Healthcare Industry News: Takeda Pharmaceutical
News Release - May 4, 2006
Combined Use of ATACAND(R) (candesartan cilexetil) and ACE Inhibitor Improves Heart Failure Outcomes More Than ACE Inhibitor AloneAmerican Heart Journal Publishes Analysis of Landmark CHARM-Added Trial
WILMINGTON, Del., May 4 (HSMN NewsFeed) -- AstraZeneca (NYSE: AZN ) today announced the publication of a supplemental analysis from the Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Added trial in the May issue of the American Heart Journal. This analysis provides evidence that the clinical benefits of ATACAND in reducing the risk of cardiovascular death and heart failure hospitalizations in patients with symptomatic heart failure and reduced heart pump function were not modified by baseline dose of ACE inhibitor, beta-blocker use at baseline, or ACE inhibitor dose during the trial. ATACAND is the only angiotensin II receptor blocker (ARB) indicated to provide these clinical benefits for heart failure patients already receiving adequate doses of an ACE inhibitor. This analysis also supports the concept that ACE inhibitors and the ARB ATACAND, in addition to sharing some common clinical effects, can also complement each other when used together to further improve these outcomes in patients with heart failure (HF).
"Previously, many clinicians and heart failure treatment guidelines considered ARBs primarily as an alternative to ACE inhibitors, particularly in patients with intolerance due to side effects such as cough," said CHARM Executive Committee co-chair, Marc A. Pfeffer, MD, PhD, Brigham and Women's Hospital, Boston. "Publication of this supplemental analysis from CHARM- Added, which provides convincing evidence of the benefits of adding ATACAND to heart failure treatment regimens irrespective of ACE inhibitor dose, will give physicians the opportunity to evaluate the data that were an important component in the U.S. Food and Drug Administration's Cardiovascular & Renal Drugs Advisory Committee review of the CHARM-Added trial."
In 2005, the committee voted unanimously to recommend approval for use of ATACAND® (candesartan cilexetil) in combination with ACE inhibitors for the treatment of heart failure. Subsequently, the FDA approved an updated indication for heart failure. ATACAND is indicated 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.
Summary of Results
In the CHARM-Added trial (n=2548), candesartan reduced the relative risk for the primary end point of cardiovascular death or heart failure hospitalization significantly compared to placebo (hazard ratio (HR) 0.85, 95% confidence intervals (CI) 0.75-0.96, p=0.011). This outcome was consistent in patients taking a guideline-recommended ACE inhibitor dose (n=1291) and for those taking an FDA-designated maximum ACE inhibitor dose (n=529) (hazard ratio (HR) 0.79, 95% CI 0.67-0.95; HR 0.75, 95% CI 0.57-0.98, respectively).(1)
The results of this analysis demonstrate that the addition of ATACAND to other standard therapies including ACE inhibitors, even at maximum doses, and in combination with beta-blockers, can further reduce serious consequences of heart failure, specifically heart disease related death and heart failure hospitalizations. Monitoring of blood pressure, serum creatinine, and serum potassium is recommended during dose escalation of ATACAND and periodically thereafter in order to minimize potential side effects.
About the CHARM Program(2)
The CHARM program, sponsored by AstraZeneca, consisted of three parallel, randomized, placebo-controlled, double-blind trials in 7,599 symptomatic heart failure patients. CHARM-Added (2,548 patients receiving an ACE inhibitor) and CHARM-Alternative (2,028 patients not receiving an ACE inhibitor due to intolerance) enrolled patients with left-ventricular ejection fraction (LVEF) less than or equal to 40%, and CHARM-Preserved (n=3023) enrolled patients with LVEF > 40%. Patients were randomized to either ATACAND® (candesartan cilexetil) or matching placebo initiated at 4 mg or 8 mg once daily and titrated as tolerated to 32 mg once daily added to conventional therapy. Patients were followed for a minimum of two years, with median follow-up of 38 months. The primary end point of each trial was cardiovascular death or heart failure hospitalization.
IMPORTANT SAFETY INFORMATION
The recommended initial dose for treating 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.
USE IN PREGNANCY: 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. See WARNINGS in full Prescribing Information, Fetal/Neonatal Morbidity and Mortality
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 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 ATACAND and lithium, careful monitoring of serum 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® (candesartan cilexetil) in total daily doses up to 32 mg once daily (n=3803) with placebo (n=3796), 21.0% of patients discontinued ATACAND for adverse events versus 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.
AstraZeneca is a major international health care business engaged in the research, development, manufacture, and marketing of prescription pharmaceuticals and the supply of health care services. It is one of the world's leading pharmaceutical companies with health care sales of $23.95 billion and leading positions in sales of gastrointestinal, cardiovascular, neuroscience, respiratory, oncology, and infection products. In the United States, AstraZeneca is a $10.77 billion health care 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 2005.
Manufactured under the license from Takeda Pharmaceutical Company, Ltd. by: AstraZeneca AB, S-151, 85 Sodertalje, Sweden.
(1) McMurray JJV, et al Relationship of dose of background angiotensin converting enzyme inhibitor to the benefits of candesartan in the Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity (CHARM) - Added trial. American Heart Journal. In press.
(2) Pfeffer MA, Swedberg K, Granger CB, et al for the CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;362:759-766.
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