What is the recommended treatment approach for a patient with heart failure with reduced ejection fraction, specifically regarding Guideline-Directed Medical Therapy (GDMT) quad therapy?

GDMT Quad Therapy for Heart Failure with Reduced Ejection Fraction

All patients with HFrEF should receive four foundational medication classes simultaneously as soon as possible after diagnosis: an ARNI (sacubitril/valsartan), a beta-blocker (carvedilol, metoprolol succinate, or bisoprolol), a mineralocorticoid receptor antagonist (spironolactone or eplerenone), and an SGLT2 inhibitor (dapagliflozin or empagliflozin), initiated at low doses with rapid up-titration to target doses within 2 months. 1, 2

The Four Pillars of Quadruple Therapy

1. ARNI (Angiotensin Receptor-Neprilysin Inhibitor)

• Sacubitril/valsartan is the preferred first-line agent over ACE inhibitors or ARBs, providing superior mortality reduction of at least 20% 1
• Starting dose for adults: 49 mg/51 mg orally twice daily 3
• Target maintenance dose: 97 mg/103 mg orally twice daily 3
• Critical contraindication: Never combine with ACE inhibitors—must wait 36 hours after stopping ACE inhibitor before initiating ARNI 3
• Reduce starting dose to 24 mg/26 mg twice daily in patients not currently on ACE inhibitor/ARB, those with severe renal impairment, or moderate hepatic impairment 3

2. Beta-Blockers

• Use only evidence-based beta-blockers: carvedilol, metoprolol succinate, or bisoprolol—these reduce mortality by at least 20% and decrease sudden cardiac death 1
• Initiate at low doses in clinically stable patients and gradually up-titrate to maximum tolerated dose 1
• Administer in the morning rather than at night to minimize sleep disturbances 4

3. Mineralocorticoid Receptor Antagonists (MRAs)

• Spironolactone or eplerenone for all symptomatic patients with LVEF ≤35% 1, 5
• Provide at least 20% mortality reduction and reduce sudden cardiac death 1
• Require monitoring of renal function and serum potassium levels 1
• Can be used if eGFR >30 ml/min/1.73 m² 6
• Contraindication: Avoid triple combination of ACE inhibitor + ARB + MRA due to hyperkalemia and renal dysfunction risk 1

4. SGLT2 Inhibitors

• Dapagliflozin or empagliflozin reduce cardiovascular death and HF hospitalization regardless of diabetes status 1, 2
• Key advantage: Minimal blood pressure effect (only -1.50 mmHg in patients with baseline SBP 95-110 mmHg, diminishing to <1 mmHg after 4 months), making them ideal first agents 1
• Once-daily dosing with no up-titration required 6
• Benefits occur within weeks of initiation 6
• Can be used if eGFR ≥30 ml/min/1.73 m² for empagliflozin, or ≥20 ml/min/1.73 m² for dapagliflozin 6

Implementation Strategy: The "4×4 Approach"

Start all four medication classes simultaneously at low doses rather than sequentially achieving target doses of fewer medications, with the goal of achieving optimal treatment within 2 months. 2

Sequencing Algorithm

1. Start SGLT2 inhibitor and MRA first as they have minimal blood pressure effects 6, 1
2. Then add beta-blocker if heart rate >70 bpm 4
3. Then add low-dose ARNI (or ACEi/ARB if ARNI not tolerated) 4
4. Up-titrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved 1, 2

Real-World Feasibility

• In a prospective study of 81 patients, 48% achieved all four medications within 4 weeks using this approach 7
• Patients who did not achieve quadruple therapy had a 2.25-fold increased risk of hospitalization or death compared to those who achieved it 7
• Only 5 patients (6%) experienced significant side effects during up-titration, most commonly symptomatic hypotension 7

Managing Low Blood Pressure During Optimization

Low blood pressure alone (even <90 mmHg systolic) without symptoms or hypoperfusion is NOT a contraindication to GDMT. 2

