Drugs Used in Heart Failure
Pharmacology · CVS · lean revision notes
Drugs Used in Heart Failure
Heart failure pharmacology is one of the highest-yield therapeutic blocks in NEET PG, because the field has been completely reorganised around the concept of mortality-modifying versus symptom-relieving drugs. Mastering which agent saves lives, which only improves symptoms, the drug of choice in HFrEF versus HFpEF, and the classic contraindications (bilateral renal artery stenosis, hyperkalaemia, hypotension) earns reliable marks.
Classification of heart failure and the therapeutic logic
Heart failure (HF) is classified by ejection fraction (EF), because the drugs that reduce mortality work almost exclusively in reduced-EF disease.
| Type | EF cut-off | Pathophysiology | Mortality-proven drugs? |
|---|---|---|---|
| HFrEF (reduced) | EF ≤ 40% | Systolic pump failure, neurohormonal activation | Yes — the "four pillars" |
| HFmrEF (mildly reduced) | EF 41–49% | Intermediate | Modest benefit, extrapolated |
| HFpEF (preserved) | EF ≥ 50% | Diastolic dysfunction, stiff ventricle | Only SGLT2 inhibitors proven |
High-yield: The only drug class with class I evidence for reducing hospitalisation in HFpEF is the SGLT2 inhibitors (empagliflozin, dapagliflozin). All the other neurohormonal blockers were repeatedly shown to be ineffective for mortality in HFpEF.
The therapeutic paradigm shift: HF is no longer treated as a pure haemodynamic (pump) problem. It is a neurohormonal disease driven by chronic activation of the renin–angiotensin–aldosterone system (RAAS) and the sympathetic nervous system (SNS). Drugs that block these systems prolong life; drugs that merely flog the heart or unload it acutely (digoxin, diuretics, inotropes) relieve symptoms but do not prolong survival.
The Four Pillars of HFrEF (Guideline-Directed Medical Therapy)
Modern guidelines (ACC/AHA 2022, ESC 2021) recommend starting all four pillars early and together rather than the old sequential up-titration. Memorise this set cold.
Four pillars → (1) ARNI / ACE inhibitor / ARB → (2) Beta-blocker → (3) MRA (mineralocorticoid receptor antagonist) → (4) SGLT2 inhibitor
High-yield mnemonic — "ABCD2": ARNI/ACEi, Beta-blocker, C (aldosterone antagonist — think "Corticoid antagonist"), Dapagliflozin (SGLT2i). These four reduce mortality.
| Pillar | Prototype drugs | Primary benefit |
|---|---|---|
| RAAS blockade (ARNI > ACEi > ARB) | Sacubitril-valsartan; enalapril, ramipril; valsartan, candesartan | Mortality + symptoms |
| Beta-blocker | Carvedilol, metoprolol succinate, bisoprolol, nebivolol | Mortality |
| MRA | Spironolactone, eplerenone | Mortality |
| SGLT2 inhibitor | Dapagliflozin, empagliflozin | Mortality + HF hospitalisation (works in HFpEF too) |
1. RAAS blockade: ACE inhibitors, ARBs and ARNI
ACE inhibitors (ACEi)
Mechanism: Inhibit angiotensin-converting enzyme → reduce angiotensin II (less vasoconstriction, less aldosterone, less cardiac remodelling) and reduce bradykinin breakdown (vasodilatation, but also cough/angio-oedema).
- Proven mortality benefit in HFrEF (CONSENSUS trial with enalapril was landmark).
- Reduce both preload and afterload; reverse pathological remodelling.
- Drugs: enalapril, ramipril, lisinopril, captopril.
Adverse effects (mnemonic "CAPTOPRIL"): Cough (dry, bradykinin-mediated), Angio-oedema, Potassium excess (hyperkalaemia), Taste disturbance, Orthostatic hypotension, Pregnancy contraindication (foetal renal damage), Renal failure/Rash, Increased renin, Leukopenia.
High-yield: ACE inhibitors are absolutely contraindicated in bilateral renal artery stenosis (or stenosis in a solitary functioning kidney). In such patients the efferent arteriole is kept constricted by angiotensin II to maintain glomerular filtration pressure; blocking it causes a precipitous fall in GFR and acute renal failure. The same logic applies to ARBs and ARNI.
