Pharmacology
FDA Approves Candesartan Cilexetil for Treatment of Heart Failure
By Akanksha, Pharmacology Correspondent
Feb 24, 2005, 08:23

AstraZeneca today announced that the US Food and Drug Administration (FDA) has approved its angiotensin receptor blocker (ARB) ATACAND(R)(candesartan cilexetil)tablets for the treatment of heart failure (NYHA class II-IV and ejection fraction less than or equal to 40%) to reduce the risk of death from cardiovascular causes and reduce hospitalizations for heart failure.

Candesartan cilexetil is the first ARB to receive an indication for reducing both cardiovascular mortality and hospitalizations for heart failure.

The approval was primarily based on results from Candesartan in Heart Failure Assessment of Reduction in Mortality and morbidity Alternative Trial (CHARM-Alternative), which examined the effect of candesartan cilexetil (n=1013) compared to placebo (n=1015) in 2,028 heart failure patients who were intolerant to ACE inhibitors, but were receiving other standard heart failure therapy.

The trial demonstrated that in these CHF patients, the use of candesartan cilexetil resulted in a 23% (p less than 0.001) relative risk reduction in cardiovascular death or heart failure hospitalization (406 events in the placebo arm compared to 334 events in the patients receiving candesartan cilexetil), with both components contributing to this effect.

This finding was supported by a second study of 2,548 subjects (CHARM-Added) with NYHA Class II-IV heart failure and ejection fraction less than or equal to 40%, in which subjects were mostly on submaximal doses of ACE inhibitors. Together, in these studies, patients on candesartan cilexetil had a 15% lower risk of cardiovascular mortality (p=0.005). In these studies, symptoms of heart failure as assessed by NYHA functional class were also improved (p less than 0.001).

The recommended initial dose of candesartan cilexetil 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 two-week intervals, as tolerated by the patient.

The CHARM Alternative trial was an international, double-blind, placebo-controlled, parallel study that evaluated 2,028 patients with symptomatic heart failure (NYHA Class II-IV) and a left ventricular ejection fraction (LVEF) less than or equal to 40%, who were intolerant to ACE inhibitors.
They randomly received either candesartan cilexetil or a placebo.

In most cases, the starting dose of candesartan cilexetil was 4 mg once daily, which was doubled every two weeks up to the sixth week. 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 after until the end of the trial (34 months on average).The primary endpoint was time to either
cardiovascular mortality or first hospitalization for heart failure.

The CHARM clinical trial program was sponsored by AstraZeneca.

When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected,candesartan cilexetil should be discontinued as soon as possible.

In the CHARM program, hypotension was reported in 18.8% of patients on candesartan cilexetil vs. 9.8% of patients on placebo; the incidence of hypotension leading to drug discontinuation in the candesartan-treated patients was 4.1% compared with 2.0% in placebo-treated patients. The incidence of abnormal renal function (e.g., creatinine increase) leading to drug discontinuation in patients treated with candesartan cilexetil was 6.3% vs. 2.9% in placebo-treated patients.

Evaluation of patients with heart failure should always include assessment of renal function and volume status. The incidence of hyperkalemia was 6.3% in patients receiving candesartan cilexetil vs. 2.1% in those receiving placebo.

The incidence of hyperkalemia leading to drug discontinuation in patients receiving candesartan cilexetil was 2.4% vs. 0.6% in the placebo-treated patients. During treatment with candesartan cilexetil in patients with heart failure, monitoring of blood pressure, serum creatinine, and serum potassium is recommended during dose escalation and periodically thereafter.

The adverse event profile of candesartan cilexetil in heart failure patients was consistent with the pharmacology of the drug and the health status of the patients.In the CHARM program, comparing candesartan cilexetil in total daily doses up to 32 mg once daily (n=3803) with placebo (n=3796), 21% of patients receiving candesartan cilexetil discontinued for adverse events vs. 16.1% of placebo patients.For full Prescribing Information, including boxed WARNING, call1-800-236-9933 or visit the related website.

Heart failure, also called chronic heart failure or CHF, is a condition in which the heart is unable to pump blood adequately to the rest of the body.When the heart is not pumping as it should, less oxygen and nutrients are
carried through the body, and some of the wastes may not be removed from the body. This can result in fatigue, shortness of breath, and fluid buildup in the lungs, liver, or ankles. It is a serious, progressive, debilitating
condition and frequently leads to a fatal outcome.

Many heart failure patients have impaired left ventricular systolic function and this is the population that has been studied in most previous heart failure trials. In these patients, the heart's ability to function as a pump is compromised, as evidenced by a reduced ejection fraction, which is the percentage of blood ejected by the heart with each contraction. The normal heart ejects more than 50% of the blood in the left ventricle with each beat.

Common causes of heart failure include coronary artery disease, heart attacks (or myocardial infarction), high blood pressure (or hypertension), and heart disease of
unknown origin (or cardiomyopathy).

The American Heart Association estimates that nearly 5 million Americans are currently living with heart failure, and more than half a million new cases are diagnosed each year.

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