In a patient with heart failure with reduced ejection fraction and hypotension (blood pressure 90/60 mm Hg), what is the recommended sequence for initiating the foundational guideline‑directed therapies?

Foundational Therapy Sequencing for HFrEF with Blood Pressure 90/60 mmHg

In a patient with HFrEF and blood pressure 90/60 mmHg, initiate SGLT2 inhibitor and mineralocorticoid receptor antagonist (MRA) first, followed by beta-blocker if heart rate >60 bpm, then ARNI/ACEi/ARB—this sequence prioritizes medications with minimal blood pressure effects while maximizing mortality benefit. 1

Why This Sequence Matters

Your patient's BP of 90/60 mmHg should not delay guideline-directed medical therapy (GDMT), as asymptomatic or mildly symptomatic low blood pressure is not a reason for GDMT reduction or cessation. 1 The key is adequate organ perfusion—patients with adequate perfusion can tolerate systolic BP 80-100 mmHg. 1, 2

Step-by-Step Initiation Algorithm

Step 1: Start SGLT2 Inhibitor Immediately

• Dapagliflozin 10 mg once daily OR empagliflozin 10 mg once daily 2
• SGLT2 inhibitors have minimal blood pressure effect (average decrease only -1.50 mmHg in patients with baseline SBP 95-110 mmHg, diminishing to <1 mmHg after 4 months) 1
• No dose titration required—full benefit at starting dose 2
• Benefits occur within weeks of initiation 2
• Can be used if eGFR ≥30 ml/min/1.73 m² for empagliflozin or ≥20 ml/min/1.73 m² for dapagliflozin 2

Step 2: Add Mineralocorticoid Receptor Antagonist (MRA) Simultaneously or Within Days

• Spironolactone 12.5-25 mg once daily OR eplerenone 25 mg once daily 2
• MRAs have minimal blood pressure effect, making them ideal for low BP patients 1, 2
• Provides ≥20% mortality reduction 2
• Requires eGFR >30 ml/min/1.73 m² and potassium <5.0 mEq/L 2
• Target dose: spironolactone 50 mg daily or eplerenone 50 mg daily 2

Step 3: Initiate Beta-Blocker (If Heart Rate >60 bpm)

• Carvedilol 3.125 mg twice daily OR metoprolol succinate 12.5-25 mg once daily OR bisoprolol 1.25 mg once daily 2
• If heart rate >60 bpm, initiate or uptitrate beta-blocker 1
• If heart rate <60 bpm, delay beta-blocker initiation until after ARNI is started 1
• Beta-blockers provide ≥20% mortality reduction and reduce sudden cardiac death 2
• Target doses: carvedilol 25-50 mg twice daily, metoprolol succinate 200 mg daily, bisoprolol 10 mg daily 2

Step 4: Add ARNI/ACEi/ARB

• Sacubitril/valsartan 24/26 mg or 49/51 mg twice daily (preferred) 2
• OR Lisinopril 2.5-5 mg once daily OR Enalapril 2.5 mg twice daily if ARNI not tolerated 2
• ARNI provides ≥20% mortality reduction superior to ACEi/ARB 2
• Target dose: sacubitril/valsartan 97/103 mg twice daily 2
• If switching from ACEi to ARNI, observe strict 36-hour washout period to avoid angioedema 2

Critical Timing Considerations

All four medication classes should be initiated within the first 2 weeks after diagnosis, with uptitration every 1-2 weeks until target doses are achieved. 2, 3 This simultaneous initiation approach addresses the massive treatment gap where only 1% of patients receive target doses of all medications. 2

Managing the Low Blood Pressure

What NOT to Do:

• Never withhold GDMT for asymptomatic hypotension with adequate perfusion 1, 2
• Never discontinue medications for systolic BP >80 mmHg if patient has adequate organ perfusion 1
• Reduction or cessation of GDMT is advisable only if systolic BP <80 mmHg or low BP with relevant symptoms 1

What TO Do First:

1. Stop unnecessary cardiac medications (e.g., alpha-blockers for BPH, non-essential antihypertensives) 1
2. Look for transient and reversible causes (dehydration, infection, acute illness) 1
3. Non-pharmacological interventions: compression leg stockings for orthostatic symptoms, adequate salt/fluid intake if not volume overloaded, exercise training 1, 2

Monitoring Schedule

• Week 1-2: Initial follow-up after GDMT initiation 2
• Every 1-2 weeks: Check blood pressure, renal function (creatinine, eGFR), and electrolytes (potassium) after each dose increment 2
• More frequent monitoring in elderly patients (≥65 years) and those with chronic kidney disease 2
• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation 2

Diuretic Management

• Add loop diuretics only if fluid overload is present (peripheral edema, elevated JVP, pulmonary congestion) 2
• Initial IV loop diuretic dose should equal or exceed chronic oral daily dose 2
• Once euvolemic, consider cautiously decreasing diuretic dose to minimize BP-lowering effects 2

Expected Outcomes with Quadruple Therapy

Combined quadruple therapy (SGLT2i + MRA + beta-blocker + ARNI/ACEi/ARB) reduces mortality risk by approximately 73% over 2 years compared to no treatment and extends life expectancy by approximately 6 years. 2

Common Pitfalls to Avoid

• Delaying initiation of all four medication classes due to BP concerns 2
• Accepting suboptimal doses without attempting forced-titration 2
• Sequential rather than simultaneous initiation—this delays mortality benefit 2
• Overreacting to laboratory changes—modest creatinine elevation (up to 30% above baseline) is acceptable 2
• Stopping medications for asymptomatic hypotension—discontinuing RAASi after hypotension is associated with two to fourfold higher risk of subsequent adverse events 2

Special Consideration: One Case Report Caveat

One 2024 case report described severe hypotension requiring hospitalization in a euvolemic patient on sacubitril/valsartan after initiating dapagliflozin, raising awareness of potential increased diuretic effect with concomitant use. 4 However, this represents a single case and should not prevent SGLT2i initiation—instead, provide education about volume depletion signs and ensure close follow-up within 7-14 days. 2