Algorithm for Symptomatic Hypotension

1. First, address reversible non-HF causes 6:

   • Stop alpha-blockers (tamsulosin, doxazosin) 1
   • Stop other non-essential BP-lowering medications 6
   • Evaluate for dehydration, infection, or other acute illness 6

2. If SBP <80 mmHg or major symptoms persist 6:

   • Maintain SGLT2 inhibitors and MRAs as they have the least impact on BP 6, 4
   • If heart rate >70 bpm: Consider reducing ARNI/ACEi/ARB first 4
   • If heart rate <60 bpm: Consider reducing beta-blocker first 4

3. Non-pharmacological interventions 6:

   • Space out medications to reduce synergistic hypotensive effects 6, 4
   • Engage in exercise and physical training to improve orthostatic tolerance 6
   • Use compression leg stockings to minimize orthostatic drops 6

Critical Pitfall to Avoid

Never down-titrate or stop GDMT for asymptomatic hypotension—adverse events occur in 75-85% of HFrEF patients regardless of treatment, with no substantial difference between GDMT and placebo arms in clinical trials. 1

Additional Diuretic Therapy

• Loop diuretics are essential for congestion control but do not reduce mortality 1
• Starting doses: furosemide 20-40 mg once or twice daily, torsemide 10-20 mg once daily, or bumetanide 0.5-1.0 mg once or twice daily 1
• Titrate to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use the lowest dose that maintains this state 1

Additional Therapies for Selected Patients

Ivabradine

• Consider if heart rate ≥70 bpm in sinus rhythm despite maximally tolerated beta-blocker 1, 8
• Reduces risk of hospitalization for worsening heart failure 8
• Starting dose: 2.5-5 mg twice daily 1
• Note: Survival benefit is modest or negligible in the broad HFrEF population 1

Hydralazine/Isosorbide Dinitrate

• Indicated for self-identified Black patients with NYHA class III-IV symptoms despite optimal therapy 1
• Starting dose: hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily 1
• Can prolong survival but may be inferior to ACE inhibitors for mortality 1

Expected Outcomes with Quadruple Therapy

The combination of all four foundational medications provides approximately 73% mortality reduction over 2 years. 1

• Patients who commence comprehensive therapy at age 55 were projected to gain an additional 8.3 years free of cardiovascular mortality or first HF hospitalization compared to conventional therapy 6
• A simple GDMT score ≥5 (based on combination and dosage of medications) was significantly associated with reduction of all-cause death, HF readmission, and composite outcomes 9

Common Barriers and How to Overcome Them

Clinical Inertia

• 66% of clinicians identify hypotension as a major concern, but GDMT medications have proven efficacy and safety across all baseline systolic blood pressure levels, with benefits maintained even in patients with SBP <110 mmHg 1
• Target doses of all recommended drugs were simultaneously achieved in only 1% of eligible patients in real-world registries, with discontinuation rates as high as 55% for ACEIs 6

Patient-Related Factors

• Advanced age, female sex, lower blood pressure, and greater severity of HF are consistently associated with lower prescription or up-titration of GDMT 6
• Solution: Recognize that a large proportion of patients with HFrEF do not have clinical contraindications to GDMT but are not treated with these therapies 10

Polypharmacy Concerns

• Solution: Remove therapies that do not have clear cardiovascular benefit to lower polypharmacy and reduce risk of adverse side effects 10
• Statins should not be initiated specifically for HFrEF management in patients without other indications for lipid-lowering therapy 1

Monitoring Requirements

• Close follow-up within 1-2 weeks of medication changes 4
• Monitor blood pressure, heart rate, renal function (eGFR), and electrolytes (potassium) 4, 1
• Hyperkalaemia poses a significant challenge, but discontinuation of RAASi after hyperkalaemia was associated with two to fourfold higher risk of subsequent adverse events 6

When to Refer to HF Specialist

• Persistent NYHA class III-IV symptoms despite optimal GDMT 2
• Recurrent hospitalizations for HF 2
• Persistent hypotension with inability to optimize GDMT 4
• Need for continuous or intermittent inotropic support 2
• Consideration for advanced therapies (transplant, mechanical circulatory support) 2