ACE Inhibitor and ARB Combination in Resistant Hypertension
No, you should not prescribe an ACE inhibitor and ARB together for resistant hypertension—this combination is explicitly contraindicated and increases harm without providing cardiovascular or renal benefits. 1, 2
Why Dual Therapy Is Harmful
The combination of ACE inhibitors and ARBs has been definitively shown to cause more harm than benefit:
Two major clinical trials demonstrated no benefits on cardiovascular disease or chronic kidney disease outcomes, while the drug combination had significantly higher adverse event rates including hyperkalemia and acute kidney injury. 1
The ONTARGET trial in high-risk vascular patients demonstrated that dual blockade increased harm without reducing cardiovascular events in any CKD subgroup, despite lowering proteinuria more than single agents. 2
The American College of Cardiology issues a Class III Harm recommendation with Level A evidence against simultaneous use of ACE inhibitors and ARBs. 2
The American Diabetes Association explicitly states that the combined use of ACE inhibitors and ARBs should be avoided. 1
Specific Risks of Combination Therapy
Hyperkalemia
- Hyperkalemia risk is substantially elevated when both agents are used together, as both classes raise serum potassium levels through different mechanisms of renin-angiotensin system blockade. 2
Acute Kidney Injury
- Acute kidney injury occurs more frequently with dual therapy compared to either agent alone. 2
FDA Drug Label Warnings
The FDA label for lisinopril explicitly states: "Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. In most patients no benefit has been associated with using two RAS inhibitors concomitantly. In general, avoid combined use of RAS inhibitors." 3
The FDA label for olmesartan similarly warns: "Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors." 4
What to Do Instead for Resistant Hypertension
Optimize Single RAS Blocker First
Use either an ACE inhibitor OR an ARB as monotherapy, not both, for hypertension management. 2, 5
Optimize the dose of a single RAS blocker (either ACE inhibitor or ARB) to the maximum approved dose for hypertension treatment, rather than adding a second RAS blocker. 2
Add Different Antihypertensive Classes
If blood pressure remains uncontrolled, add a different class such as a calcium channel blocker or thiazide diuretic rather than combining ACE inhibitor with ARB. 2
Dihydropyridine calcium channel blockers are proven alternatives for additional blood pressure control when combined with a single RAS blocker. 1
Consider Mineralocorticoid Receptor Antagonists
Mineralocorticoid receptor antagonists (spironolactone, eplerenone, finerenone) in combination with ACE inhibitors or ARBs are effective for management of resistant hypertension and have shown cardiovascular benefits. 1
However, there is an increased risk of hyperkalemic episodes with this combination, requiring close monitoring of serum potassium levels. 1, 6
Finerenone combined with ACE inhibitors has shown significant benefits in reducing composite endpoints related to progression of renal disease and cardiovascular disease in patients with chronic kidney disease and type 2 diabetes. 6
Critical Monitoring If Patient Already on Dual Therapy
Transition to a single agent with close monitoring of blood pressure, renal function, and electrolytes if a patient is already on dual therapy. 2
Monitor serum creatinine, estimated glomerular filtration rate, and potassium levels closely during the transition. 2
Common Pitfall to Avoid
Do not be misled by older studies showing proteinuria reduction with dual therapy—while ACE inhibitor plus ARB combinations do reduce proteinuria more than monotherapy, this surrogate marker does not translate into improved clinical outcomes (cardiovascular events, progression to end-stage renal disease, or mortality), and the increased risks of hyperkalemia and acute kidney injury outweigh any theoretical benefits. 1, 2, 7