What is the initial management guideline for a patient with heart failure, specifically using Guideline-Directed Medical Therapy (GDMT)?

Guideline-Directed Medical Therapy (GDMT) for Heart Failure

All patients with heart failure with reduced ejection fraction (HFrEF, LVEF ≤40%) should be started on four foundational medication classes simultaneously at low doses—ARNI (preferably) or ACE inhibitor/ARB, beta-blocker, mineralocorticoid receptor antagonist (MRA), and SGLT2 inhibitor—then uptitrated every 1-2 weeks to target doses regardless of symptom severity. 1, 2, 3

The Four Pillars of GDMT for HFrEF

1. Renin-Angiotensin System Inhibitors

• ARNI (sacubitril/valsartan) is preferred over ACE inhibitors or ARBs, providing at least 20% reduction in mortality risk with superior outcomes compared to enalapril 2, 3
• Start sacubitril/valsartan at 24/26 mg or 49/51 mg twice daily, targeting 97/103 mg twice daily 3
• Critical safety requirement: When switching from an ACE inhibitor to ARNI, observe a strict 36-hour washout period to avoid angioedema 2, 3
• If ARNI is not tolerated or available, use ACE inhibitors (Class I, Level A) or ARBs (Class I, Level B-R for post-MI patients intolerant to ACEi) and uptitrate to target doses 1, 2

2. Beta-Blockers

• Only three beta-blockers have proven mortality benefit: carvedilol, metoprolol succinate, or bisoprolol—do not substitute with other beta-blockers 2, 3
• These provide at least 20% reduction in mortality risk 2
• Start at low doses and uptitrate to target doses every 1-2 weeks 3
• For patients who cannot tolerate beta-blockers due to bradycardia, ivabradine may be considered as an alternative for heart rate control if heart rate remains ≥70 bpm despite maximally tolerated beta-blocker doses 2, 4

3. Mineralocorticoid Receptor Antagonists (MRAs)

• Use spironolactone (12.5-25 mg daily) or eplerenone (25 mg daily), uptitrating to target doses 2, 3
• These provide at least 20% reduction in mortality risk 2, 3
• Eplerenone avoids the 5.7% higher rate of male gynecomastia seen with spironolactone 2, 3
• Monitor potassium and creatinine closely, especially during uptitration 3

4. SGLT2 Inhibitors

• Use dapagliflozin or empagliflozin—these are the newest class with significant mortality benefits 2, 3
• Major advantages: no blood pressure, heart rate, or potassium effects; no dose titration required; benefits occur within weeks of initiation, independent of background therapy 2, 3
• Safe in moderate kidney dysfunction with eGFR ≥30 ml/min/1.73 m² for empagliflozin and ≥20 ml/min/1.73 m² for dapagliflozin 2

Combined Therapy Impact

Quadruple therapy reduces mortality risk by approximately 73% over 2 years compared to no treatment and extends life expectancy by approximately 6 years compared to traditional dual therapy (ACE inhibitor and beta-blocker). 2, 3

Critical Implementation Strategy: Simultaneous Initiation

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 This approach is supported by the 2022 ACC/AHA/HFSA guidelines, which explicitly state that there is no need to achieve target dosing before initiating the next medication 1, 2

Uptitration Protocol

• Uptitrate every 1-2 weeks until target doses are achieved 2, 3
• Check blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment 1, 2, 3
• More frequent monitoring is needed in elderly patients and those with chronic kidney disease 1
• Prioritize ARNI/ACE inhibitor/ARB uptitration if eGFR >30 mL/min/1.73m² and heart rate >60 bpm 3

Managing Common Barriers to Uptitration

Low Blood Pressure

• Asymptomatic or mildly symptomatic low blood pressure should never prompt GDMT reduction or cessation 2, 3
• Patients with adequate perfusion can tolerate systolic BP 80-100 mmHg 1, 2, 3
• Only reduce or stop GDMT if systolic BP <80 mmHg or low BP with major symptoms (confusion, syncope, oliguria) 3
• If blood pressure is low but perfusion adequate, prioritize medications in this order: SGLT2 inhibitors and MRAs first (minimal BP impact), then beta-blockers, then ARNI/ACE inhibitor/ARB 2, 3

Renal Function Changes

• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation of ARNI/ACE inhibitor/ARB 1, 2, 3
• Temporary reduction or hold only if substantial renal deterioration occurs 2, 3

Hyperkalemia

• Monitor potassium closely with MRA initiation and uptitration 3
• Adjust MRA dose or consider potassium binders if needed rather than discontinuing therapy 3

