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Zeneca Pharmaceuticals
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Judith Auchard
Zeneca Inc.
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LANDMARK HEART FAILURE STUDY SHOWS HIGH DOSES OF ACE INHIBITOR ZESTRIL(lisinopril) PROVIDE SIGNIFICANT THERAPEUTIC BENEFITS
Study May Prompt Physicians to Rethink Treatment Practices
ATLANTA -- March 30, 1998 -- For the five million Americans who suffer from congestive heart failure (CHF), a new study shows that patients taking high doses of the angiotensin converting enzyme (ACE) inhibitor ZESTRIL (lisinopril)1 may live longer and be hospitalized less often than those on low dose therapy. The results were announced today at the 47th Annual American College of Cardiology (ACC) Scientific Session.
Low-Dose Therapy Not Optimal According to Milton Packer, M.D., the study's principal investigator and chairman of the ATLAS Steering Committee, "ACE inhibitors are a life-saving therapy for the treatment of heart failure. However, current practice is to use lower doses of these drugs than were
shown beneficial in clinical studies. ATLAS tells us that low doses may not be optimal therapy and that patients may derive additional benefits by using a higher dose of the same drug, with no significant increase in side effects." Dr. Packer is Professor of Medicine and Pharmacology and Director of the Center for Heart Failure Research at Columbia-Presbyterian Medical Center, N.Y.
The landmark study, entitled "Assessment of Treatment with Lisinopril and Survival," or ATLAS, was a five-year, randomized, double-blind trial that compared the effect of high and low doses of lisinopril on mortality and cardiovascular morbidity in patients with chronic heart failure. It is estimated that 30 to 40 percent of eligible heart failure patients in the U.S. receive these drugs and that when prescribed, they are used at low doses at initiation of therapy and for maintenance.
Study Enrolled More Than 3,000 Patients Worldwide The study, sponsored by Zeneca Pharmaceuticals based in Wilmington, Del., compared high doses of lisinopril (32.5-35.0 milligrams per day) with low doses (2.5-5.0 milligrams) on the mortality and morbidity of 3,164 patients with moderate to severe heart failure over a period of nearly five years.
Significant Results High dose lisinopril was shown to reduce, by 12 percent, the combined risk of death from all causes and hospitalizations (p=0.002). This endpoint is increasingly recognized as the most comprehensive measure of the long term efficacy of drug treatment for heart failure. It was also found that high dose lisinopril reduced the total number of hospitalizations due to heart failure. Additionally, high dose lisinopril was associated with an 8 percent risk reduction in death from all causes (p=0.12) and a 10 percent risk reduction in cardiovascular mortality (p=0.07).
Higher Doses Well-Tolerated ATLAS also demonstrates that it is possible to utilize high doses of ACE inhibitors in most heart failure patients. Although high doses of lisinopril were well-tolerated, there
was a slightly higher incidence of hypotension/dizziness and worsening renal function. However, the Steering Committee concluded that the incidence rate was not great enough to lead to withdrawal or discourage the careful titration to high doses.
Impact on Healthcare Costs
"The results of ATLAS have significant implications for improved treatment and decreased healthcare costs in the future. ZESTRIL is now the only ACE inhibitor for which the benefits of moving to higher doses have been appropriately explored," said Gerard T. Kennealey, Vice President, Medical Affairs, Zeneca Pharmaceuticals. "Given that 250,000 Americans die each year from CHF and approximately 400,000 new cases are diagnosed annually, these findings offer physicians a new strategy for heart failure treatment."
In addition to benefiting patients' well-being, applications of the findings from this study may help to significantly reduce the cost of hospitalizations, which is estimated in the U.S. alone to be $20.2 billion per year for the treatment and management of heart failure, of which $14.5 billion is spent on hospitalization alone.2
ZESTRIL Background ZESTRIL, marketed by Zeneca Pharmaceuticals, is an oral, long-acting ACE inhibitor indicated for the treatment of hypertension, as adjunctive therapy in the management of heart failure in patients not responding adequately to diuretics and digitalis, and in treatment of hemodynamically stable patients within 24 hours of heart attack to improve survival. The usual effective dosage range for ZESTRIL in CHF patients is 5mg. to 20mg. administered in a single daily dose.
ZESTRIL suppresses the renin-angiotensin-aldosterone system to reduce blood pressure, with an onset of action within one hour. ACE inhibition limits the conversion of angiotensin I to angiotensin II (AII), resulting in decreased plasma AII, reduced vasopressor activity and lower aldosterone levels. AII is a potent vasoconstrictor that increases blood pressure and fluid retention that may play a role in CHF.
Administration of ZESTRIL to patients with hypertension results in a reduction in blood pressure to about the same extent in both reclining and standing positions with no compensatory rapid heart beat. During baseline-controlled CHF clinical trials in patients receiving digitalis and diuretics, single doses of ZESTRIL resulted in decreases in blood pressure and systemic vascular resistance, accompanied by an increase in cardiac output but no change in heart rate.
Efficacy Proven in Earlier Studies, Too The GISSI-3 study,3 a multicenter, controlled, randomized, open clinical trial conducted in 19,394 patients who suffered an acute heart attack, showed that patients treated with ZESTRIL, alone or with nitrates, had an 11 percent lower risk of death at six weeks following initiation of therapy, compared to patients who did not receive ZESTRIL. These patients had a significantly higher incidence of hypotension and kidney dysfunction compared to those not taking ZESTRIL. However, higher rates of these complications did not result in an increase in death or severe kidney failure.
ZESTRIL has been well tolerated in controlled clinical trials of 1,969 patients with hypertension or CHF. Adverse experiences were generally mild and transient; the most frequent in hypertension and CHF trials were dizziness, headache, fatigue, diarrhea, upper respiratory symptoms and cough.
Pregnant or nursing women should consult their physician before taking ZESTRIL. When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, ZESTRIL should be discontinued as soon as possible.
ZESTRIL is manufactured in Puerto Rico and is available by prescription in packages of 100 tablets in strengths of 2.5 mg, 5 mg, 10 mg, 20 mg and 40 mg.
Zeneca Pharmaceuticals Zeneca Pharmaceuticals is a business unit of Zeneca Inc., a $3.4 billion bioscience business with approximately 7,500 employees in the U.S. Zeneca Inc. is a wholly-owned subsidiary of the U.K.-based Zeneca Group PLC (NYSE:ZEN), a major $8.6 billion international bioscience business engaged in the research, development, manufacturing and marketing of ethical (prescription) pharmaceuticals, agricultural and specialty chemical products, and the supply of health care services.
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1 NOTE: For full prescribing information, please contact Rachel Bloom, Zeneca Pharmaceuticals, 302/886-7858 or [email protected], or visit the Zeneca Pharmaceuticals web site at www.usa.zeneca.com/pharm.
2 American Heart Association, "What is Congestive Heart Failure," 1998 Heart and Stroke Statistical Update. 3 Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico. GISSI-3: Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet 1994;343: 115-22.
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