What is the Guideline-Directed Medical Therapy (GDMT) for a patient with heart failure?

Guideline-Directed Medical Therapy (GDMT) for Heart Failure

All patients with heart failure with reduced ejection fraction (HFrEF, LVEF ≤40%) should be started on four foundational medication classes simultaneously at low doses—ARNI (preferably) or ACE inhibitor/ARB, beta-blocker, mineralocorticoid receptor antagonist (MRA), and SGLT2 inhibitor—then uptitrated every 1-2 weeks to target doses regardless of symptom severity. 1, 2, 3

The Four Pillars of GDMT for HFrEF

1. Renin-Angiotensin System Inhibitors

• ARNI (sacubitril/valsartan) is preferred over ACE inhibitors or ARBs, providing at least 20% reduction in mortality risk and superior outcomes compared to enalapril 1, 2, 3
• Start sacubitril/valsartan at 24/26 mg or 49/51 mg twice daily, targeting 97/103 mg twice daily 3
• Critical safety requirement: When switching from an ACE inhibitor to ARNI, observe a strict 36-hour washout period to avoid angioedema 4, 3
• If ARNI is not tolerated or available, use ACE inhibitors (e.g., enalapril, lisinopril) or ARBs (e.g., valsartan, losartan) and uptitrate to target doses 2, 3

2. Beta-Blockers

• Only three beta-blockers have proven mortality benefit: carvedilol, metoprolol succinate, or bisoprolol—do not substitute with other beta-blockers 1, 2, 3
• These provide at least 20% reduction in mortality risk 1, 2
• Start at low doses and uptitrate to target doses every 1-2 weeks 1, 3
• Carvedilol is preferred if refractory hypertension is present due to its combined α1-β1-β2-blocking properties 2

3. Mineralocorticoid Receptor Antagonists (MRAs)

• Use spironolactone (12.5-25 mg daily) or eplerenone (25 mg daily), uptitrating to target doses 1, 2, 3
• These provide at least 20% reduction in mortality risk 1, 2, 3
• Eplerenone avoids the 5.7% higher rate of male gynecomastia seen with spironolactone 1, 3
• Monitor potassium and creatinine closely, especially during uptitration 1, 3

4. SGLT2 Inhibitors

• Use dapagliflozin or empagliflozin—these are the newest class with significant mortality benefits 1, 2, 3
• Major advantages: no blood pressure, heart rate, or potassium effects; no dose titration required; benefits occur within weeks of initiation, independent of background therapy 1, 2, 3
• Safe in moderate kidney dysfunction (eGFR ≥30 ml/min/1.73 m² for empagliflozin and ≥20 ml/min/1.73 m² for dapagliflozin) 2

Combined Therapy Impact

Quadruple therapy reduces mortality risk by approximately 73% over 2 years compared to no treatment and extends life expectancy by approximately 6 years compared to traditional dual therapy (ACE inhibitor and beta-blocker). 1, 2, 3

Critical Implementation Strategy: Simultaneous Initiation

• Start all four medication classes simultaneously at low initial doses rather than waiting to achieve target dosing of one before initiating the next 4, 1, 2, 3
• This approach is supported by the STRONG-HF trial and current ACC/AHA/HFSA guidelines 4, 2
• Less than one-quarter of eligible patients currently receive all medications concurrently, and only 1% receive target doses of all medications 1, 2

Uptitration Protocol

• Uptitrate every 1-2 weeks until target doses are achieved 1, 2, 3
• Check blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment 1, 2, 3
• More frequent monitoring is needed in elderly patients and those with chronic kidney disease 2

Managing Common Barriers to Uptitration

Low Blood Pressure

• Asymptomatic or mildly symptomatic low blood pressure should never prompt GDMT reduction or cessation 2, 3
• Patients with adequate perfusion can tolerate systolic BP 80-100 mmHg 2, 3
• Only reduce or stop GDMT if systolic BP <80 mmHg or low BP with major symptoms (confusion, syncope, oliguria) 3
• If blood pressure is low but perfusion adequate, prioritize medications in this order: SGLT2 inhibitors and MRAs first (minimal BP impact), then beta-blockers, then ARNI/ACE inhibitor/ARB 2, 3

Renal Function Changes

• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation of ARNI/ACE inhibitor/ARB 2, 3
• Temporary reduction or hold only if substantial renal deterioration occurs 3
• In heart failure trials, greater than 50% increases in creatinine were observed in 3.9% of valsartan-treated patients compared to 0.9% of placebo-treated patients 5

Hyperkalemia

• Monitor potassium closely with MRA initiation and uptitration 1, 3
• Adjust MRA dose or consider potassium binders if needed rather than discontinuing therapy 3

