What is the mortality benefit of Angiotensin-Converting Enzyme (ACE) inhibitors versus Angiotensin Receptor Blockers (ARBs)?

Mortality Benefits: ACE Inhibitors vs ARBs

Both ACE inhibitors and ARBs demonstrate equivalent mortality benefits in cardiovascular disease, with no significant difference in all-cause or cardiovascular mortality across major clinical trials. 1, 2, 3

Direct Mortality Comparison

Heart Failure with Reduced Ejection Fraction (HFrEF)

• ACE inhibitors consistently reduce mortality across the clinical spectrum from asymptomatic to severely symptomatic heart failure 1
• ARBs produce similar mortality benefits in patients with mild-to-moderate heart failure who cannot tolerate ACE inhibitors 1
• The 2017 ACC/AHA/HFSA guidelines state that ARBs have been shown to reduce mortality and heart failure hospitalizations in large randomized controlled trials, with effects consistent with renin-angiotensin system blockade 1

Post-Myocardial Infarction

• The VALIANT trial (14,703 patients) demonstrated no difference in all-cause mortality between valsartan (ARB) and captopril (ACE inhibitor): hazard ratio 1.001 (95% CI 0.902-1.111, p=0.98) 2
• Valsartan mortality rate: 19.9% vs captopril: 19.5% over 2 years of follow-up 2
• Cardiovascular mortality was also equivalent: valsartan vs captopril hazard ratio 0.976 (95% CI 0.875-1.090) 2
• Non-inferiority analysis confirmed valsartan preserved the mortality benefit of captopril, demonstrating it retained at least half of the estimated 14-16% mortality reduction seen with ACE inhibitors compared to placebo 2

Hypertension and Diabetes

• A 2018 systematic review found no difference in all-cause mortality, cardiovascular mortality, myocardial infarction, heart failure, stroke, or end-stage renal disease between ARBs and ACE inhibitors in hypertensive patients 3
• Multiple diabetes guidelines confirm both drug classes are superior to placebo in reducing cardiovascular events and microvascular complications, with no significant outcome differences between them 1

Clinical Context Matters

When ACE Inhibitors Are Preferred

• Post-myocardial infarction with reduced ejection fraction: ACE inhibitors (or ARBs if intolerant) prevent symptomatic heart failure and reduce mortality 1
• Established coronary artery disease with diabetes: ACE inhibitors are recommended as first-line therapy based on cardiovascular outcome data 1
• Diabetic nephropathy in type 1 diabetes: ACE inhibitors are first-line for prevention and progression of nephropathy 1

When ARBs Are Equally Effective

• Heart failure patients intolerant to ACE inhibitors (due to cough or angioedema): ARBs provide equivalent mortality reduction 1
• Diabetic nephropathy in type 2 diabetes: ARBs are considered first-line therapy equal to ACE inhibitors 1
• Hypertension without compelling indications: ARBs and ACE inhibitors show equivalent efficacy for blood pressure control and cardiovascular outcomes 1, 3

Adverse Event Profile Differences

ACE Inhibitor-Specific Issues

• Cough occurs more frequently with ACE inhibitors than ARBs 1, 3
• Angioedema risk is present with ACE inhibitors, though rare; ARBs have lower incidence but cross-reactivity can occur 1, 3
• Overall withdrawal rates due to adverse events are lower with ARBs than ACE inhibitors 3

Shared Adverse Effects

• Both classes require monitoring for hyperkalemia and acute kidney injury, especially when combined with other renin-angiotensin system blockers 1
• Both should be used with caution in patients with low blood pressure, renal insufficiency, or elevated serum potassium (>5.0 mEq/L) 1

Critical Pitfalls to Avoid

Do NOT Combine ACE Inhibitors and ARBs

• Combination therapy is contraindicated: no added cardiovascular benefit but increased risk of hyperkalemia, syncope, and acute kidney injury 1
• The VALIANT trial showed no mortality benefit when combining valsartan with captopril compared to either agent alone: hazard ratio 0.984 (95% CI 0.886-1.093, p=0.73) 2

Dosing Considerations

• Use target doses proven in clinical trials whenever tolerated 1
• For heart failure, high-dose ACE inhibitors (e.g., lisinopril 32.5-35 mg daily) show 12% lower risk of death or hospitalization and 24% fewer heart failure hospitalizations compared to low doses (2.5-5 mg daily) 4
• Valsartan mean effective dose in VALIANT was 217 mg daily 2

Practical Algorithm for Selection

Start with ACE inhibitor if:

• Post-MI with reduced ejection fraction 1
• Established coronary disease with diabetes 1
• Type 1 diabetes with nephropathy 1
• No prior intolerance to ACE inhibitors 1

Switch to ARB if:

• Cough develops on ACE inhibitor (most common reason) 1, 3
• Angioedema occurs on ACE inhibitor (use ARB with caution) 1
• Patient already tolerating ARB for other indication when heart failure develops 1

Either agent is appropriate for:

• Hypertension without compelling indications 1, 3
• Type 2 diabetes with nephropathy 1
• Heart failure in ACE inhibitor-naive patients 1