High-yield: A rise in serum creatinine up to ~30% after starting an ACEi is acceptable and does not require stopping the drug — it reflects expected efferent dilatation.
Angiotensin receptor blockers (ARBs)
Block the AT1 receptor directly. Used when ACEi cause cough/angio-oedema. No bradykinin effect → much less cough, lower (but not zero) angio-oedema risk. Drugs: valsartan, candesartan, losartan. Mortality benefit similar to ACEi but ACEi remain first-line historically.
ARNI — sacubitril-valsartan
This is the single highest-yield HF drug in recent exams.
- Components: sacubitril (a neprilysin inhibitor, given as a prodrug) + valsartan (an ARB).
- Neprilysin is the enzyme that degrades natriuretic peptides (ANP, BNP), bradykinin and adrenomedullin. Inhibiting it raises beneficial natriuretic peptides → natriuresis, vasodilatation, anti-remodelling.
- Why combine with an ARB? Neprilysin inhibition alone raises angiotensin II too; the ARB component blocks that.
High-yield (PARADIGM-HF trial): Sacubitril-valsartan was superior to enalapril for reducing cardiovascular death and HF hospitalisation. ARNI is now preferred over ACEi/ARB as the RAAS pillar in HFrEF.
High-yield — never combine ARNI with an ACEi. A 36-hour washout is mandatory when switching from an ACEi to ARNI, because dual neprilysin + ACE inhibition stacks bradykinin and causes serious angio-oedema.
- Biomarker pearl: ARNI raises BNP (BNP is a neprilysin substrate) but NT-proBNP is not degraded by neprilysin, so NT-proBNP is the monitoring biomarker in patients on sacubitril-valsartan.
2. Beta-blockers
Mechanism: Chronic sympathetic over-activity is toxic to failing myocardium (β1 down-regulation, calcium overload, apoptosis, arrhythmia). Beta-blockers reverse this — they up-regulate β-receptors, reduce heart rate, improve diastolic filling, prevent remodelling and reduce sudden cardiac death.
High-yield: Only four beta-blockers have proven mortality benefit in HFrEF — carvedilol, metoprolol succinate (extended-release), bisoprolol, and nebivolol (the last mainly in elderly, SENIORS trial). It is a class-specific, not class-wide, effect — atenolol and metoprolol tartrate are NOT proven.
- Carvedilol is a non-selective β-blocker with additional α1-blockade (extra vasodilatation) — favoured in hypertensive HF.
- Start low, go slow. Begin in a euvolaemic, stable patient; never start during acute decompensation because the initial negative inotropy can worsen failure.
High-yield: Beta-blockers are contraindicated / withheld in acute decompensated HF, but should be continued (not stopped) in a chronic HF patient who is hospitalised but stable.
3. Mineralocorticoid receptor antagonists (MRAs / aldosterone antagonists)
Mechanism: Block aldosterone at the mineralocorticoid receptor → potassium-sparing diuresis, but more importantly anti-fibrotic / anti-remodelling effects that reduce mortality.
| Drug | Selectivity | Distinguishing point |
|---|---|---|
| Spironolactone | Non-selective | Causes gynaecomastia, breast tenderness, impotence (anti-androgen + progestogenic) |
| Eplerenone | Selective | No gynaecomastia — use when spironolactone causes endocrine side-effects |
- Landmark trials: RALES (spironolactone) and EPHESUS (eplerenone, post-MI).
- Main danger = hyperkalaemia, especially when combined with ACEi/ARB and in renal impairment.
High-yield: Do not start an MRA if serum K⁺ > 5.0 mEq/L or eGFR < 30 mL/min/1.73m². Monitor potassium and creatinine within 1 week of initiation.
4. SGLT2 inhibitors ("gliflozins")
The newest pillar and a current examiner favourite.
Mechanism: Block the sodium-glucose co-transporter 2 in the proximal convoluted tubule → glycosuria, natriuresis, osmotic diuresis, reduced preload/afterload, improved cardiac energetics and reduced cardiac fibrosis. Benefit is independent of diabetes status.
- Drugs: dapagliflozin (DAPA-HF trial), empagliflozin (EMPEROR-Reduced/Preserved).
High-yield: SGLT2 inhibitors reduce HF hospitalisation and CV death across the whole spectrum — HFrEF AND HFpEF, and whether or not the patient is diabetic. This makes them unique among HF drugs.