Fatigue and Weakness

• Temporary symptoms of fatigue and weakness with dose increases usually resolve within days—do not prematurely discontinue GDMT 2, 3

Special Clinical Scenarios

Hospitalized Patients

• Continue GDMT except when hemodynamically unstable or contraindicated 1, 2, 3
• Initiate GDMT after ≥24 hours of stabilization with adequate organ perfusion 2, 3
• In-hospital initiation substantially improves post-discharge medication use compared to deferring initiation to outpatient setting 2, 3
• Initial IV loop diuretic dose should equal or exceed chronic oral daily dose 2

Improved Ejection Fraction

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

Self-Identified Black Patients

• For self-identified black patients with NYHA Class III-IV symptoms, add hydralazine/isosorbide dinitrate to quadruple therapy 4, 2

Additional Therapies Beyond the Four Pillars

Loop Diuretics

• Add loop diuretics only if fluid overload is present—they are for volume management but provide no mortality benefit 1, 2, 3
• Titrate based on symptoms and volume status, not as routine therapy 3

Ivabradine

• Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF ≤35%) who are receiving GDMT, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of 70 bpm or greater at rest 4
• Given the well-proven mortality benefits of beta-blocker therapy, it is important to initiate and uptitrate these agents to target doses, as tolerated, before assessing the resting heart rate for consideration of ivabradine initiation 4
• In the SHIFT trial, only 25% of patients studied were on optimal doses of beta-blocker therapy 4, 6

Vericiguat

• Consider vericiguat for higher-risk patients with worsening HFrEF (LVEF <45%, NYHA class II-IV, elevated natriuretic peptides, recent HF hospitalization or IV diuretic therapy) who remain symptomatic despite GDMT 3
• Vericiguat reduced the primary outcome of cardiovascular death or HF hospitalization by 10% (HR 0.90, P=0.019) in the VICTORIA trial 3
• Patients in the highest quartile of NT-proBNP (>5314 pg/mL) did not benefit from vericiguat 3

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

• Mineralocorticoid receptor antagonists have a weaker recommendation (Class 2b) based on TOPCAT trial data showing benefit in reducing HF hospitalizations 2
• Hypertension control is a cornerstone of HFpEF management (Class I recommendation) 2
• Treatment of atrial fibrillation for symptom management (Class 2a recommendation) 2
• HFpEF has primarily reduction in hospitalizations rather than mortality, with SGLT2i having the strongest evidence 2

Implementation Strategies to Improve GDMT Use

• Multidisciplinary care teams including pharmacists and nurses improve GDMT titration, reduce all-cause mortality (OR 0.66,95% CI 0.48-0.92), and reduce HF hospitalizations 1, 2, 3
• Nurse-led titration programs are effective for achieving target doses 2, 3
• Referral to HF specialty care maximizes GDMT optimization in newly diagnosed HFrEF patients 2, 3
• Digital solutions such as best practice advisories, electronic health record-based interventions, and telehealth visits increase GDMT prescription rates 2, 3
• Pharmacist involvement improves GDMT adherence and dosing 2, 7

Common Pitfalls to Avoid

• Do not wait to achieve target dosing of one medication before initiating the next—this delays life-saving therapy 2, 3
• Do not overreact to laboratory changes—modest creatinine elevation (up to 30% above baseline) is acceptable 2, 3
• Do not discontinue GDMT for asymptomatic hypotension if perfusion is adequate 2, 3
• Do not use non-evidence-based beta-blockers (e.g., atenolol, propranolol) as substitutes for carvedilol, metoprolol succinate, or bisoprolol 1, 3
• Avoid non-dihydropyridine calcium channel blockers, moxonidine, and alpha-adrenergic blockers in HFrEF patients, as they may increase the risk of worsening heart failure 2

The Reality of GDMT Implementation

Despite clear guideline recommendations, most patients are not receiving target (or the highest tolerated) doses of all essential drugs, even when patients are treated by clinical investigators with considerable expertise in heart failure. 4

• In one prospective study, only 23% of patients were receiving ≥50% of target doses of beta-blockers, renin–angiotensin inhibitors and mineralocorticoid receptor antagonists 4
• In a second survey, target doses of angiotensin receptor–neprilysin inhibitors, beta-blockers and mineralocorticoid receptor antagonists were prescribed in <1% 4
• In the HELP-HF registry of patients with severe HFrEF, up to half of the patients did not receive target doses for unknown causes (51%, 41%, and 55% for beta-blockers, ACEi/ARB/ARNI and MRA, respectively), suggesting a potential role of clinical inertia 8

Treatment with beta-blockers and ACEi/ARB/ARNI was associated with lower mortality/morbidity even in patients with severe HFrEF (adjusted HR 0.63,95% CI 0.48-0.84, and HR 0.74,95% CI 0.58-0.95, respectively). 8