What is the guideline-directed medical therapy for a newly diagnosed patient with heart failure?

Guideline-Directed Medical Therapy for Newly Diagnosed Heart Failure with Reduced Ejection Fraction

For a newly diagnosed patient with heart failure with reduced ejection fraction (HFrEF), initiate all four foundational medication classes simultaneously at low doses and rapidly uptitrate to target doses using a forced-titration strategy: SGLT2 inhibitors, beta-blockers (carvedilol, metoprolol succinate, or bisoprolol), ARNI (sacubitril/valsartan) or ACE inhibitors/ARBs, and mineralocorticoid receptor antagonists (MRAs). 1

The Four Pillars of HFrEF Therapy

1. SGLT2 Inhibitors (Dapagliflozin or Empagliflozin)

• Start immediately at diagnosis as the newest and most strongly recommended class with significant mortality benefits 1
• These agents provide cardiovascular benefits through improved decongestion, metabolic shifts toward ketone utilization, and renal protection 2
• SGLT2 inhibitors are safe and effective even in advanced chronic kidney disease (CKD stage 4) 2

2. Renin-Angiotensin System Inhibitors

• Preferentially use ARNI (sacubitril/valsartan) over ACE inhibitors or ARBs, as ARNI provides at least 20% reduction in mortality risk compared to 5-16% for ACEi/ARBs 1
• In the PARADIGM-HF trial, sacubitril/valsartan reduced all-cause mortality by 34% (HR 0.66,95% CI 0.53-0.81) and cardiovascular mortality by 38% (HR 0.62,95% CI 0.50-0.78) 3
• Start at 24/26 mg or 49/51 mg twice daily and uptitrate to target dose of 97/103 mg twice daily 3
• If ARNI is not tolerated or available, use ACE inhibitors or ARBs and uptitrate to target doses shown effective in trials 4

3. Evidence-Based Beta-Blockers

• Use only carvedilol, metoprolol succinate, or bisoprolol - these specific agents provide at least 20% reduction in mortality risk 1
• In the MERIT-HF trial, metoprolol succinate reduced all-cause mortality by 34% (nominal p=0.00009) 5
• Start at low doses and uptitrate to target: metoprolol succinate 200 mg daily, carvedilol 25-50 mg twice daily, or bisoprolol 10 mg daily 5
• Do not use other beta-blockers as only these three have proven mortality benefit 6

4. Mineralocorticoid Receptor Antagonists

• Initiate spironolactone or eplerenone to provide at least 20% reduction in mortality risk 1
• Start at low doses (spironolactone 12.5-25 mg daily or eplerenone 25 mg daily) and uptitrate to target doses 4
• Monitor potassium and creatinine closely: check 5-7 days after initiation and after each dose change 4

The Forced-Titration Strategy: Critical for Survival Benefit

The survival benefits demonstrated in landmark trials were achieved through forced-titration strategies, not through maintenance on low starting doses. 4

Key Principles of Forced-Titration:

• Start all four medication classes at low doses simultaneously or in rapid sequence 4
• Uptitrate progressively at specific time intervals (typically every 1-2 weeks) until target doses are achieved 4
• Target doses are the same for every patient - not individualized based on symptoms alone 4
• Temporary dose reductions should be followed by aggressive attempts to restore target doses 4
• Asymptomatic changes in vital signs and laboratory tests should not prevent uptitration 4

The Reality Gap in Clinical Practice:

• In clinical practice, <1% of patients receive all life-prolonging treatments at trial-proven doses 4
• Most patients are started on low doses and maintained indefinitely on these starting doses without uptitration 4
• For sacubitril/valsartan specifically, <25% of patients are ever titrated to the target dose of 97/103 mg twice daily in real-world practice, despite >70% maintaining target doses throughout the PARADIGM-HF trial 4
• This practice pattern lacks evidence for mortality benefit - only target doses have been proven to prolong life 4

Combined Therapy: The Mortality Benefit

Combined quadruple therapy reduces mortality risk by approximately 73% over 2 years compared to no treatment. 1

