Can olmesartan (angiotensin II receptor antagonist), spironolactone (aldosterone antagonist), and enalapril (angiotensin-converting enzyme inhibitor) be prescribed together for a patient with hypertension and heart failure?

Can Olmesartan, Spironolactone, and Enalapril Be Prescribed Together?

No, the combination of olmesartan (ARB), enalapril (ACE inhibitor), and spironolactone should not be prescribed together due to significantly increased risks of hyperkalemia, renal dysfunction, and adverse cardiac outcomes without additional clinical benefit.

Why This Triple Combination Is Contraindicated

Dual RAS Blockade Is Explicitly Prohibited

The FDA drug label for olmesartan explicitly warns against dual blockade of the renin-angiotensin system (RAS), stating that combining ARBs with ACE inhibitors is associated with increased risks of hypotension, hyperkalemia, and changes in renal function including acute renal failure compared to monotherapy 1. The 2024 ESC Guidelines confirm that combining two RAS blockers is not recommended as an exception to standard combination therapy 2.

• Most patients receiving two RAS inhibitors do not obtain any additional benefit compared to monotherapy 1.
• The combination dramatically increases hyperkalemia risk without providing mortality or morbidity benefit 3.

Evidence of Harm from Triple Combination

The SUPPORT trial (2015) provides the strongest evidence against this combination in heart failure patients 4:

• Triple therapy with an ARB, ACE inhibitor, and beta-blocker was associated with a 47% increased risk of the primary composite endpoint (HR 1.47; 95% CI 1.11-1.95, P=0.006) 4.
• All-cause mortality increased by 50% (HR 1.50; 95% CI 1.01-2.23, P=0.046) with triple combination 4.
• Renal dysfunction increased by 85% (HR 1.85; 95% CI 1.24-2.76, P=0.003) 4.

Guideline-Based Contraindications

The 2009 ACC/AHA Heart Failure Guidelines explicitly state: "The safety of the combination of ACE inhibitors, ARBs, and aldosterone antagonists has not been explored adequately, and this combination cannot be recommended" 2.

• Although 17% of patients in the CHARM trial received spironolactone with an ARB, this was not a planned comparison and safety was not established 2.

The Correct Approach: Choose One RAS Blocker

For Heart Failure with Reduced Ejection Fraction

Use either an ACE inhibitor OR an ARB (not both), combined with spironolactone, beta-blocker, and SGLT2 inhibitor 2, 5:

• ACE inhibitors (enalapril, ramipril, lisinopril) are first-line with Class I, Level A evidence 2.
• ARBs (candesartan, valsartan) are equivalent alternatives if ACE inhibitors are not tolerated 2.
• Spironolactone should be added to the single RAS blocker in NYHA class II-IV patients with EF <40% 2.

For Hypertension

Use a single RAS blocker (either olmesartan OR enalapril) combined with a calcium channel blocker and/or thiazide diuretic 2:

• The 2024 ESC Guidelines recommend upfront combination therapy with two drug classes from: ACE inhibitors, ARBs, dihydropyridine CCBs, or thiazide/thiazide-like diuretics 2.
• Spironolactone should only be considered as fourth-line therapy for resistant hypertension after maximally tolerated triple therapy with a single RAS blocker, CCB, and diuretic 2.

Critical Safety Monitoring If Spironolactone Is Combined with a Single RAS Blocker

When combining spironolactone with either enalapril OR olmesartan (never both), strict monitoring is mandatory 3:

Pre-Treatment Requirements

• Serum potassium must be <5.0 mEq/L 2, 3.
• Serum creatinine must be <2.5 mg/dL in men or <2.0 mg/dL in women 2.
• eGFR must be >30 mL/min/1.73m² 3.

Monitoring Schedule

• Check potassium and creatinine at 1 week and 4 weeks after initiation 3.
• Continue monitoring at 1,2,3, and 6 months after achieving maintenance dose 3.
• Monitor every 6 months thereafter 3.

Dose Adjustment Thresholds

• If potassium rises to 5.5-6.0 mEq/L: Halve the spironolactone dose 3.
• If potassium exceeds 6.0 mEq/L: Stop spironolactone immediately 3.
• Start spironolactone at 25 mg daily (not higher) when combined with ACE inhibitors or ARBs 3.

Common Pitfalls to Avoid

• Never combine an ACE inhibitor with an ARB, even if adding spironolactone seems beneficial 2, 3.
• Do not assume that lower doses of each agent will mitigate the hyperkalemia risk—the interaction is pharmacological, not dose-dependent 6.
• Avoid NSAIDs, potassium supplements, and salt substitutes containing potassium in patients on this combination 1.
• Do not use this combination in elderly patients (≥75 years) or those with baseline renal dysfunction without extremely close monitoring 3.

The Bottom Line

Choose either olmesartan OR enalapril (not both), and combine with spironolactone only if indicated for heart failure with reduced ejection fraction or resistant hypertension, with rigorous potassium and renal function monitoring 2, 3, 1.