What additional medications can be added to a patient already on an Angiotensin-Converting Enzyme (ACE) inhibitor and an Angiotensin Receptor Blocker (ARB)?

Medication Options for Patients Already on ACE Inhibitor and ARB

Routine combined use of an ACE inhibitor and ARB is not recommended due to increased risks of adverse effects without significant clinical benefit, and adding a third RAS blocker is potentially harmful. 1, 2

Current Evidence on Dual RAS Blockade

The combination of ACE inhibitors and ARBs raises significant safety concerns:

• Increased risk of hypotension, renal dysfunction, and hyperkalemia 1, 2
• No additional mortality benefit compared to monotherapy 3
• Class III: Harm recommendation from ACC/AHA guidelines against routine combined use 2

Recommended Medication Options

First-line Addition (Preferred):

1. Beta-blockers (Class I recommendation)

   • Specifically one of the three proven to reduce mortality: bisoprolol, carvedilol, or sustained-release metoprolol succinate 2
   • Can reduce risk of death and hospitalization
   • Effective regardless of presence of CAD, diabetes, gender, or race 2

2. Mineralocorticoid Receptor Antagonists (MRAs) (Class I recommendation)

   • Spironolactone or eplerenone for patients with:
     • NYHA class II-IV heart failure
     • LVEF ≤35%
     • Prior cardiovascular hospitalization or elevated natriuretic peptide levels 2, 4
   • Monitor for hyperkalemia (especially important with dual RAS blockade) 4
   • Contraindicated if creatinine >2.5 mg/dL in men or >2.0 mg/dL in women 2

3. Diuretics

   • Loop diuretics (furosemide, bumetanide, torsemide) or thiazides 2
   • Particularly useful for managing fluid overload and congestion
   • Can act synergistically with existing medications 2

4. Calcium Channel Blockers (CCBs)

   • Dihydropyridine CCBs (amlodipine, felodipine) are preferred 2
   • Non-dihydropyridine CCBs (verapamil, diltiazem) should be avoided due to negative inotropic effects 2

5. Hydralazine and Isosorbide Dinitrate Combination

   • Particularly beneficial for African American patients with NYHA class III-IV heart failure 2
   • Alternative for patients who cannot tolerate ACE inhibitors or ARBs

Algorithm for Medication Selection

1. Assess clinical status:

   • If heart failure with LVEF ≤35%: Add MRA (if renal function permits) 2
   • If hypertension predominates: Add dihydropyridine CCB or diuretic 2
   • If African American with NYHA III-IV heart failure: Consider hydralazine/isosorbide dinitrate 2

2. Consider comorbidities:

   • Fluid overload: Prioritize diuretics 2
   • Coronary artery disease: Beta-blocker may provide additional benefit 2
   • Proteinuria/CKD: MRA may provide additional renoprotection (with careful monitoring) 5

Monitoring and Precautions

• For all patients: Monitor blood pressure, renal function, and potassium levels within 1-2 weeks of medication initiation and after dose changes 2, 4
• Particular caution with MRAs when combined with dual RAS blockade due to increased risk of hyperkalemia 4, 5
• High-risk patients requiring closer monitoring: those with systolic BP <80 mmHg, low serum sodium, diabetes mellitus, or impaired renal function 2

Important Considerations

• Consider discontinuing one of the RAS blockers (either ACE inhibitor or ARB) and optimizing the remaining one before adding new agents 1
• The ESC guidelines explicitly state that routine combined use of ACE inhibitor, ARB, and aldosterone antagonist is potentially harmful 2
• If maintaining dual RAS blockade, use lower doses of each agent and monitor very closely 2

Remember that the current standard of care is to use either an ACE inhibitor OR an ARB, not both simultaneously, due to the increased risk of adverse effects without additional benefit 1, 3.