How do I initiate guideline‑directed medical therapy in a clinically stable patient with heart failure with reduced ejection fraction (≤40%) who has no severe hypotension, bradycardia, hyperkalemia, or advanced renal dysfunction (eGFR ≥ 30 mL/min/1.73 m²)?

How to Initiate GDMT in Clinically Stable HFrEF

Start all four foundational medication classes—SGLT2 inhibitor, beta-blocker, MRA, and ARNI (or ACEi/ARB)—simultaneously at low doses within the first 1-2 weeks, then uptitrate one drug at a time every 1-2 weeks until target or maximally tolerated doses are achieved. 1, 2

Initial Assessment Before Starting GDMT

Before initiating therapy, verify the following parameters:

• Confirm LVEF ≤40% with echocardiography or other imaging modality 2
• Check baseline labs: serum potassium <5.0 mmol/L, eGFR ≥30 mL/min/1.73 m² (≥20 for empagliflozin), and baseline creatinine 1, 3
• Measure baseline blood pressure and heart rate to guide initial dosing 2
• Assess volume status to determine diuretic needs 2
• Obtain baseline natriuretic peptides (BNP or NT-proBNP) for prognostic information 2

Step 1: Initiate All Four Pillars Simultaneously (Week 1-2)

SGLT2 Inhibitor (Start First—No BP Effect)

Begin dapagliflozin 10 mg daily or empagliflozin 10 mg daily immediately, as these agents have minimal blood pressure-lowering effects and reduce cardiovascular mortality and HF hospitalizations regardless of diabetes status. 1, 2

• Dapagliflozin requires eGFR ≥30 mL/min/1.73 m² 1
• Empagliflozin requires eGFR ≥20 mL/min/1.73 m² 1
• No titration needed—use full dose from the start 1
• Monitor for volume depletion and adjust loop diuretics as needed 3

Mineralocorticoid Receptor Antagonist (Start Second—Minimal BP Effect)

Initiate spironolactone 12.5-25 mg daily or eplerenone 25 mg daily, as MRAs have minimal blood pressure effects and reduce mortality in patients with LVEF ≤35% and NYHA class II-IV symptoms. 1, 2

• Contraindicated if potassium >5.0 mmol/L or eGFR <30 mL/min/1.73 m² 1, 3
• In patients with CKD, start with lower doses (6.25-12.5 mg daily or every other day) 3
• Check potassium and creatinine 2-3 days after initiation, then monthly for 3 months, then every 3 months 1
• Target dose: spironolactone 25-50 mg daily or eplerenone 50 mg daily 1

Beta-Blocker (Start Third)

Begin carvedilol 3.125 mg twice daily, metoprolol succinate 12.5-25 mg daily, or bisoprolol 1.25 mg daily, as beta-blockers reduce mortality and sudden cardiac death across all HFrEF patients. 1, 2

• Start only if heart rate >50 bpm and no significant bradycardia 2
• Uptitrate every 2 weeks by doubling the dose until target is reached 2, 1
• Target doses: carvedilol 25-50 mg twice daily, metoprolol succinate 200 mg daily, bisoprolol 10 mg daily 1, 2
• If beta-blocker not tolerated due to bradycardia and patient is in sinus rhythm with HR ≥70 bpm, consider ivabradine 2.5-5 mg twice daily as alternative or adjunct 2, 1

ARNI or ACEi/ARB (Start Fourth)

Initiate sacubitril/valsartan 24/26 mg or 49/51 mg twice daily (preferred over ACEi/ARB for superior mortality reduction), or if ARNI not feasible, start enalapril 2.5-5 mg twice daily or lisinopril 2.5-5 mg daily. 2

• Wait 36 hours after stopping ACEi before starting ARNI to avoid angioedema 2
• Contraindicated if history of angioedema or eGFR <30 mL/min/1.73 m² for ARNI 2, 3
• Uptitrate every 2-4 weeks to target dose of sacubitril/valsartan 97/103 mg twice daily 2, 1
• ARBs (valsartan, losartan, candesartan) are reserved only for patients intolerant to both ACEi and ARNI 2, 4

Step 2: Sequential Uptitration (Weeks 2-12)

Uptitrate one medication at a time every 1-2 weeks, prioritizing the drug class most likely to be tolerated based on patient's hemodynamics. 2

Uptitration Strategy in Stable Patients:

1. If heart rate >70 bpm: Uptitrate beta-blocker first 2
2. If blood pressure adequate (SBP >100 mmHg): Uptitrate ARNI/ACEi next 2
3. If potassium <4.5 mmol/L and eGFR stable: Uptitrate MRA 2
4. SGLT2i remains at full dose throughout 1

Monitoring During Uptitration:

• Check blood pressure and heart rate before each dose increase 2
• Recheck potassium and creatinine 1-2 weeks after each MRA or ARNI/ACEi dose increase 1, 3
• Accept up to 30% increase in creatinine or decrease in eGFR as acceptable with ARNI/ACEi initiation 3
• Temporary mild dizziness upon standing is acceptable and does not require dose reduction if patient is otherwise stable 2

Step 3: Managing Common Barriers

Low Blood Pressure (SBP 90-100 mmHg) But Asymptomatic:

Continue all four medications without dose reduction, as asymptomatic low BP does not predict adverse outcomes and should not limit GDMT. 2

• Educate patient that transient dizziness is expected and does not require stopping medications 2
• Review and discontinue non-essential antihypertensives (alpha-blockers for BPH, antidepressants) 2
• Reduce or stop loop diuretics if patient is euvolemic 2

Symptomatic Hypotension (SBP <80 mmHg or Severe Symptoms):

Temporarily reduce or hold the most recently uptitrated medication, then rechallenge at lower dose once BP stabilizes. 2

• Stop non-GDMT BP medications first 2
• Reduce loop diuretic dose if overdiuresed 2
• Consider splitting ARNI to three times daily dosing or switching to ACEi at lower dose 2
• Never stop SGLT2i or MRA for low BP alone—these have minimal BP effects 2

Hyperkalemia (K+ 5.5-6.0 mmol/L):

Reduce or temporarily hold MRA, optimize dietary potassium restriction, and consider potassium binders (patiromer, sodium zirconium cyclosilicate) to enable continuation of ARNI/ACEi. 3, 5

• Recheck potassium in 3-5 days after intervention 3
• Restart MRA at lower dose once K+ <5.0 mmol/L 3, 5

Worsening Renal Function (Creatinine Increase >30% or eGFR Drop >25%):

Recheck labs in 1-2 weeks before making changes, as transient increases often stabilize. 3, 5

• If persistent, reduce ARNI/ACEi dose by 50% and recheck in 1 week 3
• Continue SGLT2i unless eGFR falls below initiation threshold 3
• Reduce MRA dose or hold temporarily if eGFR <30 mL/min/1.73 m² 3

Bradycardia (HR <50 bpm):

Reduce beta-blocker dose by 50% and consider adding ivabradine if patient is in sinus rhythm with HR ≥70 bpm despite lower beta-blocker dose. 2, 1

• Rule out AV block with ECG before continuing beta-blocker 2
• If severe bradycardia persists, consider pacemaker evaluation 2

Step 4: Special Populations

African American Patients with NYHA Class III-IV:

Add hydralazine 37.5 mg three times daily plus isosorbide dinitrate 20 mg three times daily to quadruple therapy, as this combination provides additional mortality benefit in this population. 2, 1

• Uptitrate to target doses: hydralazine 75 mg three times daily and isosorbide dinitrate 40 mg three times daily 2

Atrial Fibrillation with Rapid Ventricular Rate:

Uptitrate beta-blocker more aggressively for rate control, or add digoxin 0.125 mg daily if beta-blocker insufficient. 2, 5

• Avoid amiodarone for rate control due to toxicity profile 5

Chronic Kidney Disease (eGFR 30-60 mL/min/1.73 m²):

Use all four pillars with closer monitoring, starting MRA at lower doses (6.25-12.5 mg daily or every other day) and checking labs more frequently. 3, 5

• Bisoprolol may accumulate in renal impairment but still titrate to target dose based on clinical response 3
• Dapagliflozin and empagliflozin are effective down to eGFR 25-20 mL/min/1.73 m² respectively 3

Step 5: Long-Term Maintenance

Continue GDMT Indefinitely:

Never discontinue GDMT even if LVEF improves to >40% (HFimpEF), as withdrawal leads to relapse of LV dysfunction and clinical HF in most patients. 2

Reassess LVEF Every 6-12 Months:

Repeat echocardiography to track trajectory and adjust device therapy eligibility (ICD if LVEF remains ≤35% after ≥3 months optimal GDMT). 1, 4

Ongoing Monitoring:

• Potassium and creatinine every 3 months once stable on target doses 1
• Clinical follow-up every 3-6 months to assess symptoms, adherence, and tolerance 4
• Natriuretic peptides can guide therapy adjustments if clinical status unclear 2

Common Pitfalls to Avoid

• Do not wait for symptoms to worsen before starting GDMT—early initiation in asymptomatic LV dysfunction prevents progression 4
• Do not uptitrate only one or two drug classes to target while neglecting others—partial doses of all four pillars are superior to target doses of only two 6
• Do not stop GDMT for asymptomatic low BP readings—this is a common cause of undertreatment 2
• Do not rely on a single LVEF measurement—confirm with repeat imaging before making major therapeutic decisions 4
• Do not delay SGLT2i initiation—this class has the fastest onset of benefit and should be started immediately 1, 7