What is the guideline-directed therapy for Heart Failure with Reduced Ejection Fraction (HFrEF), Heart Failure with Mid-range Ejection Fraction (HFmrEF), and Heart Failure with Preserved Ejection Fraction (HFpEF)?

Guideline-Directed Medical Therapy for Heart Failure

Key Differences Between HF Subtypes

The fundamental difference is that HFrEF has four medication classes with Class I recommendations that dramatically reduce mortality, while HFpEF and HFmrEF have weaker evidence focused primarily on reducing hospitalizations rather than death. 1

HFrEF (EF ≤40%): Four Pillars with Strong Mortality Benefit

All four medication classes should be started simultaneously at low doses and uptitrated, rather than using the outdated sequential approach. 1, 2

The four foundational classes are:

• SGLT2 inhibitors (dapagliflozin or empagliflozin) - Class I recommendation, provide significant mortality benefits and should be started first as they have minimal blood pressure effects 1, 2
• ARNI (sacubitril/valsartan preferred) or ACE inhibitors/ARBs - Class I recommendation, reduce mortality by 5-16% for ACEi/ARBs and at least 20% for ARNI 2
• Beta-blockers (carvedilol, metoprolol succinate, or bisoprolol) - Class I recommendation, provide at least 20% reduction in mortality risk 2
• Mineralocorticoid receptor antagonists (spironolactone or eplerenone) - Class I recommendation, provide at least 20% reduction in mortality risk 2

Combined quadruple therapy reduces mortality risk by approximately 73% over 2 years compared to no treatment, and transitioning from dual to quadruple therapy can extend life expectancy by approximately 6 years. 2

HFmrEF (EF 41-49%): Weaker Recommendations

SGLT2 inhibitors have the strongest evidence with Class 2a recommendation, while all other HFrEF medications receive only Class 2b recommendations. 1

• SGLT2 inhibitors - Class 2a 1
• ARNI, ACE inhibitors, ARBs, MRAs, and beta-blockers - all Class 2b 1

HFpEF (EF ≥50%): Limited Options Focused on Hospitalization Reduction

SGLT2 inhibitors are the only medication class with Class 2a recommendation for HFpEF, based on DELIVER and EMPEROR-PRESERVED trials showing reduction in HF hospitalizations and cardiovascular death. 1, 2

The evidence-based options include:

• SGLT2 inhibitors - Class 2a recommendation (strongest evidence) 1, 2
• MRAs - Class 2b recommendation based on TOPCAT trial 1, 2
• ARNI - Class 2b recommendation based on PARAGON-HF trial 1
• ARBs - Class 2b recommendation 1
• Hypertension control - Class I recommendation (cornerstone of management) 1, 2
• Atrial fibrillation treatment - Class 2a recommendation for symptom management 1, 2

Nitrates and phosphodiesterase-5 inhibitors should be avoided as they provide no benefit (Class 3: No Benefit). 1

Implementation Strategy for HFrEF

Simultaneous Initiation Approach

Start all four foundational medications simultaneously at low doses rather than waiting to achieve target dosing of one before initiating the next. 2, 3

For patients with adequate blood pressure (SBP ≥100 mmHg): 2, 3

• Start SGLT2 inhibitor and MRA first (minimal BP impact)
• Add low-dose beta-blocker if heart rate >70 bpm
• Add low-dose ARNI (or ACEi/ARB if ARNI not feasible)
• Adjust diuretics according to volume status to avoid overdiuresis

For patients with low blood pressure (SBP <100 mmHg but adequate perfusion): 2, 3

• Prioritize SGLT2 inhibitors and MRAs first (minimal BP-lowering effects)
• Use selective β₁ receptor blockers (lesser BP effect)
• Consider very low-dose ARNI or ACEi/ARB
• If beta-blockers not tolerated and patient in sinus rhythm, consider ivabradine 2, 4

Uptitration Strategy

Uptitrate medications at 1-2 week intervals until target doses are achieved, monitoring blood pressure, renal function, and electrolytes after each dose increment. 2

Common barriers should not prevent uptitration: 2

• Modest creatinine increases (up to 30% above baseline) are acceptable
• Patients with adequate perfusion can tolerate systolic BP 80-100 mmHg
• Temporary symptoms of fatigue and weakness with dose increases usually resolve within days

Hospitalized Patients

Continue GDMT in hospitalized patients except when hemodynamically unstable or contraindicated, as continuation is associated with lower risk of post-discharge death and readmission. 2, 3

In-hospital initiation substantially improves post-discharge medication use compared to deferring initiation to outpatient setting. 2

Special Populations

Improved EF (Previously HFrEF, Now EF >40%)

Patients with previous HFrEF whose EF improves to >40% should continue their HFrEF treatment regimen, as discontinuation may lead to clinical deterioration. 1, 2

Role of Heart Failure Specialty Care

Referral to HF specialty care maximizes GDMT optimization, with multidisciplinary teams improving GDMT titration and adherence. 2, 5

Being seen in an HF clinic is independently associated with initiation of new GDMT across all medication classes, with hazard ratios ranging from 1.54 to 2.49. 5

Common Pitfalls to Avoid

Do not use the traditional step-by-step approach that delays benefits of comprehensive therapy. 2, 3

Do not overreact to laboratory changes - modest creatinine elevation (up to 30% above baseline) is acceptable in patients with adequate perfusion. 2

Do not cause excessive diuresis, which can lead to hypotension and impair tolerance of other HF medications. 2, 3

Do not prematurely discontinue GDMT - temporary symptoms usually resolve within days. 2

Do not withhold GDMT in patients with low baseline BP if they have adequate organ perfusion - prioritize SGLT2 inhibitors and MRAs first. 2, 3