced ejection fraction (HFrEF) rests on four drug classes, each with proven mortality benefit - often called the "four pillars":

1. ARNI: Sacubitril/Valsartan

Sacubitril/valsartan combines the neprilysin inhibitor sacubitril with the ARB valsartan. Neprilysin degrades natriuretic peptides (which promote natriuresis, vasodilation, and anti-remodeling effects); inhibiting it raises natriuretic peptide levels. Because neprilysin inhibition alone also raises angiotensin II, an ARB is co-formulated. In the PARADIGM-HF trial, sacubitril/valsartan reduced cardiovascular death and heart-failure hospitalization by about 20% versus enalapril.

The critical exam point is the 36-hour washout: when switching a patient from an ACE inhibitor to sacubitril/valsartan, stop the ACE inhibitor and wait 36 hours before the first dose. Overlapping ACE and neprilysin inhibition dramatically raises bradykinin and the risk of angioedema. The combination is contraindicated with any ACE inhibitor, in pregnancy, and after prior angioedema. Main adverse effects: hypotension, hyperkalemia, and renal impairment.

2. Evidence-Based Beta-Blockers

Only three beta-blockers carry mortality evidence in HFrEF: carvedilol, bisoprolol, and metoprolol succinate (the extended-release form - metoprolol tartrate and atenolol are not evidence-based for HFrEF). They block chronic sympathetic overstimulation, reducing mortality by roughly a third. Initiate only in stable, euvolemic patients, start low and uptitrate slowly, and expect possible transient worsening of congestion during initiation. Do not start during acute decompensated heart failure.

3. Mineralocorticoid Receptor Antagonists (MRAs)

Spironolactone (RALES) and eplerenone (EPHESUS, EMPHASIS-HF) block aldosterone's sodium-retaining and pro-fibrotic effects. The practical limits are hyperkalemia and renal function: avoid starting when serum potassium exceeds 5.0 mEq/L or eGFR is below 30 mL/min, and recheck potassium and creatinine within the first week and periodically thereafter - especially in patients also on ACE inhibitors, ARBs, or ARNIs. Spironolactone causes gynecomastia in about 10% of men through anti-androgen activity; eplerenone is more receptor-selective and spares this effect.

4. SGLT2 Inhibitors

Dapagliflozin (DAPA-HF) and empagliflozin (EMPEROR-Reduced) reduce heart-failure hospitalization and cardiovascular death in HFrEF regardless of diabetes status. Counsel about genital mycotic infections, volume depletion, and the rare but serious euglycemic diabetic ketoacidosis.

Symptomatic and Add-On Agents

Loop diuretics (furosemide, torsemide, bumetanide) relieve congestion and improve symptoms but have no mortality benefit - titrate to the lowest dose that maintains euvolemia.

Digoxin inhibits the membrane Na+/K+-ATPase, raising intracellular sodium, which reduces Na+/Ca2+ exchange and raises intracellular calcium - a positive inotropic effect. Vagomimetic effects slow AV nodal conduction, making digoxin useful for rate control in atrial fibrillation, particularly when blood pressure limits other agents. It reduces hospitalizations but not mortality.

Digoxin has a narrow therapeutic index: the traditional therapeutic range is 0.5-2.0 ng/mL, with many HF clinicians targeting 0.5-0.9 ng/mL. Draw levels at least 6 hours post-dose (ideally 6-12 hours) to allow distribution. Toxicity presents with:

• GI: nausea, vomiting, anorexia
• Visual/neurologic: blurred vision, yellow-green halos (xanthopsia), confusion
• Cardiac: virtually any arrhythmia - classically atrial tachycardia with AV block, or bidirectional ventricular tachycardia

Toxicity is potentiated by hypokalemia, hypomagnesemia, hypercalcemia, renal impairment, and hypothyroidism - a thiazide or loop diuretic causing hypokalemia can push a stable digoxin patient into toxicity. Amiodarone, verapamil, quinidine, and macrolide antibiotics raise digoxin concentrations (P-glycoprotein inhibition); reduce the digoxin dose, by about half with amiodarone. Digoxin is renally cleared, so reduce dosing in CKD and the elderly. Life-threatening toxicity is treated with digoxin immune Fab fragments.

Hydralazine plus isosorbide dinitrate combines an arterial and a venous vasodilator. It improved outcomes in self-identified Black patients with HFrEF (A-HeFT) and is an alternative when ACE inhibitors, ARBs, and ARNIs are not tolerated (e.g., advanced renal dysfunction or refractory hyperkalemia). Hydralazine can cause drug-induced lupus and reflex tachycardia; the nitrate component causes headache and tolerance (see section 2.3).

Antiarrhythmics: Vaughan-Williams Classification

The Cardiac Arrhythmia Suppression Trial (CAST) is a favorite exam fact: flecainide and encainide suppressed ventricular ectopy after myocardial infarction but increased mortality. Hence Class Ic agents are reserved for patients without structural or ischemic heart disease (e.g., selected paroxysmal AF "pill-in-pocket" use).

Amiodarone Deep Dive

Amiodarone is a Class III agent with properties of all four Vaughan-Williams classes and is effective for atrial and ventricular arrhythmias. It is a structural analogue of thyroxine, about 37% iodine by weight, with an enormous volume of distribution and a half-life of roughly 40-55 days - loading doses are needed, and effects persist for weeks after stopping.

Organ toxicities to memorize:

• Pulmonary fibrosis/pneumonitis - the most serious; baseline chest X-ray and pulmonary function tests, with evaluation of any new dyspnea or cough
• Thyroid dysfunction - both hypothyroidism (common) and amiodarone-induced thyrotoxicosis; check TSH at baseline and every 6 months
• Hepatotoxicity - monitor liver enzymes
• Corneal microdeposits - nearly universal, usually benign; eye exam if visual symptoms
• Photosensitivity and blue-gray skin discoloration
• Bradycardia and QT prolongation - despite prolonging the QT, amiodarone has a relatively low torsades risk

Key interactions: amiodarone inhibits CYP2C9 and P-glycoprotein, so it potentiates warfarin (reduce the warfarin dose by roughly 25-30% and monitor INR closely) and raises digoxin levels (reduce digoxin by ~50%). Avoid combining with other QT-prolonging drugs.

Adenosine

Adenosine is an endogenous nucleoside that activates A1 receptors, producing transient AV nodal blockade - it is the drug of choice for terminating paroxysmal supraventricular tachycardia (SVT). Give it as a rapid IV push followed by a fast saline flush because its half-life is under 10 seconds. Patients experience brief flushing, chest pressure, dyspnea, and a moment of asystole - warn them beforehand. Use caution in asthma (bronchospasm) and avoid in high-degree AV block. Effects are antagonized by methylxanthines (caffeine, theophylline) and potentiated by dipyridamole.