May 19, 2005 FDA Approves Atacand for Use With an ACE Inhibitor in the Treatment of Heart Failure

DRUG NEWS -- May 19, 2005

FDA Approves AstraZeneca's Atacand (candesartan cilexetil) for Use With an ACE Inhibitor in the Treatment of Heart Failure
Atacand is the Only ARB Proven to Provide Benefits When Added to Conventional Heart Failure Therapy, Including ACE Inhibitors Plus Beta-Blockers

WILMINGTON, Delaware, May 19, 2005-- 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 less than or equal to 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) 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. 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.

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 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.

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

For additional information, including boxed WARNING regarding use in pregnancy, please see Atacand PDR Information

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.

Posted: May 2005


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