What are the four guideline‑directed medication classes for systolic (reduced ejection fraction) heart failure?

The Four Guideline-Directed Medication Classes for Systolic Heart Failure

All patients with heart failure with reduced ejection fraction (HFrEF) should receive quadruple therapy consisting of: (1) an ARNI/ACE inhibitor/ARB, (2) a beta-blocker, (3) a mineralocorticoid receptor antagonist (MRA), and (4) an SGLT2 inhibitor—these four medication classes should be started simultaneously at low doses as soon as possible after diagnosis. 1

The Four Foundational Medication Classes

1. Renin-Angiotensin System Inhibitors

• ARNI (sacubitril/valsartan) is preferred over ACE inhibitors or ARBs, providing at least 20% mortality reduction superior to traditional ACE inhibitors 1, 2
• If ARNI is not tolerated or available, use ACE inhibitors or ARBs as alternatives 1
• Target dose for sacubitril/valsartan is 97/103 mg twice daily 2
• Critical warning: Observe a strict 36-hour washout period when switching from ACE inhibitor to ARNI to avoid angioedema 1

2. Beta-Blockers

• Use only evidence-based beta-blockers: carvedilol, metoprolol succinate, or bisoprolol 1, 2
• These provide at least 20% mortality reduction and decrease sudden cardiac death 1, 2
• Beta-blockers provide 34% mortality reduction, the highest relative risk reduction among the four medication classes 2
• Avoid non-evidence-based beta-blockers as they lack proven mortality benefit 1

3. Mineralocorticoid Receptor Antagonists (MRAs)

• Use spironolactone or eplerenone 1, 2
• Provide at least 20% mortality reduction and reduce sudden cardiac death 1, 2
• Start at low doses (spironolactone 12.5-25 mg daily or eplerenone 25 mg daily) with close monitoring of potassium and creatinine 1
• Can be used if eGFR >30 ml/min/1.73 m² 2

4. SGLT2 Inhibitors

• Use dapagliflozin or empagliflozin 1, 2
• Reduce cardiovascular death and heart failure hospitalization regardless of diabetes status 1, 2
• Key advantages: No blood pressure, heart rate, or potassium effects; no dose titration required; benefits occur within weeks of initiation 1, 2
• Can be used if eGFR ≥30 ml/min/1.73 m² for empagliflozin or ≥20 ml/min/1.73 m² for dapagliflozin 1, 2

Combined Mortality Benefit

• Quadruple therapy reduces mortality risk by approximately 73% over 2 years compared to no treatment 1
• Transitioning from traditional dual therapy (ACE inhibitor and beta-blocker) to quadruple therapy extends life expectancy by approximately 6 years 1
• The aggregate treatment effect yields a hazard ratio of 0.38 (95% CI 0.30-0.47) for cardiovascular death or heart failure hospitalization 3

Initiation Strategy: Simultaneous vs Sequential

Start all four medication classes simultaneously at low initial doses rather than sequential initiation. 1, 2

Recommended Sequencing for Uptitration

• Start SGLT2 inhibitor and MRA first since they have minimal blood pressure effects 1, 2
• Then add beta-blocker if heart rate >70 bpm 2
• Finally add ARNI/ACE inhibitor/ARB at low dose 2
• Uptitrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved 1, 2

Why Simultaneous Initiation Matters

• Less than one-quarter of eligible patients currently receive all medications concurrently, and only 1% receive target doses of all medications 1
• Sequential initiation delays full therapeutic benefit and contributes to the massive treatment gap 1
• In-hospital initiation substantially improves post-discharge medication use compared to deferring to outpatient setting 1

Critical Pitfalls to Avoid

1. Do Not Withhold Therapy for Asymptomatic Hypotension

• Patients with adequate perfusion can tolerate systolic BP 80-100 mmHg 1, 2
• GDMT medications maintain efficacy and safety even in patients with baseline SBP <110 mmHg 2
• Asymptomatic or mildly symptomatic low blood pressure should not be a reason for GDMT reduction or cessation 1

2. Do Not Overreact to Laboratory Changes

• Modest creatinine elevation (up to 30% above baseline) is acceptable and should not prompt discontinuation 1, 2
• Discontinuing RAAS inhibitors after hypotension or hyperkalemia is associated with two to fourfold higher risk of subsequent adverse events 2

3. Do Not Accept Suboptimal Doses

• Clinical trials demonstrated benefits at target doses, not low doses 2
• Target doses provide the greatest mortality benefit 1
• Only 1% of patients receive all medications at target doses, representing a critical treatment gap 1

4. Do Not Use Non-Evidence-Based Medications

• Avoid diltiazem or verapamil in HFrEF as they increase risk of worsening heart failure and hospitalization 1, 2
• Do not use non-evidence-based beta-blockers 1
• Never combine ACE inhibitor with ARNI due to angioedema risk 1, 2
• Avoid triple combination of ACE inhibitor + ARB + MRA due to hyperkalemia and renal dysfunction risk 1, 2

Monitoring Requirements

• Check blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment 1, 2
• More frequent monitoring needed in elderly patients and those with chronic kidney disease 1, 2
• Early follow-up (within 7-14 days) after medication adjustments is recommended 1

Additional Therapy for Specific Populations

• For self-identified Black patients with NYHA Class III-IV symptoms: Add hydralazine/isosorbide dinitrate to quadruple therapy 1, 2
• For patients with heart rate ≥70 bpm despite maximally tolerated beta-blocker: Consider ivabradine 1, 2

Diuretics: The Fifth Component

• Loop diuretics are essential for congestion control but do not reduce mortality 2
• Add only if fluid overload is present 1
• Titrate to achieve euvolemia, then use lowest dose that maintains this state 2