What is the recommended guideline‑directed medical therapy for an adult patient diagnosed with heart failure?

Guideline-Directed Medical Therapy for Heart Failure

All adult patients with heart failure and reduced ejection fraction (HFrEF, LVEF ≤40%) should receive four foundational medication classes initiated as early as possible: ACE inhibitors (or ARB/ARNI), beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors, with diuretics added for fluid overload. 1, 2, 3

Initial Assessment and Diagnosis

Before initiating therapy, perform the following essential evaluations:

• Measure B-type natriuretic peptide (BNP) or NT-proBNP to confirm heart failure diagnosis in patients with dyspnea of uncertain etiology 4
• Obtain 12-lead ECG and chest radiograph (PA and lateral) in all patients 4
• Perform two-dimensional echocardiography with Doppler to assess LVEF, left ventricular size, wall thickness, and valve function 4
• Complete laboratory evaluation: CBC, urinalysis, serum electrolytes (including calcium and magnesium), BUN, creatinine, fasting glucose, lipid profile, liver function tests, and TSH 4
• Assess volume status, orthostatic blood pressure changes, weight, height, and calculate BMI 4
• Identify precipitating factors: acute coronary syndrome, severe hypertension, arrhythmias, infections, pulmonary emboli, renal failure, medication/dietary noncompliance 4

First-Line Pharmacotherapy (Stage C: Symptomatic HFrEF)

ACE Inhibitors or Alternatives

Start ACE inhibitors immediately in all patients with HFrEF unless contraindicated 4, 2. ACE inhibitors reduce mortality and morbidity and should be initiated before hospital discharge 5, 6.

• Switch to ARB only if ACE inhibitor adverse effects are intolerable (not for convenience), as ACE inhibitors have a stronger evidence base 4
• Consider ARNI (sacubitril/valsartan) as a substitute for ACE inhibitors/ARBs in appropriate patients, as it reduces cardiovascular death and hospitalization more than enalapril 7, 8
  • Allow 36-hour washout period when switching from ACE inhibitor to ARNI 7
  • Starting dose: 49/51 mg twice daily, titrate to target 97/103 mg twice daily after 2-4 weeks 7

Beta-Blockers

Initiate beta-blockers as first-line therapy alongside ACE inhibitors in all patients with HFrEF, regardless of symptom severity or age 4, 1. Beta-blockers reduce mortality by 34%, the highest relative risk reduction among foundational HFrEF medications 1.

Only three beta-blockers have proven mortality benefit:

• Bisoprolol: Start 1.25 mg once daily, target 10 mg once daily 1
• Carvedilol: Evidence-based dosing per clinical trials 4
• Metoprolol succinate (CR/XL): Not metoprolol tartrate 4, 1

Initiation strategy ("start-low, go-slow"):

• Double the dose at minimum 2-week intervals if tolerated 4, 1, 2
• Monitor heart rate, blood pressure, and clinical status after each titration 4, 1
• Continue uptitration to target doses even if symptoms improve at lower doses 1
• Do not withhold beta-blockers in older adults, patients with peripheral vascular disease, erectile dysfunction, diabetes, interstitial pulmonary disease, or COPD 4

Patient counseling:

• Symptomatic improvement may take 3-6 months 1
• Temporary worsening occurs in 20-30% during initiation 1
• Treatment prevents disease progression and increases survival 1

Diuretics for Fluid Overload

Administer intravenous loop diuretics immediately in patients with significant fluid overload, starting in the emergency department without delay 4, 2.

• If already on loop diuretics, initial IV dose should equal or exceed the oral maintenance dose 4
• Recommended starting dose: 20-40 mg IV furosemide or equivalent for new-onset heart failure 2
• Diuretics relieve symptoms but do not improve survival 4

Second-Line Pharmacotherapy

After initiating ACE inhibitors and beta-blockers, add one of three options based on disease severity, ethnicity, and comorbidities 4:

Mineralocorticoid Receptor Antagonists (Aldosterone Antagonists)

Add aldosterone antagonists (spironolactone or eplerenone) for patients with NYHA class III-IV symptoms and LVEF ≤35% 4, 2.

Eligibility criteria:

• Creatinine ≤2.5 mg/dL (men) or ≤2.0 mg/dL (women) 4
• Potassium <5.0 mEq/L 4
• Close monitoring required for hyperkalemia and renal function 4

Angiotensin Receptor Blockers (ARBs)

Add ARBs to ACE inhibitors and beta-blockers if persistent symptoms remain 4.

• ARBs reduce cardiovascular mortality and hospitalization when added to ACE inhibitors and beta-blockers 4
• High risk of hyperkalemia with combination ACE inhibitor + ARB therapy 4
• Monitor potassium and renal function closely 4

Hydralazine/Isosorbide Dinitrate

Add hydralazine/nitrate combination for patients with reduced LVEF already on ACE inhibitor and beta-blocker with persistent symptoms 4.

• Particularly beneficial in African American patients 4

SGLT2 Inhibitors

SGLT2 inhibitors have demonstrated mortality benefit in HFrEF and should be considered as part of core therapy 2.

Advanced Therapies (Stage D: Refractory HF)

Device Therapy

Cardiac resynchronization therapy (CRT) for patients with:

• LVEF <35% 4
• QRS duration ≥150 ms, or 120-149 ms with mechanical dyssynchrony on echocardiography 4
• Persistent symptoms despite optimal medical therapy 4

Implantable cardioverter-defibrillators (ICDs) for patients with:

• LVEF <35% and sustained/inducible ventricular tachycardia 4
• LVEF <30% with QRS ≥120 ms 4

Additional Therapies

Ivabradine reduces hospitalization risk in patients with:

• Stable symptomatic chronic HF with LVEF ≤35% 9
• Sinus rhythm with resting heart rate ≥70 bpm 9
• On maximally tolerated beta-blockers or contraindication to beta-blockers 9

Monitoring Requirements

Check renal function and electrolytes:

• Before medication initiation 2
• 1-2 weeks after initiation 1, 2
• 1-2 weeks after final dose titration 1, 2
• At 3 months, then every 6 months 2

Monitor for:

• Worsening symptoms, weight gain >1.5-2.0 kg over 2 days 1
• Bradycardia (<50 bpm) or symptomatic hypotension 1
• Hyperkalemia with aldosterone antagonists or combination RAAS inhibition 4

Critical Pitfalls to Avoid

• Never delay beta-blocker initiation in stable patients due to misconceptions about safety 1
• Never stop beta-blockers when clinical improvement occurs; continue uptitration to target doses 1
• Never use NSAIDs or COX-2 inhibitors, as they worsen heart failure and increase hospitalization 2
• Avoid thiazolidinediones, which increase heart failure risk 2
• Do not use inotropic agents unless patient is symptomatically hypotensive or hypoperfused 2
• Do not readily switch from ACE inhibitor to ARB for convenience; only switch if adverse effects are intolerable 4
• Do not underdose medications; uptitrate to target doses used in clinical trials 1, 10

Implementation Strategy

Initiate all four foundational medication classes as early as possible, ideally before hospital discharge 1, 2, 5, 6. The medication initiation burden is substantial—25% of hospitalized HF patients need to start more than one medication to meet quality measures 6.

Schedule early follow-up within 7-14 days after hospital discharge 2. Referral to a heart failure clinic significantly increases appropriate GDMT initiation across all medication classes 10.