FDA Approves Atacand for Use with an ACE Inhibitor in the Treatment of Heart Failure

Main Category: Cardiovascular / Cardiology
Article Date: 22 May 2005 - 6:00 PST

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AstraZeneca today announced that the US Food and Drug Administration (FDA) has approved a new use for its angiotensin receptor blocker (ARB) ATACAND (candesartan cilexetil) tablets for the treatment of heart failure (NYHA class II-IV) in patients with left ventricular systolic dysfunction (ejection fraction ≤ 40%) to reduce cardiovascular death and to reduce heart failure hospitalizations. ATACAND also has an added effect on these outcomes when used with an ACE inhibitor.

ATACAND 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.

"ACE inhibitors and beta-blockers have improved the treatment of heart failure. Despite this, rates of cardiovascular death and heart failure hospitalization remain high," said Howard Hutchinson, Vice President of Clinical Research at AstraZeneca. "With this approval, physicians will have an option to add ATACAND to conventional therapies, including an ACE inhibitor, which can improve treatment outcomes for heart failure patients."

The current label change follows the unanimous recommendation for approval by the Cardio-Renal Advisory Committee to the FDA on February 24, 2005. 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.

About the CHARM-Added Trial

CHARM-Added was an international, 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) ≤ 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. The CHARM clinical trials were sponsored by AstraZeneca Pharmaceuticals.

IMPORTANT SAFETY INFORMATION

BOXED 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. For full Prescribing Information for ATACAND, including boxed WARNING regarding use in pregnancy, call 1-800-236-9933 or visit http://www.atacand-us.com.

In heart failure patients receiving ATACAND, hypotension, increases in serum creatinine, and hyperkalemia have occurred. Caution should be observed for hypotension when initiating therapy. Evaluation of patients with HF 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 ATACAND and lithium, careful monitoring of lithium levels is recommended.

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.

About Heart Failure

Heart failure 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.1 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.2 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 a half million new cases are diagnosed each year.3

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.

Candesartan cilexetil is marketed by AstraZeneca under trademark Atacand® and is manufactured under agreement from Takeda Pharmaceutical Company Ltd.

References:

1 Dosh SA. Diagnosis of heart failure in adults. Am Fam Physician. 2004;70(11):2145-52.

2. Rich MW. Drug therapy of heart failure in the elderly. Am J Geriatr Cardiol. 2003;12(4):235-242.

3. American Heart Association. Heart Disease and Stroke Statistics-2005 Update. Dallas, Texas. American Heart Association; 2005.

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