What are the guideline-directed medical therapy (GDMT) medications for a patient with heart failure (HF), particularly those with heart failure with reduced ejection fraction (HFrEF) and a history of hypertension?

Guideline-Directed Medical Therapy (GDMT) for Heart Failure with Reduced Ejection Fraction

All patients with HFrEF should be started on four foundational medication classes simultaneously at low doses: an ARNI (or ACE inhibitor/ARB if ARNI not tolerated), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor, along with loop diuretics for volume management. 1, 2

The Four Pillars of GDMT

1. Renin-Angiotensin System Inhibition

ARNI (Angiotensin Receptor-Neprilysin Inhibitor) is preferred over ACE inhibitors or ARBs for patients with NYHA class II-III symptoms, providing superior mortality reduction of at least 20% compared to enalapril. 1, 2, 3

• Sacubitril/valsartan (Entresto): Start at 49/51 mg twice daily, titrate to target dose of 97/103 mg twice daily after 2-4 weeks 4, 5
• Critical washout requirement: Allow 36 hours between stopping an ACE inhibitor and starting ARNI to avoid angioedema 1, 4, 5

If ARNI is not tolerated or feasible, use an ACE inhibitor as the next best option:

• Enalapril: Start 2.5 mg twice daily, target 10-20 mg twice daily 4
• Lisinopril: Start 2.5-5 mg daily, target 20-40 mg daily 4
• Ramipril: Start 1.25-2.5 mg daily, target 10 mg daily 4

If ACE inhibitor causes cough or angioedema, use an ARB:

• Valsartan: Start 20-40 mg twice daily, target 160 mg twice daily 4
• Candesartan: Start 4-8 mg daily, target 32 mg daily 4

2. Beta-Blockers (Evidence-Based Only)

Use only the three beta-blockers proven to reduce mortality in HFrEF trials, which provide at least 20% reduction in mortality risk and decrease sudden cardiac death. 1, 2, 3

• Carvedilol: Start 3.125 mg twice daily, target 50 mg twice daily 4
• Metoprolol succinate (extended-release): Start 12.5-25 mg daily, target 200 mg daily 4
• Bisoprolol: Start 1.25 mg daily, target 10 mg daily 4

Do not use atenolol, metoprolol tartrate, or calcium channel blockers (diltiazem, verapamil) as these lack mortality benefit and may worsen outcomes. 3

3. Mineralocorticoid Receptor Antagonists (MRAs)

MRAs provide at least 20% mortality reduction and reduce sudden cardiac death in patients with NYHA class II-IV symptoms. 6, 1, 2

• Spironolactone: Start 12.5-25 mg daily, target 25-50 mg daily 6, 4, 7
• Eplerenone: Start 25 mg daily, target 50 mg daily 4

Eligibility criteria for MRAs:

• eGFR >30 mL/min/1.73 m² 6, 2
• Serum creatinine ≤2.5 mg/dL (men) or ≤2.0 mg/dL (women) 6
• Serum potassium <5.0 mEq/L 6, 2

Eplerenone avoids the 5.7% higher rate of gynecomastia seen with spironolactone, making it preferable in men concerned about this side effect. 8

4. SGLT2 Inhibitors (Newest Addition)

SGLT2 inhibitors reduce cardiovascular death and HF hospitalization regardless of diabetes status, with benefits occurring within weeks of initiation. 1, 2, 3

• Dapagliflozin: 10 mg once daily (no titration required), can use if eGFR ≥20 mL/min/1.73 m² 3, 8
• Empagliflozin: 10 mg once daily (no titration required), can use if eGFR ≥30 mL/min/1.73 m² 3, 8

SGLT2 inhibitors have minimal blood pressure effects (only -1.50 mmHg decrease in patients with baseline SBP 95-110 mmHg), making them ideal first agents in patients with low blood pressure. 3

Combined Mortality Benefit

Quadruple therapy reduces all-cause mortality by approximately 73% over 2 years compared to no treatment (HR 0.39,95% CI: 0.32-0.49), translating to approximately 5.3 additional life-years. 3, 8

