What is Guideline-Directed Medical Therapy (GDMT) for heart failure?

Guideline-Directed Medical Therapy (GDMT) for Heart Failure

GDMT for heart failure with reduced ejection fraction (HFrEF) now consists of four foundational medication classes that should be initiated simultaneously at low doses: ACE inhibitors/ARBs (preferably ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and SGLT2 inhibitors. 1

The Four Pillars of GDMT for HFrEF

1. Renin-Angiotensin System (RAS) Inhibitors

• ACE inhibitors or ARBs reduce mortality by 5-16% in HFrEF patients 2
• ARNI (sacubitril/valsartan) is preferred over ACE inhibitors/ARBs, providing at least 20% reduction in mortality risk 1, 2
• Start with low doses and uptitrate to target doses shown effective in trials 3

2. Evidence-Based Beta-Blockers

• Only three beta-blockers are recommended: carvedilol, metoprolol succinate, or bisoprolol 1, 2
• These provide at least 20% reduction in mortality risk 2
• Approximately 92% of eligible patients receive beta-blockers, but only 64% receive the correct HF-specific beta-blockers 4

3. Mineralocorticoid Receptor Antagonists (MRAs)

• Spironolactone or eplerenone provide at least 20% reduction in mortality risk 2
• Start at low doses (spironolactone 12.5-25 mg daily or eplerenone 25 mg daily) with close monitoring of potassium and creatinine 2
• Despite strong evidence, only 17.6% of newly diagnosed HFrEF patients receive MRAs in community practice 4

4. SGLT2 Inhibitors

• Dapagliflozin or empagliflozin are the newest class with significant mortality benefits 1, 2
• These medications have Class 1 recommendation for HFrEF 1
• SGLT2 inhibitors provide benefits through multiple mechanisms including improved decongestion and metabolic shifts 5

Combined Therapy Impact

Quadruple therapy reduces mortality risk by approximately 73% over 2 years compared to no treatment 2, and transitioning from traditional dual therapy (ACE inhibitor and beta-blocker) to quadruple therapy extends life expectancy by approximately 6 years 1, 2.

Critical Implementation Strategy: Simultaneous Initiation

Start all four foundational medications simultaneously at low initial doses rather than waiting to achieve target dosing of one medication before initiating the next 1, 2, 3. This approach directly addresses the massive treatment gap where less than one-quarter of eligible patients receive all medications concurrently, and only 1% receive target doses of all medications 2.

Forced-Titration Protocol

• Begin all four classes at low doses simultaneously or in rapid sequence 2, 3
• Uptitrate at specific time intervals (typically every 1-2 weeks) until target doses are achieved 2
• Temporary dose reductions should be followed by aggressive attempts to restore target doses 2
• Asymptomatic changes in vital signs and laboratory tests should not prevent uptitration 2

GDMT for Heart Failure with Preserved Ejection Fraction (HFpEF)

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.

Additional therapies for HFpEF include:

• MRAs (Class 2b recommendation) based on TOPCAT trial data 1, 2
• ARNI (Class 2b recommendation) 1
• Hypertension control as a cornerstone (Class I recommendation) 1, 2
• Treatment of atrial fibrillation for symptom management (Class 2a recommendation) 1, 2

GDMT for Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF)

• SGLT2 inhibitors have Class 2a recommendation 1
• Weaker recommendations (Class 2b) are made for ARNI, ACE inhibitors, ARBs, MRAs, and beta-blockers 1

Monitoring Requirements

Monitor blood pressure, renal function, and electrolytes at 1-2 weeks after each dose increment 2, 3. More frequent monitoring is needed in elderly patients and those with chronic kidney disease 2.

Managing Common Laboratory Changes

• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation of ACE inhibitors/ARBs/ARNI 2
• Temporary reduction or hold only if substantial renal deterioration occurs 2
• Hyperkalemia occurred in 2.2% of hypertensive patients and 4.8% of heart failure patients treated with lisinopril 6
• Patients with adequate perfusion can tolerate systolic blood pressure 80-100 mmHg 2

Special Clinical Scenarios

In-Hospital Initiation

Continue GDMT in hospitalized patients except when hemodynamically unstable or contraindicated 2, 3. In-hospital initiation substantially improves post-discharge medication use compared to deferring initiation to outpatient setting 2.

Inpatient optimization of GDMT is feasible and associated with improved 30-day hospitalization-free survival (HR 0.73,95% CI 0.62-0.86) and 1-year survival 7.

Low Blood Pressure Management

For patients with low systolic blood pressure (<90 mmHg) but adequate perfusion:

• Prioritize SGLT2 inhibitors and MRAs first as they have minimal blood pressure impact 2
• Use selective β₁ receptor blockers 2
• Consider low-dose ACE inhibitors/ARBs or very low-dose ARNI 2
• Small incremental dose increases with close monitoring are recommended 2
• If beta-blockers are not hemodynamically tolerated, ivabradine may be considered as an alternative for heart rate control 2

Improved Left Ventricular Ejection Fraction

Patients with previous HFrEF whose ejection fraction improves to >40% should continue their HFrEF treatment regimen 1, 2, 3. Discontinuation of HFrEF medications after ejection fraction improvement may lead to clinical deterioration 2.

End-Stage Chronic Kidney Disease

• SGLT2 inhibitors are the most strongly recommended therapy for patients with HFrEF and end-stage CKD, with evidence of safety and efficacy extending to CKD stage 4 5
• Hydralazine and isosorbide dinitrate combination is recommended for patients who cannot tolerate RAS inhibitors due to renal insufficiency, particularly in self-identified African American patients 5
• Higher doses or combination diuretic therapy may be needed due to decreased diuretic efficacy in advanced CKD 5

Additional GDMT Components

Diuretics

Add loop diuretics only if fluid overload is present 2, 3. Loop diuretics should be used for volume management but do not provide mortality benefit 5. Initial IV dose should equal or exceed chronic oral daily dose, and titrate based on urine output and congestion symptoms 2.

Other Medications

Ivabradine, vericiguat, and hydralazine-isosorbide dinitrate may be considered in selected patients 3. In one study, 68% of hospitalized HFrEF patients would have been suitable for vericiguat, 83% for ARNI, and 84% for SGLT2 inhibitors 8.

Common Pitfalls to Avoid

Do not prescribe subtarget doses without following forced-titration strategies 3. Temporary symptoms of fatigue and weakness with dose increases usually resolve within days and should not prompt premature discontinuation of GDMT 2.

Do not overreact to laboratory changes such as modest creatinine elevation 3. Adverse events are common in heart failure patients, but most are not attributable to GDMT medications and should not prevent appropriate therapy initiation 2.

Do not withhold GDMT in patients with adequate organ perfusion even if blood pressure is low 2.

Strategies to Improve GDMT Implementation

Multidisciplinary care teams including pharmacists and nurses improve GDMT titration and adherence 1. A systematic review of 7 randomized controlled trials (N=1,684) comparing nurse-led titration with usual care reported reductions in all-cause mortality (RR: 0.66; 95% CI: 0.48-0.92) and HF hospitalizations (RR: 0.51; 95% CI: 0.36-0.72) 1.

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 for any beta-blocker to 2.49 for HF-specific beta-blockers 4.