Should Angiotensin-Converting Enzyme (ACE) inhibitors, spironolactone, and nitrates be avoided in patients with Coronary Artery Disease (CAD) or Heart Failure with reduced Ejection Fraction (HFrEF)?

ACE Inhibitors, Spironolactone, and Nitrates in CAD and HFrEF

ACE inhibitors and spironolactone should be used in HFrEF, while nitrates should be avoided in HFrEF unless the patient has concurrent CAD with angina symptoms. Both ACE inhibitors and spironolactone are cornerstone therapies for HFrEF that reduce mortality and morbidity, while nitrates have shown no benefit in HFrEF without angina.

ACE Inhibitors in HFrEF and CAD

Benefits in HFrEF

• ACE inhibitors are first-line therapy for HFrEF with Class I, Level A recommendation 1
• They reduce mortality and hospitalization in patients with reduced ejection fraction
• The Number Needed to Treat (NNT) to prevent one death at 12 months is 63 2
• ACE inhibitors should be used in all patients with HFrEF unless contraindicated

Benefits in CAD

• ACE inhibitors are recommended in patients with a history of MI and reduced EF to prevent HF (Class I, Level A) 1
• They are particularly beneficial in patients with CAD and left ventricular dysfunction 3

Contraindications and Cautions

• Hypotension (systolic BP <90 mmHg)
• Renal insufficiency (creatinine >2.5 mg/dL in men or >2.0 mg/dL in women)
• Hyperkalemia (K+ >5.0 mEq/L)
• Pregnancy
• History of angioedema

Spironolactone in HFrEF

Benefits

• Spironolactone is indicated for NYHA Class III-IV HFrEF to increase survival and reduce hospitalizations 4
• In the Randomized Spironolactone Evaluation Study, spironolactone reduced mortality by 30% compared to placebo 4
• It also reduced hospitalization for cardiac causes by 30% 4

Patient Selection

• Recommended for patients with NYHA Class III-IV symptoms despite optimal therapy with ACE inhibitors and beta-blockers 4
• Baseline requirements:
  • Serum creatinine <2.5 mg/dL
  • Serum potassium <5.0 mEq/L
  • eGFR >30 mL/min/1.73m²

Monitoring

• Check potassium and renal function:
  • Every 4 weeks for first 12 weeks
  • Every 3 months for first year
  • Every 6 months thereafter

Nitrates in HFrEF and CAD

HFrEF Without CAD

• Routine use of nitrates in HFrEF without CAD is not recommended (Class III: No Benefit, Level B-R) 1
• The NEAT-HFpEF trial showed no beneficial effects on activity levels, quality of life, exercise tolerance, or NT-proBNP levels 1

HFrEF With CAD and Angina

• Nitrates may be used for symptom relief in patients with HFrEF who also have CAD with angina symptoms 1
• This is an exception to the general recommendation against nitrates in HFrEF

Treatment Algorithm for HFrEF

1. First-line therapy:

   • ACE inhibitor (or ARB if ACE inhibitor not tolerated)
   • Evidence-based beta-blocker
   • Diuretics for fluid overload

2. Add for persistent symptoms:

   • For NYHA Class II-IV with LVEF ≤35%: Consider ARNI (sacubitril/valsartan) in place of ACE inhibitor 5
   • For NYHA Class III-IV with LVEF ≤35%: Add spironolactone 4

3. Special considerations:

   • For HFrEF with CAD and angina: Add nitrates for symptom relief
   • For HFrEF without angina: Avoid routine use of nitrates

Treatment Algorithm for CAD Without HFrEF

1. First-line therapy:

   • Antiplatelet therapy
   • Statin therapy
   • Beta-blocker (particularly post-MI)

2. Consider ACE inhibitor for:

   • Patients with hypertension
   • History of MI
   • Diabetes mellitus
   • Chronic kidney disease

3. Nitrates:

   • Can be used for symptom relief of angina
   • No mortality benefit established

Common Pitfalls to Avoid

1. Inappropriate medication combinations:

   • Routine combined use of ACE inhibitor, ARB, and aldosterone antagonist is not recommended (Class III) 1
   • This combination increases risk of hyperkalemia and renal dysfunction

2. Inadequate monitoring:

   • Failure to monitor potassium and renal function when using ACE inhibitors and spironolactone
   • Risk of hyperkalemia is highest with combination therapy

3. Underdosing:

   • Not titrating ACE inhibitors to target doses shown to reduce cardiovascular events in clinical trials
   • Starting at low doses and gradually increasing is recommended

4. Discontinuation during decompensation:

   • Abrupt withdrawal of ACE inhibition can lead to clinical deterioration
   • Temporary dose reduction is preferable to discontinuation

5. Using nitrates in HFrEF without angina:

   • No proven benefit and may cause unnecessary side effects

By following these evidence-based recommendations, clinicians can optimize outcomes for patients with CAD and HFrEF while minimizing adverse effects.