What is the role of Angiotensin II receptor blockers (ARBs) in managing hypertension and heart failure in adults, including older adults with comorbidities such as diabetes and impaired renal function?

Angiotensin II Receptor Blockers (ARBs): Clinical Overview

Primary Indications and Role

ARBs are first-line alternatives to ACE inhibitors for hypertension, heart failure with reduced ejection fraction, and diabetic nephropathy, with the strongest evidence supporting candesartan and valsartan for heart failure outcomes. 1, 2

Hypertension Management

• Target blood pressure in diabetic patients is <130/80 mmHg, with ARBs serving as preferred agents alongside ACE inhibitors, beta-blockers, and diuretics 1
• ARBs effectively lower blood pressure through peripheral vascular resistance reduction without increasing heart rate, maintaining 24-hour control with once-daily dosing 3
• If ACE inhibitors are not tolerated due to cough or angioedema, ARBs (specifically valsartan and candesartan) are the recommended alternatives 1

Heart Failure Applications

• Candesartan and valsartan have demonstrated mortality reduction and decreased hospitalizations in heart failure patients intolerant to ACE inhibitors 1, 2
• ARBs produce similar hemodynamic and neurohormonal effects to ACE inhibitors in heart failure with reduced ejection fraction 4
• ACE inhibitors remain the first-choice for renin-angiotensin system inhibition in chronic heart failure, but ARBs are reasonable alternatives 1

Diabetic Nephropathy and Renal Protection

• Both ACE inhibitors (type 1 and type 2 diabetes) and ARBs (type 2 diabetes) are first-line therapy for preventing and slowing progression of nephropathy 1
• Losartan and irbesartan significantly reduced heart failure incidence in patients with type 2 diabetes and nephropathy 1
• ARBs should be a regular component of treatment when microalbuminuria or proteinuria is present, even with high-normal blood pressure, due to blood pressure-independent antiproteinuric effects 5

Specific ARB Selection and Dosing

Evidence-Based Agent Selection

For heart failure patients with renal impairment, candesartan (4-32 mg once daily) and valsartan (80-320 mg daily, divided twice daily) are superior to losartan based on mortality and hospitalization data 2

Standard dosing for hypertension 2, 3:

• Losartan: 50-100 mg once daily
• Valsartan: 80-320 mg once daily
• Candesartan: 4-32 mg once daily
• Irbesartan: 150-300 mg once daily
• Telmisartan: 40-80 mg once daily
• Olmesartan: 20-40 mg once daily

Dose Equivalency

Olmesartan 20 mg daily equals losartan 50 mg daily; olmesartan 40 mg daily equals losartan 100 mg daily 2

Initiation and Monitoring Protocol

Starting ARB Therapy

• Begin with the lowest starting dose shown above, particularly in elderly patients who require more gradual titration 1, 5
• All ARBs can be administered with or without food, except valsartan (40-50% reduction in bioavailability with food) 3
• Titration is achieved by doubling doses every 1-2 weeks until target dose or blood pressure goal is reached 1

Critical Pre-Treatment Assessment

Do not initiate ARB therapy if serum potassium >5.0 mmol/L or creatinine >250 μmol/L until these conditions are corrected 2

Mandatory Monitoring Schedule

Check blood pressure (including orthostatic measurements in elderly), serum creatinine, and potassium within 1-2 weeks after initiation and after each dose increase 1, 2, 5

Patients requiring closer surveillance 1:

• Systolic blood pressure <80 mmHg
• Low serum sodium
• Diabetes mellitus
• Pre-existing renal dysfunction (creatinine clearance <50 mL/min)

Acceptable Changes During Therapy

A temporary increase in serum creatinine up to 30% is acceptable and not a reason to discontinue therapy 5

Discontinue or reduce dose if 5:

• Serum creatinine rises >30% within 4 weeks of initiation
• Uncontrolled hyperkalemia develops
• Symptomatic hypotension occurs

Side Effect Profile and Tolerability

ARBs have a significantly more favorable side effect profile compared to ACE inhibitors, with markedly lower incidence of cough (up to 20% with ACE inhibitors vs. rare with ARBs) and angioedema (<1% with ACE inhibitors vs. much rarer with ARBs) 4, 6

Common side effects include 3:

• Headache
• Upper respiratory infection
• Back pain
• Muscle cramps
• Fatigue and dizziness

Critical warning: Although angioedema is much less frequent with ARBs, cases exist of patients developing angioedema to both ACE inhibitors and subsequently to ARBs 1

Combination Therapy: Critical Pitfalls

What NOT to Do

Do not routinely combine ARBs with both ACE inhibitors and aldosterone antagonists—this dramatically increases risks of renal dysfunction and hyperkalemia without mortality benefit 1, 2

Avoid adding ARBs to adequate-dose ACE inhibitors, as there is no evidence of added benefit and increased risk of adverse effects 2

Do not initiate an ARB within 36 hours of discontinuing an ACE inhibitor due to risk of overlapping effects 4

Acceptable Combinations

• ARBs can be added to chronic ACE inhibitor therapy in select cases, producing modest decreases in hospitalization, though with increased risks of hypotension, renal dysfunction, and hyperkalemia 1
• ARBs combine effectively with diuretics, beta-blockers, and calcium channel blockers for blood pressure control 1

Clinical Decision Algorithm

When to Choose ARB Over ACE Inhibitor

Start with an ACE inhibitor for initial therapy in most cardiovascular conditions 4

Switch to an ARB if 4:

• Patient develops persistent dry cough on ACE inhibitor
• Angioedema occurs with ACE inhibitor
• History of ACE inhibitor-induced cough or angioedema
• Patient is at higher risk for ACE inhibitor side effects

Special Populations

Elderly patients 5:

• Use more gradual initial dosing
• Measure blood pressure in both sitting and standing positions to detect orthostatic hypotension
• No age-based contraindication to ARB therapy exists

Patients with proteinuria 5:

• Start losartan 25 mg daily while continuing current antihypertensive regimen
• Restrict dietary sodium to <2.0 g/day to enhance antiproteinuric effect
• Normalize weight through diet and exercise

Patients requiring multiple agents 1:

• Most patients require three or more drugs to achieve target blood pressure of 130/80 mmHg
• Achievement of target blood pressure with tolerable side effects at reasonable cost is more important than specific drug strategy

Cardiovascular and Renal Outcomes

ARBs reduce morbidity and mortality in hypertension, heart failure, myocardial infarction, stroke, diabetic nephropathy, and chronic kidney disease 7

Specific outcome benefits 1, 3:

• Reduction in left ventricular hypertrophy
• Improvement in diastolic function
• Decrease in ventricular arrhythmias
• Reduction in microalbuminuria
• Improvement in renal function
• Cardioprotective effects in heart failure

Recent Japanese trials (JIKEI and Kyoto studies) suggest that valsartan's protective effect on major cardiovascular events may be partly independent of blood pressure reduction, with significant reductions in composite outcomes (42%), angina pectoris (38%), heart failure hospitalization (43%), and cerebrovascular events (42%) 8

Pharmacologic Distinctions Between ARBs

Candesartan exhibits insurmountable (tight-binding) antagonism at the AT1 receptor with the highest binding affinity, suggesting longer duration of action than predicted by its elimination half-life alone 9

Losartan is partially converted to the more active metabolite EXP3174, while candesartan cilexetil is a prodrug completely converted during absorption 3, 9

Antihypertensive potency ranking (by daily mg dose): candesartan > telmisartan ≈ losartan > irbesartan ≈ valsartan > eprosartan 3