Initiation Strategy: Simultaneous vs Sequential

Start all four medication classes simultaneously at low initial doses rather than waiting to achieve target dosing of one before initiating the next. 1, 2, 3

Recommended initiation sequence when starting simultaneously:

1. Start SGLT2 inhibitor and MRA first (minimal BP effects) 3
2. Add beta-blocker if heart rate >70 bpm 3
3. Add low-dose ARNI/ACEi/ARB 3

Uptitrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved. 6, 3

Volume Management with Diuretics

Loop diuretics are essential for congestion control but do not reduce mortality. 3

• Furosemide: Start 20-40 mg once or twice daily 3
• Torsemide: Start 10-20 mg once daily 3
• Bumetanide: Start 0.5-1.0 mg once or twice daily 3

Titrate diuretic dose to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use the lowest dose that maintains this state. 3

Additional Therapies for Specific Subgroups

For Self-Identified Black Patients with NYHA Class III-IV

Hydralazine/isosorbide dinitrate should be added to standard GDMT:

• Start hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily 3
• Target: hydralazine 75 mg three times daily + isosorbide dinitrate 40 mg three times daily 4

For Persistent Tachycardia Despite Beta-Blocker

Ivabradine can be added if heart rate ≥70 bpm in sinus rhythm despite maximally tolerated beta-blocker:

• Start 2.5-5 mg twice daily, target 7.5 mg twice daily 4, 3

Managing Low Blood Pressure During GDMT Optimization

Never discontinue or reduce GDMT for asymptomatic hypotension with adequate perfusion. Patients with adequate perfusion can tolerate systolic BP 80-100 mmHg. 3, 8

For symptomatic hypotension (SBP <80 mmHg or major symptoms):

Step 1: Address reversible non-HF causes first 3

• Stop alpha-blockers (tamsulosin, doxazosin, terazosin) 3
• Discontinue other non-essential BP-lowering medications 3
• Evaluate for dehydration, infection, or acute illness 3

Step 2: Non-pharmacological interventions 3

• Compression leg stockings for orthostatic symptoms 3
• Space out medication timing throughout the day 3
• Adequate salt and fluid intake if not volume overloaded 3

Step 3: If symptoms persist, reduce GDMT in this specific order 3

• If heart rate >70 bpm: reduce ACEi/ARB/ARNI dose first 3
• If heart rate <60 bpm: reduce beta-blocker dose first 3
• Always maintain SGLT2 inhibitor and MRA (minimal BP effects) 3

Monitoring Requirements

Check blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment, with more frequent monitoring in elderly patients and those with chronic kidney disease. 3, 8

Acceptable laboratory changes during uptitration:

• Creatinine increases up to 30% above baseline are acceptable and should not prompt discontinuation 3, 8
• Potassium levels require close monitoring with MRAs; consider potassium binders (patiromer) rather than discontinuing life-saving medications if hyperkalemia develops 3

Critical Contraindications

Never combine:

• ACE inhibitor with ARNI (risk of angioedema) 3, 8
• ACE inhibitor + ARB + MRA (triple combination increases hyperkalemia and renal dysfunction risk) 3

Common Pitfalls to Avoid

1. Delaying initiation of all four medication classes – only 1% of eligible patients receive all medications at target doses in real-world practice 3, 8
2. Accepting suboptimal doses – target doses provide the greatest mortality benefit 3
3. Stopping medications for asymptomatic hypotension – discontinuing RAASi after hypotension is associated with two to fourfold higher risk of adverse events 3
4. Inadequate monitoring – leads to preventable complications 3
5. Using non-evidence-based beta-blockers (atenolol, metoprolol tartrate) – these lack proven mortality benefit 3

Special Populations

Patients with History of Hypertension

All four GDMT medication classes effectively lower blood pressure while providing mortality benefit in HFrEF. 9 The principal drug treatment of HF is the same regardless of blood pressure history, directed by symptoms, signs, severity (NYHA class), and concomitant conditions. 9

Hospitalized Patients

Continue GDMT except when hemodynamically unstable or contraindicated. 8 In-hospital initiation substantially improves post-discharge medication use compared to deferring initiation to outpatient setting. 8