What are the Guideline-Directed Medical Therapies (GDMT) for Chronic Heart Failure (ChF)?

Guideline-Directed Medical Therapy for Chronic Heart Failure

All patients with heart failure with reduced ejection fraction (HFrEF, EF ≤40%) should be initiated on four foundational medication classes simultaneously at low doses: ARNI (sacubitril/valsartan preferred) or ACE inhibitors/ARBs, beta-blockers (carvedilol, metoprolol succinate, or bisoprolol only), mineralocorticoid receptor antagonists (MRAs), and SGLT2 inhibitors (dapagliflozin or empagliflozin), with rapid uptitration to target doses every 1-2 weeks. 1, 2

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 1, 2
• ACE inhibitors remain acceptable first-line therapy if ARNI is not tolerated or available, with proven mortality reduction of 5-16% 1
• ARBs serve as alternatives for patients intolerant to ACE inhibitors 3
• When switching from ACE inhibitor to ARNI, observe a strict 36-hour washout period to avoid angioedema 1

2. Beta-Blockers

• Only three beta-blockers are evidence-based for HFrEF: carvedilol, metoprolol succinate, or bisoprolol, providing at least 20% reduction in mortality risk 1, 2
• Other beta-blockers lack mortality benefit and should not be used 2
• If beta-blockers are not hemodynamically tolerated, ivabradine may be considered as an alternative for heart rate control in patients with sinus rhythm and heart rate ≥70 bpm 1, 4

3. Mineralocorticoid Receptor Antagonists (MRAs)

• Spironolactone or eplerenone provide at least 20% reduction in mortality risk 1, 2
• Start at low doses (spironolactone 12.5-25 mg daily or eplerenone 25 mg daily) and uptitrate to target doses 1
• Spironolactone has a 5.7% higher rate of male gynecomastia, which can be avoided with eplerenone 1
• Monitor potassium and creatinine closely; modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation 1, 5

4. SGLT2 Inhibitors

• Dapagliflozin or empagliflozin have significant mortality benefits with Class 1 recommendation 1, 2
• No blood pressure, heart rate, or potassium effects; no dose titration required 1
• Treatment benefits occur within weeks of initiation, independent of background therapy 1
• Only 0.9% higher rate of genital infection compared to placebo 1

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 alone). 1, 2

Initiation Strategy

Simultaneous vs Sequential Approach

• 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
• This approach is supported by the STRONG-HF trial and current ACC/AHA/HFSA guidelines 1
• Less than one-quarter of eligible patients currently receive all medications concurrently, and only 1% receive target doses of all medications 1

Uptitration Protocol

• Uptitrate every 1-2 weeks until target doses are achieved 1, 2
• Check blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment 1, 2
• More frequent monitoring is needed in elderly patients and those with chronic kidney disease 1
• Temporary dose reductions should be followed by aggressive attempts to restore target doses 1

Diuretics (Symptomatic Treatment Only)

• Add loop diuretics only if fluid overload is present, manifesting as pulmonary congestion or peripheral edema 3, 2
• Diuretics provide rapid improvement of dyspnea and increased exercise tolerance but have no proven mortality benefit 3
• Always administer diuretics in combination with ACE inhibitors if possible 3
• Initial IV dose of loop diuretics should equal or exceed chronic oral daily dose, titrated based on urine output and congestion symptoms 1

Special Clinical Scenarios

Low Blood Pressure (<90 mmHg)

• If patient has adequate organ perfusion, do not withhold GDMT 1
• Prioritize medications in this order: SGLT2 inhibitors and MRAs first (minimal BP impact), then selective β₁ receptor blockers, then low-dose ACEi/ARB or very low-dose ARNI 1
• Patients with adequate perfusion can tolerate systolic BP 80-100 mmHg 1, 5

Hospitalized Patients

• Continue GDMT except when hemodynamically unstable or contraindicated 1, 2
• Initiate GDMT after ≥24 hours of stabilization with adequate organ perfusion 1
• In-hospital initiation substantially improves post-discharge medication use compared to deferring to outpatient setting 1

Improved Ejection Fraction

• Patients with previous HFrEF whose EF improves to >40% should continue their HFrEF treatment regimen 1
• Discontinuation of HFrEF medications after EF improvement may lead to clinical deterioration 1

GDMT for Heart Failure with Preserved Ejection Fraction (HFpEF, EF ≥50%)

SGLT2 inhibitors have the strongest recommendation (Class 2a) for HFpEF based on DELIVER and EMPEROR-PRESERVED trials showing reduction in HF hospitalizations and cardiovascular death. 1, 2

• MRAs have a weaker recommendation (Class 2b) based on TOPCAT trial data 1
• Hypertension control is a cornerstone of HFpEF management (Class I recommendation) 1
• Treatment of atrial fibrillation for symptom management (Class 2a recommendation) 1
• HFpEF has primarily reduction in hospitalizations rather than mortality, unlike HFrEF 1

Common Pitfalls to Avoid

• Do not prematurely discontinue GDMT for temporary symptoms of fatigue and weakness with dose increases, as these usually resolve within days 1
• Do not overreact to modest creatinine elevation (up to 30% above baseline), which is acceptable 1, 5
• Do not withhold GDMT for asymptomatic or mildly symptomatic low blood pressure if perfusion is adequate 1
• Avoid excessive diuresis before ACE inhibitor initiation, which increases hypotension risk 3, 5
• Do not start potassium-sparing diuretics during ACE inhibitor initiation due to dangerous hyperkalemia risk 5
• Avoid NSAIDs or COX-2 inhibitors, which worsen heart failure and interfere with ACE inhibitor efficacy 5

Monitoring Requirements

• Blood pressure, renal function, and electrolytes at 1-2 weeks after each dose increment 1, 2
• Early follow-up within 7-14 days after medication adjustments 1, 5
• Monitor for changes in volume status, symptoms of worsening heart failure 1

Implementation Strategies

• Multidisciplinary care teams including pharmacists and nurses improve GDMT titration and adherence, reducing all-cause mortality with odds ratio of 0.66 (95% CI 0.48-0.92) 1, 2
• Refer newly diagnosed HFrEF patients to HF specialty care to maximize GDMT optimization 1
• Virtual peer-to-peer consultation and electronic health record-based interventions increase GDMT initiation rates 1

Non-Pharmacological Management

• Explain heart failure pathophysiology, symptom recognition, and when to seek help 5
• Teach daily self-weighing and report weight gain >2 kg in 3 days 5
• Smoking cessation is mandatory, with nicotine replacement acceptable 5
• Regular exercise is recommended for stable NYHA Class II-III patients to prevent muscle deconditioning 5
• Control sodium intake in severe heart failure, avoid excessive fluid intake, and limit alcohol consumption 5