Adverse effects: genital mycotic infections, urinary tract infections, euglycaemic diabetic ketoacidosis, volume depletion, rare Fournier gangrene.
Symptom-relieving drugs (NO independent mortality benefit)
These remain essential for symptom control but, in MCQs, the discriminating fact is that they do not prolong survival.
Diuretics
- Loop diuretics (furosemide, torsemide, bumetanide) are the drug of choice for relieving congestion / pulmonary oedema and volume overload. They give rapid symptom relief but do not reduce mortality.
- Thiazides used as add-on for diuretic resistance (sequential nephron blockade).
High-yield: Loop diuretics relieve breathlessness and oedema but do not improve survival — congestion control only.
Digoxin
Mechanism: Inhibits the Na⁺/K⁺-ATPase → raised intracellular Na⁺ → reduced Ca²⁺ extrusion via Na⁺/Ca²⁺ exchanger → raised intracellular calcium → positive inotropy. Also increases vagal tone (negative chronotropy).
- DIG trial: digoxin reduces hospitalisations but NOT mortality.
- Best niche: HFrEF with concomitant atrial fibrillation needing rate control, or persistently symptomatic patients despite GDMT.
- Narrow therapeutic index. Toxicity worsened by hypokalaemia (digoxin and K⁺ compete for the same site on the pump), hypomagnesaemia, hypercalcaemia and renal failure.
High-yield: Digoxin toxicity — yellow-green vision (xanthopsia), nausea, confusion, and arrhythmias; the most characteristic is bidirectional ventricular tachycardia and PAT with block. Treatment of life-threatening toxicity = digoxin-specific antibody fragments (Digibind / DigiFab).
Hydralazine + isosorbide dinitrate (H-ISDN)
- Hydralazine = arterial vasodilator (reduces afterload); nitrate = venodilator (reduces preload); together they unload the ventricle and the combination supplies nitric-oxide donor effect that reduces nitrate tolerance.
High-yield (A-HeFT trial): The hydralazine + nitrate combination has a mortality benefit specifically in self-identified African-American / Black patients with HFrEF, added on top of standard therapy. It is also the RAAS-blockade alternative when ACEi/ARB/ARNI are contraindicated (e.g., bilateral renal artery stenosis, severe renal failure, hyperkalaemia, pregnancy).
Ivabradine
- Selective inhibitor of the funny current (I_f) in the SA node → pure heart-rate reduction without affecting contractility or BP.
- SHIFT trial: reduces HF hospitalisation in patients in sinus rhythm with HR ≥ 70 bpm already on maximally tolerated beta-blocker.
High-yield: Ivabradine works only in sinus rhythm (no effect in atrial fibrillation). Characteristic side-effect = visual phosphenes (luminous brightness sensations) from retinal I_h channel block.
Vericiguat & other agents
- Vericiguat = soluble guanylate cyclase (sGC) stimulator (VICTORIA trial) — adjunct in worsening HFrEF.
- Acute decompensation inotropes: dobutamine, milrinone (PDE-3 inhibitor), dopamine, levosimendan (calcium sensitiser). All improve haemodynamics acutely but increase mortality with chronic use — bridge therapy only.
Drug of choice — quick decision flow
- HFrEF, chronic, stable → start all four pillars (ARNI + beta-blocker + MRA + SGLT2i), add loop diuretic for congestion.
- HFrEF + ACEi-induced cough → switch to ARB; ACEi-induced angio-oedema → switch to ARB (cautiously) or hydralazine-nitrate.
- HFrEF + atrial fibrillation needing rate control → add digoxin (or beta-blocker for rate).
- HFrEF in Black patients, still symptomatic → add hydralazine-nitrate.
- HFrEF, sinus rhythm, HR ≥ 70 despite max beta-blocker → add ivabradine.
- HFpEF → SGLT2 inhibitor + treat congestion with diuretic + control BP/AF; no other neurohormonal blocker has proven mortality benefit.
- Acute pulmonary oedema → sit up, oxygen, IV furosemide + nitrates + morphine (the classic "LMNOP": Lasix, Morphine, Nitrates, Oxygen, Position).
Drugs to AVOID in heart failure
High-yield: Memorise drugs that worsen HF — common single-best-answer question.