Fatigue and Weakness

• Temporary symptoms of fatigue and weakness with dose increases usually resolve within days—do not prematurely discontinue GDMT 1, 3
• In the absence of instability in vital signs, reassure patients that these symptoms are often transient 1

Special Clinical Scenarios

Hospitalized Patients

• Continue GDMT except when hemodynamically unstable or contraindicated 1, 2, 3
• Initiate GDMT after ≥24 hours of stabilization with adequate organ perfusion 2, 3
• In-hospital initiation substantially improves post-discharge medication use compared to deferring initiation to outpatient setting 2, 3
• Initial IV loop diuretic dose should equal or exceed chronic oral daily dose 1, 5

Improved Ejection Fraction

• Patients with previous HFrEF whose EF improves to >40% should continue their HFrEF treatment regimen 2, 3
• Discontinuation of HFrEF medications after EF improvement may lead to clinical deterioration 2, 3

Device Therapy Considerations

• ICD therapy is recommended for primary prevention of sudden cardiac death in patients at least 40 days post-MI with LVEF ≤30% and NYHA class I symptoms while receiving GDMT 1
• CRT can be useful for patients with LVEF ≤35%, sinus rhythm, LBBB with QRS duration ≥150 ms, and NYHA class II-IV symptoms on GDMT 1

Additional Therapies

Loop Diuretics

• Add loop diuretics only if fluid overload is present—they are for volume management but provide no mortality benefit 3
• Titrate based on symptoms and volume status, not as routine therapy 3
• Diuretics should be used for relief of symptoms due to volume overload (Class I, Level C) 1

Vericiguat

• Consider vericiguat for higher-risk patients with worsening HFrEF (LVEF <45%, NYHA class II-IV, elevated natriuretic peptides, recent HF hospitalization or IV diuretic therapy) who remain symptomatic despite GDMT 3
• Vericiguat reduced the primary outcome of cardiovascular death or HF hospitalization by 10% (HR 0.90, P=0.019) 3
• Patients in the highest quartile of NT-proBNP (>5314 pg/mL) did not benefit from vericiguat 3

Heart Failure with Preserved Ejection Fraction (HFpEF)

For HFpEF, SGLT2 inhibitors are the strongest recommendation (Class 2a) based on DELIVER and EMPEROR-PRESERVED trials showing reduction in HF hospitalizations and cardiovascular death. 2

• Hypertension control is a cornerstone of HFpEF management (Class I recommendation) 1, 2
• MRAs have a weaker recommendation (Class 2b) based on TOPCAT trial data 2
• Treatment of atrial fibrillation for symptom management (Class 2a recommendation) 2
• Use of beta-blockers, ACE inhibitors, and ARBs for hypertension in HFpEF (Class IIa, Level C) 1

Implementation Strategies to Improve GDMT Use

• Multidisciplinary care teams including pharmacists and nurses improve GDMT titration, reduce all-cause mortality (OR 0.66,95% CI 0.48-0.92), and reduce HF hospitalizations 2, 3
• Nurse-led titration programs are effective for achieving target doses 2, 3
• Referral to HF specialty care maximizes GDMT optimization in newly diagnosed HFrEF patients 3, 6
• Being seen in an HF clinic is independently associated with initiation of new GDMT across all medication classes (HR 1.54-2.49 depending on medication class) 6
• Digital solutions such as best practice advisories, electronic health record-based interventions, and telehealth visits increase GDMT prescription rates 2, 3

Common Pitfalls to Avoid

• Do not wait to achieve target dosing of one medication before initiating the next—this delays life-saving therapy 2, 3
• Do not overreact to laboratory changes—modest creatinine elevation (up to 30% above baseline) is acceptable 1, 2, 3
• Do not discontinue GDMT during acute episodes of noncardiac illnesses without discussion; consider temporary adjustments instead 1
• Discourage sudden spontaneous discontinuation of GDMT medications by the patient and/or other clinicians without discussion with managing clinicians 1
• Carefully review doses of other medications for HF symptom control (eg, diuretics, nitrates) during uptitration 1

Current Treatment Gaps

• Less than one-quarter of eligible patients currently receive all three medications concurrently, and only 1% receive target doses of all medications 2, 3
• Only 73% of eligible patients receive ACE inhibitors/ARBs/ARNIs, 66% receive beta-blockers, and 33% receive MRAs within 30 days post-hospitalization 5
• In community practice, only 63.8% of patients were treated with an HF beta-blocker (metoprolol succinate, carvedilol, bisoprolol), and few received MRAs (17.6%) 6