What is the best course of treatment for an elderly male patient with a history of coronary artery disease (CAD) status post coronary artery bypass grafting (CABG), heart failure with reduced ejection fraction (HFrEF), tachycardia-induced cardiomyopathy, sick sinus syndrome (SSS) status post single-chamber pacemaker, persistent atrial fibrillation (A-fib) on anticoagulation, hypertension (HTN), hyperlipidemia (HLD), diabetes mellitus type 2 (DM2), and chronic obstructive pulmonary disease (COPD), who presents with increased shortness of breath and has severely reduced left ventricular (LV) function with a left ventricular ejection fraction (LVEF) of 25-30%?

Immediate Initiation of Quadruple Guideline-Directed Medical Therapy for HFrEF

This patient requires immediate initiation of all four foundational therapies for HFrEF—SGLT2 inhibitor, sacubitril/valsartan (ARNI), beta-blocker, and mineralocorticoid receptor antagonist—started simultaneously or in rapid sequence before discharge, as he is currently on none of these life-saving medications despite having severely reduced LVEF of 25-30%. 1, 2, 3

Critical Gap in Current Management

Your patient has severe HFrEF (LVEF 25-30%) with symptomatic dyspnea but is not on any guideline-directed medical therapy (GDMT), representing a major treatment gap that directly impacts his mortality and quality of life. 4 The fact that he has multiple comorbidities (COPD, DM2, CKD likely given his age and comorbidities) does not contraindicate GDMT—rather, these patients derive substantial benefit from optimized therapy. 4

The Four Pillars of GDMT: Specific Initiation Strategy

1. SGLT2 Inhibitor (Start First)

• Initiate dapagliflozin 10 mg daily or empagliflozin 10 mg daily immediately, regardless of diabetes status 1, 5, 2
• Can be started even with eGFR as low as 20 mL/min/1.73 m² 5
• Benefits occur within weeks, minimal blood pressure effect, making it ideal as the first agent 2, 6
• Reduces cardiovascular death and HF hospitalization by 20-30% while protecting kidney function 5, 6

2. Sacubitril/Valsartan (ARNI) - Preferred Over ACE Inhibitor

• Start sacubitril/valsartan 24/26 mg twice daily (low dose given elderly age, multiple comorbidities, and unknown baseline BP) 1, 5
• If eGFR <30 mL/min/1.73 m², use 24/26 mg twice daily; if eGFR ≥30, can use 49/51 mg twice daily 1, 5
• Target dose: 97/103 mg twice daily, titrate every 2-4 weeks as tolerated 1, 2
• Provides 20% mortality reduction compared to ACE inhibitors 1, 3
• No washout period needed since he's not currently on ACE inhibitor or ARB 1
• Asymptomatic hypotension (SBP >100 mmHg) should not prevent initiation 1, 2

3. Evidence-Based Beta-Blocker

• Start carvedilol 3.125 mg twice daily, metoprolol succinate 12.5-25 mg daily, or bisoprolol 1.25 mg daily 5, 2
• Target doses: carvedilol 25-50 mg twice daily, metoprolol succinate 200 mg daily, or bisoprolol 10 mg daily 2, 7
• Titrate every 1-2 weeks as tolerated by heart rate and blood pressure 2, 7
• His history of SSS with pacemaker is not a contraindication—the pacemaker provides backup for bradycardia 4, 5

4. Mineralocorticoid Receptor Antagonist (MRA)

• Start spironolactone 12.5-25 mg daily or eplerenone 25 mg daily 1, 5, 2
• Target dose: spironolactone 25-50 mg daily 2, 7
• Monitor potassium closely—acceptable up to 5.0-5.5 mEq/L 1, 5
• If hyperkalemia develops, consider potassium binders rather than discontinuing therapy 5

Sequencing Strategy: Rapid Simultaneous Initiation

Start all four medications simultaneously or within 1-2 days of each other rather than the traditional sequential approach. 2, 3, 6 This approach:

• Achieves maximum mortality benefit fastest 3, 6
• Is safe and well-tolerated when starting at low doses 3, 7
• Reduces 1-year mortality when optimized before discharge 8
• Less than 20% of eligible patients receive quadruple therapy due to sequential approaches 6

