Why use an Angiotensin-Converting Enzyme (ACE) inhibitor, such as lisinopril, over an Angiotensin Receptor Blocker (ARB), like losartan, for a patient with hypertension and heart failure, given the potential for increased side effects with ACE inhibitors?

Why ACE Inhibitors Remain First-Line Over ARBs Despite Side Effects

ACE inhibitors should be your first choice for heart failure with reduced ejection fraction (HFrEF) because they have the strongest mortality and morbidity evidence from landmark trials, and the side effect profile—while real—is manageable in the vast majority of patients. 1 ARBs are reserved specifically for patients who cannot tolerate ACE inhibitors due to intractable cough or angioedema. 1

The Evidence Hierarchy

ACE Inhibitors: The Gold Standard

• Multiple large randomized controlled trials (CONSENSUS I, SOLVD-T, SAVE, AIRE, TRACE) conclusively demonstrated that ACE inhibitors increase survival, reduce hospital admissions, and improve NYHA class and quality of life in patients with all grades of symptomatic heart failure. 1
• The ACC/AHA gives ACE inhibitors a Class I, Level A recommendation for all patients with prior or current symptoms of chronic HFrEF to reduce morbidity and mortality. 1
• ACE inhibitors work across the entire clinical spectrum—from asymptomatic left ventricular dysfunction to severely symptomatic heart failure. 1

ARBs: The Alternative, Not the Equivalent

• ARBs receive a Class I, Level A recommendation ONLY for patients intolerant to ACE inhibitors due to cough or angioedema. 1
• The ACC/AHA explicitly states: "Patients intolerant to ACE inhibitors because of cough or angioedema should be started on ARBs." 1
• ARBs produce similar hemodynamic and neurohormonal effects to ACE inhibitors but lack the additional beneficial vasodilatory effects from kininase inhibition. 1

The Side Effect Reality Check

ACE Inhibitor Side Effects Are Overestimated

• Cough occurs in up to 20% of patients, but it rarely requires treatment discontinuation. 1
• The European Journal of Heart Failure guidelines note that "ACE inhibitor induced cough rarely requires treatment discontinuation" and recommend confirming the cough is truly ACE-related through withdrawal and rechallenge before switching. 1
• Angioedema occurs in less than 1% of patients (though higher in Black patients and women). 1
• In clinical trials, only 5.7% of hypertensive patients and 11% of heart failure patients discontinued ACE inhibitors due to adverse reactions. 2

ARBs Are Not Side-Effect Free

• ARBs share the same serious adverse effects as ACE inhibitors: hyperkalemia, renal failure, and hypotension. 3
• While ARBs have a lower incidence of cough and angioedema, some patients who developed angioedema with ACE inhibitors can also develop it with ARBs, requiring caution. 1
• The side effect advantage of ARBs is primarily limited to avoiding cough—not a mortality issue. 1

The Kininase Inhibition Advantage

ACE inhibitors inhibit kininase, which increases bradykinin levels—this causes the cough but also contributes to beneficial vasodilation that ARBs cannot provide. 1, 2

• This mechanism may explain why ACE inhibitors have been the agents proven in the landmark mortality trials, not ARBs. 1
• ARBs do not inhibit kininase, so they miss this potentially beneficial pathway. 1

Clinical Algorithm: When to Use What

Start Here: ACE Inhibitor First-Line

1. Initiate an ACE inhibitor (lisinopril, enalapril, ramipril) at low doses in all HFrEF patients. 1
2. Titrate upward every 2 weeks to target doses proven in clinical trials (e.g., lisinopril 30-35 mg daily, enalapril 10-20 mg twice daily). 1
3. Monitor blood pressure, renal function (creatinine, BUN), and potassium at baseline, 1-2 weeks after initiation, after each dose increase, then every 3-6 months. 1

When to Switch to ARB

Only switch to an ARB if the patient develops:

• Intractable cough that disrupts sleep or quality of life (confirm it's ACE-related by stopping and rechallenging). 1
• Angioedema (absolute contraindication to continuing ACE inhibitor). 1

Do NOT switch for:

• Asymptomatic hypotension (does not require treatment change). 1
• Mild increases in creatinine (up to 50% above baseline or to 3 mg/dL is acceptable). 1
• Mild hyperkalemia (up to 5.5-6.0 mEq/L is manageable with dose adjustments). 1

The ARNI Option (Sacubitril/Valsartan)

• If the patient tolerates an ACE inhibitor or ARB and has NYHA Class II-III symptoms, switch to sacubitril/valsartan (Entresto) for superior mortality and morbidity reduction (20% reduction in cardiovascular death or HF hospitalization vs. enalapril). 1, 4
• Requires a 36-hour washout period after stopping ACE inhibitor to prevent life-threatening angioedema from dual bradykinin pathway inhibition. 5

Common Pitfalls to Avoid

Pitfall 1: Using Subtherapeutic ACE Inhibitor Doses

• Physicians commonly prescribe ACE inhibitors at doses lower than those proven effective in trials. 6
• The ATLAS trial showed that high-dose lisinopril (32.5-35 mg daily) reduced death or hospitalization by 12% and heart failure hospitalizations by 24% compared to low-dose lisinopril (2.5-5 mg daily). 7, 6
• Push to target doses unless side effects prevent it—some ACE inhibitor is better than none, but more is better than less. 1

Pitfall 2: Switching to ARB for Minor Side Effects

• Asymptomatic hypotension, mild renal dysfunction, and mild hyperkalemia do not require switching to an ARB. 1
• Adjust concomitant medications (reduce diuretics if no congestion, stop NSAIDs, stop potassium supplements) before abandoning the ACE inhibitor. 1

Pitfall 3: Assuming ARBs Are Equivalent

• ARBs are NOT first-line therapy—they are alternatives for ACE inhibitor intolerance only. 1, 8
• Head-to-head trials showed no mortality difference between losartan and captopril, but they did not rule out that ARBs might be moderately less effective. 3

The Bottom Line

Start with an ACE inhibitor, titrate to target doses, and manage side effects aggressively before switching to an ARB. 1 The mortality and morbidity benefits of ACE inhibitors are too substantial to abandon for minor side effects that can usually be managed. 1 Reserve ARBs for true ACE inhibitor intolerance (intractable cough or angioedema), and consider upgrading to sacubitril/valsartan in patients who tolerate renin-angiotensin system inhibition. 1, 4, 5