What is Valsartan (valsarten)?

What is Valsartan?

Valsartan is a nonpeptide angiotensin II receptor blocker (ARB) that selectively blocks the AT1 receptor subtype, used primarily to treat hypertension, heart failure with reduced ejection fraction, and post-myocardial infarction left ventricular dysfunction. 1

Mechanism of Action

• Valsartan specifically antagonizes the angiotensin II type 1 (AT1) receptor, blocking the vasoconstrictive and aldosterone-secreting effects of angiotensin II 1, 2
• It has no affinity for the AT2 receptor and does not inhibit ACE (angiotensin-converting enzyme), which means it does not cause the breakdown of bradykinin—explaining why it does not cause the persistent cough commonly seen with ACE inhibitors 3, 4
• After oral administration, valsartan inhibits the pressor response to angiotensin II for 24 hours, making once-daily dosing effective for hypertension 5

Chemical Properties

• The chemical name is N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1′-biphenyl]-4-yl]methyl]-L-valine with molecular formula C24H29N5O3 and molecular weight 435.5 1
• It is a white or almost white hygroscopic powder, practically insoluble in water but freely soluble in anhydrous ethanol 1

Pharmacokinetics

• Valsartan is rapidly absorbed with peak plasma concentrations occurring 1-2 hours after oral administration 6, 3
• The elimination half-life is approximately 6-8 hours, supporting once-daily dosing for hypertension 2, 6
• Bioavailability is relatively low, but the drug is rapidly distributed 3
• Valsartan is metabolized to a negligible extent and is primarily excreted via feces 6
• No dose adjustment is required for patients with creatinine clearance >10 mL/min, though the dose should not exceed 80 mg once daily in patients with hepatic dysfunction 6

Clinical Indications

Hypertension

• FDA-approved for adults and children ≥1 year of age to lower high blood pressure 1
• Dosing for hypertension: 80-160 mg once daily initially, with titration up to 320 mg once daily as needed 7
• Efficacy is dose-dependent over the range of 80-320 mg once daily, with doses as high as 640 mg/day studied and found safe 2
• Valsartan demonstrates efficacy independent of age, sex, and race 5

Heart Failure with Reduced Ejection Fraction

• FDA-approved to treat heart failure in adults, helping to decrease hospitalization 1
• The Val-HeFT trial demonstrated a 13.2% reduction in the combined endpoint of cardiovascular mortality and morbidity compared to placebo when added to standard therapy 8, 9
• Dosing for heart failure: Start at 40 mg twice daily and uptitrate to target dose of 160 mg twice daily 7, 1
• ARBs like valsartan reduce heart failure hospitalization risk (24% reduction in Val-HeFT, 17% in CHARM-Added) 8

Post-Myocardial Infarction

• FDA-approved for adults with certain types of heart failure to increase survival after heart attack 1
• The VALIANT trial demonstrated that valsartan was non-inferior to captopril in reducing mortality in post-MI patients with heart failure or left ventricular dysfunction 8, 7
• In VALIANT, 14,703 patients were randomized, and valsartan showed equivalent efficacy to the ACE inhibitor captopril 8

Key Clinical Trial Evidence

Hypertension Studies

• The JIKEI HEART study showed that adding valsartan to treatment in high-risk hypertensive patients reduced stroke incidence by 40% over 3 years 8
• The VALUE trial compared valsartan to amlodipine in over 15,000 high-risk hypertensive patients, showing similar cardiac event rates and death, with a trend favoring valsartan for heart failure prevention 8

Heart Failure Studies

• The European Society of Cardiology guidelines recommend ARBs as alternatives to ACE inhibitors in patients intolerant of ACE inhibitors 8
• CHARM-Alternative demonstrated that in 2,028 patients intolerant of ACE inhibitors, candesartan (another ARB) reduced cardiovascular or heart failure hospitalization by 23% (NNT 14 over 34 months) 8
• However, mineralocorticoid receptor antagonists (MRAs) are now preferred over ARBs as add-on therapy to ACE inhibitors and beta-blockers because EMPHASIS-HF showed eplerenone reduced all-cause mortality, whereas ARB add-on trials did not 8

Safety and Tolerability Profile

Advantages Over ACE Inhibitors

• Valsartan has a significantly lower incidence of cough compared to ACE inhibitors, with only rare reports of angioedema 2, 4
• The side effect profile is indistinguishable from placebo in clinical trials 5, 4
• Most frequently reported adverse events (malaise/fatigue, dizziness, headache, nausea/vomiting) occur at rates similar to placebo 4
• In post-MI patients, the rate of discontinuation due to adverse events is lower with valsartan than with ACE inhibitors 4

Important Contraindications and Warnings

• Valsartan can cause fetal harm or death and must be discontinued immediately if pregnancy occurs 1
• Contraindicated in patients with diabetes who are also taking aliskiren 1
• Contraindicated in patients allergic to any ingredient in valsartan 1
• Not recommended for children <1 year of age for hypertension treatment 1

Monitoring Requirements

• Monitor blood pressure, renal function, and serum potassium regularly during treatment 7
• Serum potassium levels need closer monitoring in patients with nephropathy 4
• Patients with baseline potassium ≥5.2 mmol/L were excluded from PARADIGM-HF, highlighting the need for careful electrolyte monitoring 8

Drug Interactions

• Avoid concomitant use with potassium-containing medicines, potassium supplements, or salt substitutes containing potassium without close monitoring 1
• NSAIDs may reduce the antihypertensive effect and should be used cautiously 1
• Lithium levels require regular monitoring when used with valsartan 1
• Water pills (diuretics) and other blood pressure medications may have additive effects 1

Combination Therapy Considerations

Valsartan Plus Hydrochlorothiazide

• Single-pill fixed-dose combination with HCTZ provides enhanced blood pressure control with a more consistent 24-hour profile 2
• Valsartan counteracts the adverse metabolic effects of hydrochlorothiazide 4
• The combination is better tolerated than HCTZ alone 2

Valsartan Plus ACE Inhibitors

• The combination of valsartan and ACE inhibitors is generally not recommended based on VALIANT, which showed no increased benefit over captopril alone but higher adverse effects when both were titrated aggressively in the early post-MI period 8, 9
• However, CHARM-Added showed benefit when candesartan was added to stable patients already on established ACE inhibitor therapy 8

Sacubitril/Valsartan

• The FDA approved sacubitril/valsartan in 2015 based on PARADIGM-HF, which showed a 20% reduction in cardiovascular mortality compared to enalapril 8
• ACC/AHA/HFSA guidelines support sacubitril/valsartan use in NYHA class II-III HFrEF patients (Class I, Level of Evidence: B) 8

Dosing Principles

Target Dose Importance

• Higher doses provide greater benefits than lower doses, with little evidence that subtarget doses yield survival benefits comparable to target doses 7
• At least 50% of the target dose should be achieved for adequate treatment effect in heart failure 7
• The HEAAL trial demonstrated that losartan 150 mg daily was superior to 50 mg daily, emphasizing the importance of achieving target doses 8

Dose Titration Strategy

• For heart failure, uptitrate from 40 mg twice daily to 80 mg twice daily, then to 160 mg twice daily (target dose), with adjustments made no more frequently than every 2 weeks 7
• Temporary dose reductions may be needed for symptomatic hypotension or renal dysfunction, but efforts should be made to restore target doses when possible 7