FDA Approves Astrazeneca's Atacand(R) (Candesartan Cilexetil) For The Treatment Of Heart Failure

Main Category: Cardiovascular / Cardiology
Article Date: 25 Feb 2005 - 22:00 PST

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Atacand is first ARB to receive approval for reducing both CV mortality and hospitalizations for heart failure - 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 ˜ 40%) to reduce the risk of death from cardiovascular causes and reduce hospitalizations for heart failure. ATACAND 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 ATACAND (n= 1013) compared to placebo (n=1015) in 2028 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 ATACAND resulted in a 23% (p<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 ATACAND), with both components contributing to this effect.

This finding was supported by a second study of 2548 subjects (CHARM-Added) with NYHA Class II-IV heart failure and ejection fraction ˜ 40%, in which subjects were mostly on submaximal doses of ACE inhibitors. Together, in these studies, patients on ATACAND 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<0.001).

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 two-week intervals, as tolerated by the patient.

About CHARM Alternative Trial

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) ˜ 40%, who were intolerant to ACE inhibitors. They randomly received either ATACAND or a placebo. In most cases, the starting dose of ATACAND 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.

IMPORTANT SAFETY INFORMATION

PREGNANCY WARNING: 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, ATACAND should be discontinued as soon as possible.

In the CHARM program, hypotension was reported in 18.8% of patients on ATACAND 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 ATACAND 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 ATACAND vs. 2.1% in those receiving placebo. The incidence of hyperkalemia leading to drug discontinuation in patients receiving ATACAND was 2.4% vs.0.6% in the placebo-treated patients. During treatment with ATACAND 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 ATACAND 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 ATACAND discontinued for adverse events vs. 16.1% of placebo patients. For full Prescribing Information for ATACAND, including boxed WARNING, call 1-800-236-9933 or visit http://www.atacand-us.com.

About Chronic Heart Failure

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.

About AstraZeneca

AstraZeneca (NYSE: AZN) is a major international healthcare business engaged in the research, development, manufacture and marketing of prescription pharmaceuticals and the supply of healthcare services. It is one of the world's leading pharmaceutical companies with healthcare sales of over $21.4 billion and leading positions in sales of cardiovascular, gastrointestinal, respiratory, oncology, and neuroscience products. In the United States, AstraZeneca is a $9.6 billion healthcare business with more than 12,000 employees. AstraZeneca is listed in the Dow Jones Sustainability Index (Global) as well as the FTSE4Good Index.

For more information about AstraZeneca, please visit http://www.astrazeneca-us.com

This press release contains forward-looking statements with respect to AstraZeneca's business. By their nature, forward-looking statements and forecasts involve risks and uncertainties because they relate to events and depend on circumstances that will occur in the future. There are a number of factors that could cause actual results and developments to differ materially. For a discussion of those risks and uncertainties, please see the company's Annual Report/ Form 20-F for 2004.

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