NO – ACE Inhibitors and ARBs Should NOT Be Combined for Hypertension Treatment
The combination of an ACE inhibitor with an ARB is explicitly contraindicated for hypertension management and increases serious adverse events without providing additional cardiovascular benefit. 1, 2
Why This Combination Is Harmful
The evidence against ACE-ARB combination is unequivocal:
The ONTARGET trial demonstrated that combining an ACE inhibitor with an ARB resulted in a significant excess of end-stage renal disease (ESRD) cases compared to monotherapy with either agent. 1
The ALTITUDE trial was prematurely terminated due to excess cases of ESRD and stroke when a renin inhibitor (aliskiren) was added to pre-existing ACE inhibitor or ARB therapy in diabetic patients. 1
The European Society of Cardiology explicitly states this is the only drug combination that cannot be recommended based on trial results, showing increased risks of hyperkalemia, acute kidney injury, and syncope without cardiovascular benefit. 1, 2
All major international guidelines (ESH/ESC 2013, British Hypertension Society 2016, ACC/AHA 2017, and multiple others) uniformly advise against combining two different RAS blockers. 1
What You Should Use Instead
Preferred Two-Drug Combinations for Hypertension:
First-line combination therapy should consist of a RAS blocker (ACE inhibitor OR ARB—not both) combined with either a dihydropyridine calcium channel blocker or a thiazide-like diuretic. 1, 2
Specifically:
- ACE inhibitor + calcium channel blocker (e.g., lisinopril + amlodipine) 2
- ARB + calcium channel blocker 1, 2
- ACE inhibitor + thiazide diuretic 1
- ARB + thiazide diuretic 1
Three-Drug Combination (If Two Drugs Fail):
When blood pressure remains uncontrolled on two medications, escalate to: RAS blocker (ACE inhibitor OR ARB) + dihydropyridine calcium channel blocker + thiazide/thiazide-like diuretic, preferably as a single-pill combination. 1, 2
Four-Drug Combination (Resistant Hypertension):
If BP remains ≥140/90 mmHg on optimal doses of three drugs, add spironolactone 25-50 mg daily as the preferred fourth agent. 2
Clinical Pitfalls to Avoid
Common Mistake #1: Thinking "More RAS Blockade = Better"
- Dual RAS blockade does NOT provide incremental cardiovascular protection and actively increases harm. 1, 2
- The theoretical benefit of more complete angiotensin II suppression does not translate to clinical benefit in outcome trials. 3
Common Mistake #2: Using ACE-ARB Combination for "Resistant" Hypertension
- If a patient fails monotherapy with an ACE inhibitor, switch to a different drug class (calcium channel blocker or thiazide diuretic)—do not add an ARB. 1, 2
- Most patients with hypertension require 2-3 drugs from DIFFERENT mechanistic classes, not dual RAS blockade. 1, 2
Common Mistake #3: Confusing Heart Failure with Hypertension Indications
- While some older heart failure studies suggested potential benefits of ACE-ARB combination, this does NOT apply to hypertension management. 4, 5
- Even in heart failure, the evidence is controversial and limited to highly selected patients—this is NOT the question being asked here. 3
Specific Adverse Events You're Risking
When ACE inhibitors and ARBs are combined, expect:
- Hyperkalemia (dangerous elevation in serum potassium) 2
- Acute kidney injury (sudden decline in renal function) 1, 2
- Syncope (fainting from excessive hypotension) 2
- End-stage renal disease (requiring dialysis) 1
- Increased stroke risk (demonstrated in ALTITUDE trial) 1
The Bottom Line Algorithm
For any patient with hypertension requiring combination therapy:
Start with ONE RAS blocker (choose either ACE inhibitor OR ARB based on tolerability—ARBs have lower cough rates) 1, 6
Add a calcium channel blocker (preferred) or thiazide-like diuretic as second agent 1, 2
If still uncontrolled, add the third class (now you have RAS blocker + CCB + diuretic) 2
If STILL uncontrolled, add spironolactone—NOT a second RAS blocker 2