HEART FAILURE
Clinical Overview

Investigational Pharmacological Strategies

AIIRAs selectively block the binding of angiotensin II to the AT1 receptor found in many tissues, including vascular smooth muscle. These agents do not inhibit ACE and do not potentiate bradykinin. None of these agents currently have an FDA indication for heart failure treatment.

Actions of angiotensin II2

  • vasoconstriction --> increased systemic vascular resistance
  • aldosterone secretion --> Na and water retention --> increased fluid volume
  • sympathetic activation --> increased heart rate and vasoconstriction

ACE inhibitors vs. Angiotensin II receptor antagonists (AIIRAs)2

  • ACE inhibitors potentiate activity of bradykinins, causing side effects such as cough or angioedema
  • There have been no reports of AIIRAs causing severe hyperkalemia, suggesting some residual aldosterone activity
  • Both classes of drugs have similar hemodynamic effects; decreased afterload and increased cardiac output

Studies show that in spite of treatment with ACE inhibitors, patients will have circulating levels of angiotensin II. These angiotensin II levels have been shown to increase with decreasing ejection fraction and with increased exercise. This suggests an escape mechanism for the production of angiotensin II without the action of ACE. It has been suggested that the angiotensin II is somehow directly formed from angiotensinogen or the action of non-ACE chymases convert angiotensin I to angiotensin II.3

Place in therapy3

  • no FDA approval for heart failure
  • recommended for use in patients who cannot tolerate side effects of ACE inhibitors
  • may add to ACE inhibitor therapy if persistent dyspnea on ACE inhibitors

Dosing of losartan3

  • Start at 12.5-50mg/day
    • starting dose should be lower in volume depletion (same as ACE inhibitor dosing)
  • no need to adjust dose for renal insufficiency
  • patients with hepatic insufficiency should start at 25mg/day

AIIRAs currently available in the U.S. for hypertension only 4

  • losartan (CozaarTM)
  • valsartan (DiovanTM)
  • irbesartan (AvaproTM)
  • candesartan cilexetil (AtacandTM)
  • eprosartan (TevetenTM)
  • telmisartan (MicardisTM)

For clinical trials of AIIRAs in heart failure, refer to Trials of Interest section of this site.

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