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FDA has approved Candesartan cilexetil for use with an ACE inhibitor in heart failure


The FDA ( Food and Drug Administration ) has approved a new use for angiotensin receptor blocker ( ARB ) Candesartan cilexetil ( Atacand ) tablets for the treatment of heart failure ( NYHA class II-IV ) in patients with left ventricular systolic dysfunction ( ejection fraction less than or equal to 40% ) to reduce cardiovascular death and to reduce heart failure hospitalizations.

Candesartan is now the first ARB proven to provide these benefits with or without an ACE inhibitor and is the only ARB with proven benefit when used with conventional therapy that includes both an ACE inhibitor plus a beta- blocker.

This approval was based primarily on results from the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity-Added Trial ( CHARM-Added ), which examined the effect of Atacand ( n=1276 ) compared to placebo ( n=1272 ) in 2,548 heart failure ( HF ) patients who were already receiving conventional therapy including an ACE inhibitor.
The study demonstrated that the addition of Atacand resulted in a 15% relative-risk reduction in cardiovascular death or heart failure hospitalization ( 538 events in the placebo arm compared to 483 events in the patients receiving Atacand, [ p=0.011 ] ), with both components contributing to this effect.

The recommended initial dose of Atacand for the treatment of heart failure is 4 mg once daily. The target dose is 32 mg once daily, which is achieved by doubling the dose at approximately 2-week intervals, as tolerated by the patient.

CHARM-Added was an randomized, double-blind, placebo- controlled study that evaluated 2,548 patients, with symptomatic heart failure ( NYHA class II-IV ) and a left ventricular ejection fraction ( LVEF ) less than or equal to 40%, who were receiving an ACE inhibitor.
In the patients receiving Atacand, the starting dose was usually 4 mg once daily, which was doubled approximately every two weeks. Patients received the highest dose tolerated, up to the target dose of 32 mg once daily.
Patients were evaluated at 2, 4, and 6 weeks; at 6 months; and every 4 months thereafter until the end of the 4-year trial, with a median follow-up of 41 months.
The primary endpoint was time to either cardiovascular death or hospitalization for heart failure.

In heart failure patients receiving Candesartan, hypotension, increases in serum creatinine, and hyperkalemia have occurred.
Caution should be observed for hypotension when initiating therapy.
Evaluation of patients with heart failure should always include assessment of renal function and volume status.
Monitoring of blood pressure, serum creatinine, and serum potassium is recommended during dose escalation and periodically thereafter.
During concomitant use of Candesartan and Lithium, careful monitoring of lithium levels is recommended.

The adverse event profile of Candesartan in heart failure patients was consistent with the pharmacology of the drug and the health status of the patients.
In the CHARM program, comparing Atacand in total daily doses up to 32 mg once daily ( n=3803 ) with placebo ( n=3796 ), 21% of patients receiving Candesartan discontinued for adverse events vs. 16.1% of placebo patients.

Source: AstraZeneca, 2005

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