Device Therapy Consideration: Upgrade to CRT-D

Given his LVEF 25-30%, NYHA class II-III symptoms (dyspnea with minimal exertion), and single-chamber pacemaker, he requires evaluation for upgrade to CRT-D (cardiac resynchronization therapy with defibrillator). 4

Key criteria to assess:

• QRS duration and morphology (need ECG to determine if LBBB ≥150 ms) 4
• If LBBB with QRS ≥150 ms: Class I indication for CRT 4
• If LBBB with QRS 120-149 ms: Class IIa indication for CRT 4
• ICD indicated for primary prevention given LVEF ≤35% on GDMT 4
• His single-chamber pacemaker provides no resynchronization benefit and may worsen HF if causing significant RV pacing 4

Critical Monitoring Parameters

Initial Monitoring (1-2 weeks after each dose change):

• Blood pressure (target SBP >90 mmHg, but asymptomatic hypotension acceptable) 1, 2
• Heart rate (target 50-60 bpm on beta-blocker) 2
• Renal function: accept creatinine increases up to 30% above baseline—do not discontinue therapy 5, 2
• Potassium: recheck if elevated before making changes; use binders if needed 5
• BNP/NT-proBNP for trend monitoring (though not for dose titration) 1

Acceptable Laboratory Changes:

• eGFR decrease ≤30% from baseline 5
• Creatinine increase <0.5 mg/dL 1
• Potassium up to 5.5 mEq/L (with close monitoring) 1, 5

Medications to Discontinue or Avoid

• NSAIDs: Discontinue immediately—interfere with RAAS inhibitor efficacy and worsen renal function 2
• Never combine ACE inhibitor with ARNI (36-hour washout required if switching from ACE inhibitor) 1, 2
• Review his "several antihypertensives" and consider discontinuing non-evidence-based agents (e.g., calcium channel blockers, alpha-blockers) to reduce polypharmacy 3

Additional Considerations for Comorbidities

Atrial Fibrillation Management:

• Continue anticoagulation (already on therapy) 4
• His beta-blocker will provide rate control 4
• CRT remains beneficial in AF if near 100% ventricular pacing achieved (may need AV nodal ablation) 4

COPD:

• Beta-blockers are not contraindicated in COPD—cardioselective agents (metoprolol, bisoprolol) preferred over carvedilol 4, 5
• Benefits of beta-blocker in HFrEF outweigh theoretical COPD concerns 4

Diabetes:

• SGLT2 inhibitors provide additional glycemic benefit 5, 6
• Monitor for genital mycotic infections (common but manageable side effect) 6

Coronary Artery Disease:

• His fixed apical defect on nuclear stress suggests prior MI territory (likely LAD) 4
• No reversible ischemia means no indication for repeat revascularization 4
• CABG would only be considered if angina present with suitable anatomy 4

Titration Timeline (Next 8-12 Weeks)

Week 0-2:

• Start all four medications at low doses
• Check BP, HR, K+, creatinine at 1-2 weeks

Week 2-4:

• Increase sacubitril/valsartan to 49/51 mg twice daily
• Increase beta-blocker dose
• Recheck labs

Week 4-6:

• Increase sacubitril/valsartan to 97/103 mg twice daily (target)
• Continue beta-blocker titration
• Increase MRA if tolerated

Week 6-12:

• Achieve target doses of all medications
• Final labs and assessment

Common Pitfalls to Avoid

• Do not delay GDMT initiation due to "stable" outpatient status—his dyspnea indicates he is symptomatic and requires immediate therapy 2, 6
• Do not withhold therapy for asymptomatic hypotension or mild creatinine elevation 1, 5, 2
• Do not use sequential monthly titration—this delays benefit and many patients never reach target doses 3, 6
• Do not discontinue medications for modest lab changes—adjust doses temporarily and re-titrate 1, 2
• Do not forget device evaluation—CRT-D may provide additional 20-30% mortality reduction 4

Expected Outcomes

With optimized quadruple GDMT:

• 20-50% reduction in cardiovascular death 1, 3, 6
• 30-40% reduction in HF hospitalization 1, 6
• Improved LVEF (may increase 5-15% over 6-12 months) 1, 7
• Symptom improvement within weeks to months 1, 2, 6
• Reduced mortality evident within 3-6 months 8