Do patients with heart failure need heart failure specific Guideline-Directed Medical Therapy (GDMT) like Angiotensin Receptor Blockers (ARBs), beta blockers?

Do Patients with Heart Failure Need Heart Failure-Specific GDMT?

Yes, all patients with heart failure with reduced ejection fraction (HFrEF, EF ≤40%) absolutely require heart failure-specific guideline-directed medical therapy (GDMT) including ARBs/ACE inhibitors (or preferably ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and SGLT2 inhibitors—these four medication classes should be initiated simultaneously at low doses and uptitrated to target doses, as this approach reduces mortality risk by approximately 73% over 2 years compared to no treatment. 1, 2

The Four Pillars of GDMT for HFrEF

All four medication classes below are Class I recommendations and should be used together for maximum benefit:

1. Renin-Angiotensin System Inhibitors

• ARNI (sacubitril/valsartan) is preferred over ACE inhibitors or ARBs, providing at least 20% reduction in mortality risk 3, 1, 2
• ACE inhibitors or ARBs reduce mortality by 5-16% if ARNI is not tolerated or available 1, 2
• When switching from ACE inhibitor to ARNI, observe a strict 36-hour washout period to avoid angioedema; no washout needed when switching from ARB 3

2. Evidence-Based Beta-Blockers

• Only three beta-blockers are proven effective: carvedilol, metoprolol succinate, or bisoprolol 1, 2
• These provide at least 20% reduction in mortality risk 1, 2
• Metoprolol succinate extended-release at doses of 100-400 mg once daily has been shown effective in the MERIT-HF trial, reducing all-cause mortality by 34% 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) with close monitoring of potassium and creatinine 1
• Only 5.7% higher rate of male gynecomastia with spironolactone (can avoid with eplerenone use) 3

4. SGLT2 Inhibitors

• Dapagliflozin or empagliflozin are the newest class with significant mortality benefits 1, 2
• Unique advantage: no blood pressure, heart rate, or potassium effects; no dose titration required 3
• Treatment benefits occur within weeks of initiation, independent of background therapy 3
• Effective even in patients with moderate kidney dysfunction (eGFR ≥30 ml/min/1.73 m² for empagliflozin, ≥20 ml/min/1.73 m² for dapagliflozin) 3

Critical Implementation Strategy: Simultaneous Initiation

Start all four medication classes simultaneously at low initial doses rather than sequential initiation. 1, 2

Why Simultaneous Initiation?

• Less than one-quarter of eligible patients currently receive all three medications concurrently, and only 1% receive target doses of all medications 3, 1
• Waiting to achieve target dosing of one medication before initiating the next delays life-saving therapy 1, 2
• Achieving partial doses of all four pillars is better than target dosing of only a couple 5

Uptitration Protocol

• Uptitrate every 1-2 weeks until target doses are achieved 1, 2
• Monitor blood pressure, renal function, and electrolytes at 1-2 weeks after each dose increment 1, 2
• More frequent monitoring needed in elderly patients and those with chronic kidney disease 1

Combined Therapy Impact

Transitioning from traditional dual therapy (ACE inhibitor and beta-blocker) to quadruple therapy extends life expectancy by approximately 6 years. 1, 2

Common Pitfalls to Avoid

Do Not Overreact to Expected Changes

• Modest creatinine elevation (up to 30% above baseline) is acceptable and should not prompt discontinuation 1
• Patients with adequate perfusion can tolerate systolic BP 80-100 mmHg 1
• Temporary symptoms of fatigue and weakness with dose increases usually resolve within days 1
• Adverse events are common in HF patients (74.9-84.5% in trials) but occur at similar rates in placebo and intervention arms, suggesting they are related to HF itself rather than GDMT 3

Specific Adverse Event Rates

• ACE inhibitors: 8.9% higher rate of cough (can avoid with ARNI or ARB), 3.9% higher rate of dizziness 3
• Beta-blockers: 5.5% higher rate of dizziness, but 5% lower rate of serious adverse events compared to placebo 3
• MRAs: 5.7% higher rate of male gynecomastia with spironolactone 3
• SGLT2 inhibitors: 0.9% higher rate of genital infection, no difference in volume depletion, AKI, or hypoglycemia 3

Do Not Discontinue GDMT Inappropriately

• De-escalation or discontinuation of GDMT after heart failure hospitalization is associated with dramatically increased mortality risk (hazard ratios 2.94-4.81 depending on medication class) 6
• Providers should consider whether patients' symptoms may not be related to GDMT therapies 3
• If medications are stopped for symptoms, consider re-trialing them in the future 3

Special Clinical Scenarios

Hospitalized Patients

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

Low Blood Pressure

• If systolic BP <90 mmHg but adequate perfusion present, prioritize SGLT2 inhibitors and MRAs first (minimal BP impact) 1
• Use selective β₁ receptor blockers and low-dose ACE inhibitor/ARB or very low-dose ARNI 1
• Small incremental dose increases with close monitoring 1

Improved Ejection Fraction

• Patients with previous HFrEF whose EF improves to >40% should continue their HFrEF treatment regimen 1, 2
• Discontinuation of HFrEF medications after EF improvement may lead to clinical deterioration 1

Heart Failure with Preserved Ejection Fraction (HFpEF)

For patients with HFpEF (EF >40%), the approach differs significantly:

• SGLT2 inhibitors are the primary GDMT with the strongest recommendation (Class 2a) for reducing HF hospitalizations and cardiovascular death 1
• MRAs have a weaker recommendation (Class 2b) based on TOPCAT trial 1
• Hypertension control is cornerstone of management (Class I recommendation) 1
• Focus on phenotype-directed approach targeting comorbidities (hypertension, diabetes, obesity, atrial fibrillation) 1

Role of Heart Failure Specialty Care

• Referral to HF specialty care maximizes GDMT optimization 1
• Being seen in an HF clinic is independently associated with initiation of GDMT across all medication classes (hazard ratios 1.54-2.49) 7
• Nurse-led titration programs reduce all-cause mortality (odds ratio 0.66) 1
• Pharmacist involvement improves GDMT adherence and dosing 1