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

Practical Implementation Algorithm

At Diagnosis:

1. Initiate SGLT2 inhibitor immediately (no titration needed - use standard dose) 1
2. Start ARNI at 24/26 mg or 49/51 mg twice daily (or ACEi/ARB if ARNI unavailable) 3
3. Start evidence-based beta-blocker at low dose 5
4. Start MRA at low dose (spironolactone 12.5-25 mg or eplerenone 25 mg daily) 4
5. Add loop diuretics only if fluid overload is present 4

Uptitration Schedule:

• Week 1-2: Check blood pressure, renal function, and electrolytes 4
• Week 2-4: Increase ARNI and beta-blocker doses if tolerated 4
• Week 4-6: Continue uptitration toward target doses 4
• Repeat every 1-2 weeks until target doses achieved 4
• Monitor potassium and creatinine 5-7 days after each MRA dose change 4

Monitoring Parameters:

• Blood pressure, renal function, and electrolytes at 1-2 weeks after each dose increment 4
• Recheck at 3 months, then at 6-month intervals 4
• More frequent monitoring in patients with renal dysfunction or electrolyte disturbances 4

Managing Common Barriers to Uptitration

Hypotension:

• If systolic BP <90 mmHg but patient has adequate perfusion, continue uptitration with small incremental increases and close monitoring 1
• Prioritize medications in this order: SGLT2 inhibitors and MRAs first, then selective β₁ receptor blockers, then low-dose ACEi/ARB or very low-dose ARNI 1
• Asymptomatic hypotension alone should not prevent uptitration 4

Worsening Renal Function:

• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation 4
• SGLT2 inhibitors remain safe and effective even in CKD stage 4 2
• If substantial renal deterioration occurs, temporarily reduce or hold ACEi/ARB/ARNI, but attempt to reinstitute 4

Hyperkalemia:

• Use potassium-sparing diuretics cautiously during initiation 4
• Check potassium 5-7 days after MRA initiation and after each dose change 4
• If hyperkalemia develops, adjust diuretics and dietary potassium before discontinuing life-saving therapy 7

Bradycardia:

• If beta-blockers are not hemodynamically tolerated, consider ivabradine as an alternative for heart rate control 1

Critical Pitfalls to Avoid

The most common and lethal error is maintaining patients on low starting doses indefinitely. 4

• Do not treat heart failure like a chronic stable condition - it is more lethal than most cancers and requires aggressive uptitration similar to oncology protocols 4
• Do not discontinue or reduce GDMT during or after heart failure hospitalization - this is associated with 3-5 fold increased risk of all-cause mortality 8
• Do not use non-evidence-based beta-blockers (e.g., atenolol, propranolol) - only carvedilol, metoprolol succinate, and bisoprolol have proven mortality benefit 6
• Do not avoid NSAIDs - these interfere with ACE inhibitor efficacy 4

Role of Heart Failure Specialty Care

Patients seen in a heart failure clinic have significantly higher rates of GDMT initiation and uptitration. 6

• HF clinic involvement is independently associated with initiation across all medication classes: HR 1.54 for any beta-blocker, 2.49 for HF beta-blockers, 1.97 for ACEi/ARB/ARNI, and 2.14 for MRAs 6
• Refer newly diagnosed HFrEF patients to HF specialty care to maximize GDMT optimization 6
• Multidisciplinary teams including pharmacists and nurses improve GDMT titration and adherence 4

Special Populations

Patients with Improved Ejection Fraction:

• Continue all HFrEF medications even if EF improves to >40% 1
• Discontinuation of GDMT after EF improvement leads to clinical deterioration 1

Patients with End-Stage CKD:

• SGLT2 inhibitors remain the most strongly recommended therapy even in advanced CKD 2
• Consider hydralazine-isosorbide dinitrate combination if RAS inhibitors cannot be tolerated due to renal insufficiency, particularly in African American patients 2
• Higher doses or combination diuretic therapy may be needed due to decreased diuretic efficacy 2