What are the indications, dosing regimens, contraindications, monitoring requirements, adverse effects, and alternative therapies for candesartan in an adult?

Candesartan: Clinical Overview

Indications

Candesartan is indicated for heart failure with reduced ejection fraction (HFrEF, LVEF ≤40%) and hypertension. 1

• Heart failure patients intolerant to ACE inhibitors: Candesartan reduces cardiovascular death and heart failure hospitalizations in patients who cannot tolerate ACE inhibitors due to cough or angioedema 1
• Add-on therapy in HFrEF: Can be added to ACE inhibitors in symptomatic patients (NYHA class II-IV), though this is no longer first-line add-on therapy (eplerenone is preferred) 1
• Post-myocardial infarction with LV dysfunction: Demonstrated non-inferior benefit to ACE inhibitors 1
• Hypertension: Effective as monotherapy at 8-32 mg once daily 2, 3

Dosing Regimens

Start candesartan at 4-8 mg once daily and titrate to target dose of 32 mg once daily. 1, 4

Titration Protocol:

• Initial dose: 4 mg or 8 mg once daily 1, 5
• Titration schedule: Double the dose every 2 weeks (4→8→16→32 mg) as tolerated 6, 5
• Target dose: 32 mg once daily 1, 4, 5
• Maintenance dose for hypertension: 8-16 mg once daily 1, 3

Critical Monitoring During Titration:

• Check blood pressure (including orthostatic), serum creatinine, and potassium within 1-2 weeks after initiation and after each dose increase 1, 5
• Patients requiring intensive surveillance: Systolic BP <80 mmHg, low serum sodium, diabetes mellitus, or impaired renal function 1

Contraindications

Absolute contraindications:

• Serum potassium >5.0 mmol/L 1
• Serum creatinine >250 μmol/L (approximately 2.8 mg/dL) 1
• Pregnancy (all trimesters)
• History of angioedema to ARBs (though much less common than with ACE inhibitors, cross-reactivity can occur) 1

Relative contraindications:

• Systolic blood pressure <80 mmHg 1
• Bilateral renal artery stenosis
• Severe hepatic impairment

Monitoring Requirements

At Initiation and Dose Changes:

• Blood pressure (including postural changes) within 1-2 weeks 1, 5
• Serum creatinine within 1-2 weeks 1, 5
• Serum potassium within 1-2 weeks 1, 5

Ongoing Monitoring:

• Routine monitoring of potassium, renal function, and blood pressure throughout treatment 5
• More frequent monitoring in high-risk patients: Those with diabetes, pre-existing renal dysfunction, low sodium, or hypotension 1

Dose Adjustment Based on Monitoring:

• If potassium 5.0-5.5 mmol/L: Reduce dose by 50% 1
• If potassium >5.5 mmol/L: Stop candesartan 1
• If creatinine increases significantly: Consider dose reduction or discontinuation 5

Adverse Effects

The most common adverse effects requiring discontinuation are renal dysfunction, hypotension, and hyperkalemia. 5

Common Adverse Effects:

• Increased creatinine: 7.1% vs 3.5% placebo (leading to discontinuation) 5
• Hypotension: 4.2% vs 2.1% placebo (leading to discontinuation) 5
• Hyperkalemia: 2.8% vs 0.5% placebo (leading to discontinuation) 5
• Overall discontinuation rate: 23.1% vs 18.8% placebo 5

Important Safety Notes:

• Angioedema is much less frequent with ARBs than ACE inhibitors, but cross-reactivity can occur 1
• Adverse effects are similar to those attributed to suppression of angiotensin II (shared with ACE inhibitors) 1
• Tolerability profile similar to placebo when used appropriately 2, 3

Alternative Therapies

For Heart Failure with Reduced Ejection Fraction:

First-line alternatives to candesartan:

• ACE inhibitors remain the first choice for RAAS inhibition in HFrEF 1
  • Enalapril 10-20 mg twice daily 1
  • Lisinopril 20-40 mg once daily 1
  • Ramipril 10 mg once daily 1

Other ARB alternatives (if ACE inhibitor intolerant):

• Valsartan: 80-320 mg daily (divided twice daily dosing, target 160 mg twice daily) 1
• Losartan: 50-100 mg once daily (target 150 mg daily for maximum benefit, though 50-100 mg is standard) 1

Preferred ARBs based on evidence:

• Candesartan and valsartan have the strongest evidence for reducing hospitalizations and mortality in ACE inhibitor-intolerant patients 7
• Candesartan provides better antihypertensive efficacy than losartan and is at least as effective as telmisartan and valsartan 2

For Add-on Therapy in HFrEF:

• Mineralocorticoid receptor antagonists (MRAs) are now preferred over ARBs as add-on to ACE inhibitors 1
  • Spironolactone 12.5-25 mg once daily (target 25 mg once or twice daily) 1
  • Eplerenone 25 mg once daily (target 50 mg once daily) 1
• MRAs showed greater mortality reduction than ARB add-on therapy in recent trials 1

For Hypertension:

• ACE inhibitors, calcium channel blockers, thiazide diuretics are all appropriate alternatives 3
• Combination therapy with candesartan plus hydrochlorothiazide or amlodipine provides enhanced BP lowering 3

Critical Pitfalls to Avoid

Do not combine candesartan with both ACE inhibitors and aldosterone antagonists—this dramatically increases risks of renal dysfunction and hyperkalemia without mortality benefit. 1, 7

• Triple RAAS blockade (ARB + ACE inhibitor + MRA) is not recommended 1
• Adding ARBs to adequate-dose ACE inhibitors provides modest benefit at best, with increased adverse effects 1
• Do not use subtherapeutic doses—titrate to target dose of 32 mg daily for heart failure 1, 4, 5
• Avoid initiating therapy in patients with potassium >5.0 mmol/L or creatinine >250 μmol/L until corrected 1
• Monitor closely in patients with systolic BP <80 mmHg, as they are at higher risk for symptomatic hypotension 1

Clinical Outcomes

Candesartan significantly reduces all-cause mortality (HR 0.88), cardiovascular death (HR 0.84), and heart failure hospitalizations (HR 0.76) in patients with HFrEF. 5

• In the CHARM program (7,599 patients), candesartan reduced all-cause mortality by 10% (HR 0.90) and cardiovascular deaths by 13% (HR 0.87) 4
• Heart failure hospitalizations were reduced by 24% (HR 0.76) 5
• Benefits were consistent regardless of baseline ACE inhibitor, beta-blocker, or aldosterone antagonist use 5
• Mean achieved dose in clinical practice is approximately 21 mg daily in both men and women 6