Why should the combination of Angiotensin-Converting Enzyme inhibitors (ACEI) and Angiotensin Receptor Blockers (ARB) be avoided?

Why Combination ACEI and ARB Therapy Must Be Avoided

The combination of ACE inhibitors and ARBs is contraindicated because it increases serious adverse events—specifically hyperkalemia, acute kidney injury, and syncope—without providing any additional cardiovascular or renal protection beyond single-agent therapy. 1

Evidence-Based Rationale for Avoiding Combination Therapy

Lack of Clinical Benefit

• Dual RAAS blockade does not reduce cardiovascular events or mortality compared to monotherapy. The landmark ONTARGET trial definitively demonstrated that combining ACEIs and ARBs increased harm without reducing cardiovascular events in any patient subgroup, including those with chronic kidney disease. 2, 3

• Despite lowering proteinuria more effectively than single agents, this surrogate marker improvement has not translated into meaningful clinical outcomes such as reduced mortality or prevention of end-stage renal disease. 2

• Meta-analyses confirm no difference in overall mortality, all-cause hospitalization, or fatal/nonfatal myocardial infarction between combination therapy and ACE inhibitor monotherapy. 4

Significantly Increased Adverse Events

The combination dramatically increases three major complications:

• Hyperkalemia: Risk increases 4-5 fold with dual therapy (RR 4.87,95% CI 2.39-9.94) in heart failure patients, as both drug classes raise serum potassium through different mechanisms of RAAS blockade. 3, 5

• Acute Kidney Injury (AKI): Dual blockade significantly increases AKI risk compared to either agent alone, with worsening renal function occurring more than twice as frequently (RR 2.17,95% CI 1.59-2.97). 1, 3, 5

• Symptomatic Hypotension and Syncope: The combination increases hypotension risk by approximately 50% (RR 1.50,95% CI 1.09-2.07), leading to syncope and falls. 1, 5

• Medication Discontinuation: Adverse effects necessitate stopping therapy 38% more often with combination treatment (RR 1.38,95% CI 1.22-1.55). 5

Universal Guideline Consensus

All major cardiovascular and nephrology societies explicitly recommend against this combination:

• The American College of Cardiology/American Heart Association provides a Class III Harm recommendation with Level A evidence stating that simultaneous use of an ACE inhibitor, ARB, and/or renin inhibitor is potentially harmful and not recommended. 2, 3

• The American Diabetes Association states the combined use of ACE inhibitors and ARBs should be avoided. 1, 2

• The Canadian Society of Nephrology recommends not using ACE inhibitors with ARBs in primary care. 2, 3

• The European Society of Cardiology explicitly states that adding an ARB to an ACE inhibitor is not recommended due to risk of renal dysfunction and hyperkalemia. 2

Appropriate Clinical Approach

Use Single-Agent RAAS Blockade

• Choose either an ACE inhibitor OR an ARB as monotherapy—never both together. 2, 3

• For patients with albuminuria, proteinuria, chronic kidney disease, or diabetes with hypertension, either an ACE inhibitor or ARB alone is recommended as first-line therapy. 2

• Optimize the dose of your chosen single agent to the maximum approved dose rather than adding a second RAAS blocker. 3

Managing Uncontrolled Blood Pressure

• If blood pressure remains uncontrolled on a single RAAS blocker, add a different drug class:

  • Thiazide-like diuretics (chlorthalidone or indapamide preferred) 1
  • Dihydropyridine calcium channel blockers 1, 3
  • Mineralocorticoid receptor antagonists for resistant hypertension 1

• Multiple-drug therapy is often required to achieve blood pressure goals, but the additional agents should have complementary mechanisms of action from different drug classes. 1

Transitioning Patients Already on Dual Therapy

• If you encounter a patient on both an ACEI and ARB, transition to a single agent immediately. 2, 3

• Monitor blood pressure, serum creatinine, estimated glomerular filtration rate, and potassium levels closely during and after the transition. 2, 3

• Continue the single agent that has been better tolerated or is more appropriate for the patient's specific indication. 2

Critical Monitoring Requirements

• When using any RAAS blocker (single agent), monitor serum creatinine and potassium levels at routine visits and 7-14 days after initiation or dose changes. 1

• Patients with reduced glomerular filtration are at particularly increased risk for hyperkalemia and AKI, requiring more frequent monitoring. 1

• Both hyperkalemia and AKI independently increase risks of cardiovascular events and death, making their detection and management essential. 1

Common Clinical Pitfall to Avoid

The most dangerous misconception is that "more complete RAAS blockade" will provide superior organ protection. While theoretically appealing, this hypothesis has been definitively disproven by multiple large randomized trials showing only harm without benefit. 2, 6 The VA NEPHRON-D trial was even stopped early due to increased adverse events with combination therapy. 2