Candesartan's heart failure indication has been expanded by the Food and Drug Administration to include patients who are on ACE inhibitor therapy.
The angiotensin receptor blocker (ARB) was approved for a narrower heart failure indication in February, for patients with New York Heart Association (NYHA) class II-IV disease and a left ventricular ejection fraction (LVEF) of 40% or less to reduce cardiovascular death and heart failure hospitalizations, based largely on the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM)-Alternative trial, in which cardiovascular death or heart failure hospitalization, the primary end point, was reduced by 23% in those on candesartan, compared with those on placebo.
In May, the FDA approved the addition of the following statement to the heart failure indication in the drug's label: “Atacand also has an added effect on these outcomes when used with an ACE inhibitor.”
Candesartan, marketed as Atacand by AstraZeneca, was approved for treating hypertension in 1998. It is the first ARB approved for use with an ACE inhibitor for treating heart failure.
The latest approval was based on the results of the CHARM-Added trial, which showed that candesartan “adds a meaningful and important additional clinical benefit on top of other proven treatments, including β-blockers and ACE inhibitors,” Christopher Granger, M.D., director of the cardiac care unit at Duke University, Durham, N.C., and a member of the CHARM executive committee, said in an interview.
The relative risk of cardiovascular mortality or heart failure hospitalization was reduced by 15% in those on candesartan during a median follow-up of 41 months in CHARM-Added, which compared candesartan to placebo in 2,548 patients with NYHA class II-IV heart failure and an LVEF of 40% or less who were on an ACE inhibitor and standard therapy. Benefits were also seen in patients treated with β-blockers, suggesting there were no adverse interactions between β-blockers, candesartan, and ACE inhibitors.
Improved quality of life was also seen in the study, said Dr. Granger, who was a consultant to AstraZeneca for the FDA's cardiovascular and renal drugs advisory committee meeting in February, where the panel unanimously recommended approval of candesartan for this population of patients on an ACE inhibitor (CARDIOLOGY NEWS, April 2005, p. 10).
The recommended starting dose of candesartan for patients with heart failure is 4 mg/day, with a target dose of 32 mg once daily, achieved by doubling the dose about every 2 weeks, as tolerated.
In the CHARM studies, rates of hypotension, abnormal renal function, and hyperkalemia were higher in those on candesartan, as expected, due to a greater degree of renin-angiotensin-aldosterone system inhibition. Clinicians should monitor for hyperkalemia and renal insufficiency, especially when starting and titrating treatment, Dr. Granger advised.