Can I combine an ACE inhibitor (angiotensin-converting enzyme inhibitor) with an ARB (angiotensin receptor blocker)?

ACE Inhibitor and ARB Combination: Not Recommended

The combination of an ACE inhibitor with an ARB should not be used in routine clinical practice, as this dual RAS blockade increases the risk of hyperkalemia, acute kidney injury, and hypotension without providing meaningful clinical benefits in mortality or major cardiovascular outcomes. 1

Guideline Consensus Against Combination Therapy

Multiple major guidelines explicitly recommend against combining ACE inhibitors with ARBs:

• The 2024 ESC Hypertension Guidelines state that combining two RAS blockers (ACE inhibitor and ARB) is not recommended. 1

• The 2013 ESH/ESC Guidelines identify the ACE inhibitor plus ARB combination as the only pairing that cannot be recommended, marked with a red line indicating "not recommended combination." 1

• The 2022 ACC/AHA harmonization document states that simultaneous use of an ACE inhibitor, ARB, and/or renin inhibitor is potentially harmful and not recommended. 1

• The Canadian Society of Nephrology (2015) explicitly recommends that the combination of ACE inhibitors and ARBs not be routinely used, even in heavily proteinuric patients. 1

Evidence of Harm Without Benefit

The prohibition against dual RAS blockade is based on high-quality randomized controlled trial evidence:

• The ONTARGET trial demonstrated that combining full-dose ACE inhibitors with full-dose ARBs increased the risk of hyperkalemia and acute kidney injury without reducing cardiovascular events in any CKD subgroup, despite lowering proteinuria more than single agents. 1

• The VA NEPHRON-D study in diabetic patients with CKD showed increased harm (acute kidney injury and hyperkalemia) from combination treatment without mortality benefit. 1

• The ALTITUDE trial was prematurely terminated due to excess cases of end-stage renal disease and stroke when adding a renin inhibitor to pre-existing ACE inhibitor or ARB therapy. 1

Heart Failure Context: Limited Exception

In heart failure with reduced ejection fraction, the evidence is more nuanced but still cautious:

• The 2013 ACC/AHA Heart Failure Guidelines give a Class IIb recommendation (may be considered) for adding an ARB to patients already on ACE inhibitor plus beta-blocker when an aldosterone antagonist is not indicated or tolerated. 1

• However, the same guidelines include a Class III: Harm recommendation stating that routine combined use of an ACE inhibitor, ARB, and aldosterone antagonist is potentially harmful. 1

• The 2009 ACC/AHA update notes that addition of ARBs to chronic ACE inhibitor therapy caused only modest decreases in hospitalization with no consistent mortality benefit, and that routine combined use of all three RAS inhibitors cannot be recommended. 1

The Proteinuria Paradox

While combination therapy does reduce proteinuria more effectively than monotherapy, this surrogate endpoint does not translate to improved hard outcomes:

• The 2007 KDOQI Guidelines note that while ACE inhibitor plus ARB combination can reduce proteinuria more than either agent alone, it is reasonable to use this combination only in hypertensive patients with DKD who have controlled blood pressure but persistent high-level macroalbuminuria (ACR >500 mg/g). 1

• However, the Canadian Society of Nephrology emphasizes that evidence showing the combination alters clinically important outcomes is lacking, even in heavily proteinuric patients, and that adverse effects are increased. 1

• A 2006 meta-analysis showed combination therapy increased serum potassium by 0.11 mEq/L and decreased proteinuria by 440 mg/day, but these were short-term studies without long-term renal function outcomes. 2

Practical Clinical Algorithm

When managing patients requiring RAS blockade:

1. Choose either an ACE inhibitor OR an ARB as monotherapy—never both. 1, 3

2. Optimize the dose of your single RAS blocker to the maximum tolerated/recommended dose before considering other strategies. 3

3. If additional blood pressure control is needed, add a calcium channel blocker or thiazide/thiazide-like diuretic, not a second RAS blocker. 1

4. For persistent proteinuria despite optimized single-agent RAS blockade, consider adding a mineralocorticoid receptor antagonist (like finerenone) rather than dual RAS blockade, with careful potassium monitoring. 4

5. In heart failure patients already on ACE inhibitor plus beta-blocker who remain symptomatic and cannot tolerate aldosterone antagonists, adding an ARB may be considered as a last resort, but this requires intensive monitoring for hyperkalemia and renal dysfunction. 1, 5

Key Monitoring Pitfalls to Avoid

• Do not assume that greater proteinuria reduction automatically means better long-term outcomes—the ONTARGET and NEPHRON-D trials proved otherwise. 1

• If dual therapy is used in exceptional heart failure cases, monitor serum potassium and creatinine within 1-2 weeks of initiation and after any dose changes. 1

• Accept up to 30% creatinine increase with single-agent RAS blockade, but be more vigilant with combination therapy where acute kidney injury risk is substantially higher. 1, 3

• The combination is particularly dangerous in patients with diabetes, advanced CKD (eGFR <30), baseline hyperkalemia, or those taking other potassium-sparing medications. 1, 4