In an adult with uncomplicated primary hypertension and no contraindications, how does losartan compare to an ACE inhibitor in terms of efficacy and side‑effect profile?

Losartan vs ACE Inhibitors in Uncomplicated Primary Hypertension

Losartan and ACE inhibitors are essentially equivalent in blood pressure lowering efficacy and cardiovascular outcomes, but losartan has a superior tolerability profile with significantly lower rates of cough and angioedema, making it a preferred choice when renin-angiotensin system blockade is indicated. 1

Efficacy Comparison

Blood Pressure Reduction

• Both drug classes achieve comparable blood pressure reductions in patients with mild to moderate essential hypertension, with no significant differences in achieving target BP goals 1, 2
• In direct head-to-head trials, once-daily losartan 50 mg demonstrated significantly greater reductions in sitting diastolic blood pressure (7.8-9.1 mmHg) compared to once-daily captopril 50 mg (5.2-5.7 mmHg) 3
• However, this comparison used suboptimal captopril dosing (once daily instead of the recommended twice-daily regimen), limiting generalizability 3

Cardiovascular Outcomes

• No differences exist between ARBs and ACE inhibitors for hard clinical endpoints including all-cause mortality, cardiovascular mortality, myocardial infarction, heart failure, stroke, or end-stage renal disease 1
• Network meta-analysis from the 2017 ACC/AHA guidelines found that thiazide diuretics tended to be associated with lower cardiovascular events compared to ACE inhibitors, though both remain guideline-recommended first-line agents 4
• Both drug classes provide equivalent regression of left ventricular hypertrophy when blood pressure is controlled to similar levels 4

Side Effect Profile: The Critical Difference

ACE Inhibitor-Specific Adverse Effects

• Cough occurs commonly with ACE inhibitors (often taking 3-4 years of use to manifest) and is essentially absent with losartan 1, 2
• Angioedema, though rare, is life-threatening and occurs with both ACE inhibitors and losartan, but at lower rates with ARBs 1, 2
• ACE inhibitor-related fatalities from angioedema have been documented, whereas this risk appears lower with ARBs 1

Overall Tolerability

• Overall withdrawal rates due to adverse events are significantly lower with ARBs than ACE inhibitors 1
• Losartan demonstrates an adverse effect profile similar to placebo in clinical trials 2, 5
• The most common adverse effect with losartan is dizziness, with an overall withdrawal rate of only 2.3% compared to 3.7% for placebo 2
• First-dose hypotension is uncommon with losartan due to its slower onset of action 2

Guideline Positioning

First-Line Therapy Recommendations

• Both ACE inhibitors and ARBs are recommended as first-line agents for uncomplicated hypertension by ACC/AHA guidelines, alongside thiazide diuretics and calcium channel blockers 4
• The 2017 ACC/AHA systematic review found thiazide diuretics and calcium channel blockers are preferred first-line options due to superior efficacy data, with ACE inhibitors and ARBs as equivalent alternatives 4

Traditional Guideline Hierarchy (Now Questioned)

• Most cardiovascular disease guidelines historically recommended ACE inhibitors as first-choice therapy, with ARBs merely considered alternatives for ACE inhibitor-intolerant patients 1
• This hierarchy lacks evidence-based justification given equal efficacy but superior tolerability of ARBs 1

Special Populations

Race-Based Considerations

• In Black patients without heart failure or chronic kidney disease, thiazide diuretics and calcium channel blockers are more effective than renin-angiotensin system inhibitors (both ACE inhibitors and ARBs) for preventing heart failure and stroke 4, 6

Compelling Indications Favoring Either Class

• For heart failure with reduced ejection fraction: ACE inhibitors remain guideline-directed medical therapy, with ARBs as alternatives for ACE inhibitor intolerance 4, 6
• For diabetes with albuminuria ≥300 mg/g: Both ACE inhibitors and ARBs are Class A recommendations to reduce progressive kidney disease 7, 6
• For post-myocardial infarction with reduced ejection fraction: ACE inhibitors have stronger historical evidence, though ARBs (particularly valsartan) have demonstrated equivalence 4

Practical Clinical Algorithm

When to Choose Losartan Over ACE Inhibitors

1. Patient with prior ACE inhibitor-induced cough → Switch to losartan 1, 5
2. Patient concerned about tolerability → Start with losartan given lower adverse event burden 1
3. Uncomplicated hypertension requiring renin-angiotensin blockade → Either agent acceptable, but losartan preferred for tolerability 1

When ACE Inhibitors May Be Preferred

1. Post-MI with reduced ejection fraction → ACE inhibitors have longer track record, though ARBs are equivalent 4
2. Cost considerations → Generic ACE inhibitors may be less expensive than losartan in some markets 2

Monitoring Requirements (Identical for Both)

• Check serum creatinine/eGFR and potassium at baseline, at 2-4 weeks after initiation, and at least annually 7, 6
• Increased hyperkalemia risk in chronic kidney disease or with potassium supplements 7
• Avoid combining ACE inhibitors with ARBs due to increased adverse events without added cardiovascular benefit 6

Critical Pitfalls to Avoid

• Never use once-daily captopril for chronic hypertension; it requires twice-daily dosing for sustained BP control 3
• Do not assume ACE inhibitors are superior based on historical guideline preference; this reflects tradition rather than evidence 1
• Monitor for angioedema with both drug classes, though risk is lower with ARBs 1, 2
• Avoid dual renin-angiotensin system blockade (ACE inhibitor + ARB) as it increases adverse events without improving outcomes 6

Unanswered Questions

• Long-term tolerability data beyond 3-4 years are still needed for losartan, as ACE inhibitor cough often manifests late 2
• Effects on uric acid metabolism with losartan (increases uric acid secretion) require further investigation regarding potential uric acid stone formation 2
• Dosing adjustments in hepatic impairment need better characterization for losartan 2