Pharmacology
Heart failure — GDMT quadruple therapy
Pharmacology

Heart failure — GDMT quadruple therapy

The four pillars for HFrEF, when to add SGLT2i and ARNI, when to use ivabradine/hydralazine-ISDN, what to AVOID.

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◆Quadruple therapy for HFrEF (ALL benefit ASAP)

  • •1. ARNI (sacubitril-valsartan) — preferred over ACE-I/ARB if tolerated; 36-hr washout from ACE-I before starting
  • •2. β-blocker — carvedilol, metoprolol SUCCINATE, or bisoprolol (ONLY these three have mortality benefit)
  • •3. MRA (spironolactone or eplerenone) — eplerenone for gynecomastia from spiro
  • •4. SGLT2 inhibitor (empagliflozin, dapagliflozin) — works in both HFrEF and HFpEF, with or without diabetes

◆Second-tier add-ons

  • •Hydralazine + isosorbide dinitrate — Black patients with HFrEF on optimized GDMT (A-HeFT) or ACE-I intolerant
  • •Ivabradine — sinus rhythm + HR >70 on max β-blocker
  • •Loop diuretic (furosemide) — symptom relief (volume overload); does NOT reduce mortality
  • •Digoxin — reduces hospitalizations (not mortality) in symptomatic HFrEF

◆HFpEF

  • •Less proven mortality benefit overall — manage comorbidities (HTN, AFib, OSA, obesity)
  • •SGLT2i has mortality benefit in HFpEF (EMPEROR-Preserved, DELIVER) — NEW first-line
  • •MRA modest benefit (TOPCAT post-hoc analysis)
  • •Loop diuretics for congestion
  • •AVOID excessive ↓ preload (HFpEF needs adequate filling)

◆Acute decompensated HF

  • •LMNOP: Loop diuretics, Morphine (controversial), Nitrates, O₂, Position (upright)
  • •Hypotensive cardiogenic shock → norepinephrine + dobutamine; consider milrinone if RV failure or pulmonary HTN
  • •Refractory: mechanical support (IABP, Impella, VA-ECMO), then evaluate for LVAD or transplant

◆Drugs to AVOID in HFrEF

  • •Non-DHP CCBs (verapamil, diltiazem) — negative inotropy
  • •TZDs (pioglitazone, rosiglitazone) — fluid retention
  • •NSAIDs — Na/water retention + ↓ ACE-I efficacy
  • •Class IC antiarrhythmics (flecainide, propafenone) — proarrhythmia
  • •Most antipsychotics, some chemo (anthracyclines, trastuzumab) — direct cardiotoxicity

◆Device therapy

  • •ICD: EF ≤35% from ischemic cardiomyopathy ≥40 days post-MI OR non-ischemic on optimal med therapy ≥3 mo (NYHA II–III)
  • •CRT (biventricular pacer): EF ≤35% + LBBB QRS ≥150 ms + NYHA II–III on optimal therapy
  • •LVAD / heart transplant: end-stage refractory HF

Mortality-benefit summary HFrEF

Drug classEffect
ARNI > ACE-I > ARB↓ mortality, ↓ hospitalizations
β-blocker (carve/meto-S/biso)↓ mortality, ↓ hospitalizations
MRA (spiro, epler)↓ mortality
SGLT2 inhibitor↓ mortality, ↓ hospitalizations
Hydralazine + ISDN (Black pts)↓ mortality
Ivabradine↓ hospitalizations
Digoxin↓ hospitalizations only
Loop diureticSymptoms only, no mortality benefit

High-yield pearls

  • ◆Only THREE β-blockers in HFrEF: carvedilol, metoprolol SUCCINATE (NOT tartrate), bisoprolol
  • ◆ARNI replaces ACE-I/ARB — DON'T combine (angioedema risk)
  • ◆SGLT2 inhibitors now first-line in BOTH HFrEF and HFpEF (mortality benefit in both)
  • ◆Spironolactone → gynecomastia? switch to EPLERENONE (selective MR antagonist)
  • ◆Sacubitril-valsartan: 36-hour washout after stopping ACE-I before starting (angioedema risk overlap)
  • ◆Pioglitazone + HF = NO (fluid retention worsens HF)
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