- Non-dihydropyridine calcium channel blockers — verapamil, diltiazem (negative inotropy worsens HFrEF).
- Most other CCBs except amlodipine/felodipine (these are safe if BP control needed).
- NSAIDs — sodium/water retention, blunt diuretics, worsen renal function.
- Thiazolidinediones (pioglitazone/rosiglitazone) — fluid retention, oedema.
- Class I antiarrhythmics (flecainide) — pro-arrhythmic in structural heart disease.
- Saxagliptin (DPP-4 inhibitor) — increased HF hospitalisation (SAVOR-TIMI).
Key differentials / contrasts examiners exploit
| Comparison | Key distinguishing fact |
|---|---|
| ACEi vs ARB | ARB has no cough, much less angio-oedema (no bradykinin) |
| Spironolactone vs eplerenone | Eplerenone = selective, no gynaecomastia |
| Carvedilol vs metoprolol | Carvedilol adds α-blockade (more vasodilatation) |
| Digoxin vs diuretic vs inotrope | None improve survival; all symptom relief |
| ARNI BNP vs NT-proBNP | ARNI raises BNP; monitor with NT-proBNP |
| Ivabradine vs beta-blocker | Ivabradine reduces HR with no inotropic/BP effect; sinus rhythm only |
Recently asked / exam angle
- Mechanism of sacubitril = neprilysin inhibitor; neprilysin degrades natriuretic peptides; ARNI = sacubitril + valsartan; 36-hour washout from ACEi; superior to enalapril in PARADIGM-HF.
- Which drug works in HFpEF? → SGLT2 inhibitors (empagliflozin/dapagliflozin) — frequently tested as the "only proven" agent.
- Contraindication in bilateral renal artery stenosis → ACEi / ARB / ARNI (efferent arteriolar dilatation drops GFR).
- Beta-blocker mortality is class-specific → only carvedilol, bisoprolol, metoprolol succinate, nebivolol.
- Digoxin mechanism = Na⁺/K⁺-ATPase inhibition; toxicity worsened by hypokalaemia; antidote = digoxin-specific Fab fragments.
- Hydralazine-nitrate benefit in Black/African-American patients (A-HeFT) and as substitute when RAAS blockers contraindicated.
- Ivabradine acts on I_f current in SA node, sinus rhythm only, causes phosphenes.
- MRA initiation cut-offs — K⁺ > 5.0 or eGFR < 30 → do not start.
- Spironolactone → gynaecomastia; switch to eplerenone.
- Drugs to avoid: verapamil/diltiazem, NSAIDs, pioglitazone, saxagliptin.
Rapid revision
- Four pillars of HFrEF: ARNI/ACEi/ARB + beta-blocker + MRA + SGLT2 inhibitor — all reduce mortality; start early together.
- Mortality benefit: RAAS blockers, beta-blockers, MRAs, SGLT2i, hydralazine-nitrate (in Black patients). No mortality benefit: diuretics, digoxin, inotropes.
- ARNI = sacubitril (neprilysin inhibitor) + valsartan; superior to enalapril (PARADIGM-HF); 36-hour ACEi washout; monitor NT-proBNP.
- ACEi/ARB/ARNI contraindicated in bilateral renal artery stenosis, pregnancy, hyperkalaemia, angio-oedema.
- SGLT2 inhibitors are the only proven drugs in HFpEF and work irrespective of diabetes.
- Only carvedilol, bisoprolol, metoprolol succinate, nebivolol beta-blockers proven; never start in acute decompensation.
- Spironolactone → gynaecomastia; eplerenone selective; avoid MRA if K⁺ > 5.0 or eGFR < 30.
- Loop diuretics = drug of choice for congestion/pulmonary oedema, symptom relief only.
- Digoxin: inhibits Na⁺/K⁺-ATPase, positive inotrope; best in HFrEF + AF; toxicity worsened by hypokalaemia; antidote = Fab fragments; xanthopsia + bidirectional VT.
- Ivabradine blocks SA-node I_f current; sinus rhythm + HR ≥ 70; causes phosphenes.
- Hydralazine + isosorbide dinitrate — afterload + preload reduction; mortality benefit in Black patients; RAAS-blocker substitute.
- Avoid in HF: verapamil, diltiazem, NSAIDs, pioglitazone/rosiglitazone, flecainide, saxagliptin.