CONTACT: Rachel Bloom
Zeneca Pharmaceuticals
302-886-7858
FOR IMMEDIATE RELEASE
NEW CLINICAL DATA SHOW INTERNATIONAL DIFFERENCES IN THE USAGE OF MEDICATIONS FOR CONGESTIVE HEART FAILURE Data Also Demonstrate Safety and Potential Utility of CCBs In Treatment of Patients With Cardiovascular Disease
WILMINGTON, Del. - January 19, 1998 - Preliminary data from clinical studies of medications which treat congestive heart failure (CHF) demonstrate substantial international differences in usage of ACE inhibitors as well as the safety and potential utility of calcium channel blockers (CCBs) in the treatment of patients with cardiovascular disease.
New data from ATLAS,(1) the first CHF trial conducted in North America, Europe, and Australia, indicate that there are substantial international differences in the usage of medications, despite published guidelines reflecting international agreement concerning treatment of CHF.(2) ATLAS compares the effects of low- versus high-dose ZESTRIL(R) (lisinopril) on survival of 3,164 patients (recruited between Oct '92 and June '94) in 291 centers in 19 countries from 3 continents, with ejection fraction (EF) Û30% and NYHA class II, III, or IV CHF. There were no significant regional differences in EF or NYHA class, but a smaller proportion of patients in SW Europe had ischemic cardiomyopathy. Major differences identified included the use of digoxin in patients who were in sinus rhythm (23% in UK and Ireland compared with 74% in US, 80% in Canada, 79% in Central Europe), the use of fl-blockers (generally low, but high in Nordic countries, The Netherlands and Belgium) and the use of a! nticoagulants among patients in atrial fibrillation (42% in UK and Ireland compared with 84% in The Netherlands and Belgium and around 70% elsewhere).
"Many of the differences relate to medications for which there are limited data and few clinical trials and reflect known regional practices. However, others, such as the variable but relatively low use of anticoagulants in atrial fibrillation patients, indicate that there is room for improvement in the treatment of CHF," concluded Barry Massie M.D., University of California, San Francisco. Zeneca Pharmaceuticals markets the ACE inhibitor lisinopril in the United States under the trade name ZESTRIL, an oral once-daily medication indicated for the treatment of hypertension, as adjunctive therapy in CHF, and within 24 hours post-MI to improve survival. ACE inhibitors should be discontinued as soon as pregnancy is detected. Angioedema has been reported with ACE inhibitors, including ZESTRIL.
Zeneca Pharmaceuticals also markets the CCB nisoldipine in the United States under the trade name SULAR(R) (nisoldipine) Extended Release Tablets, an oral once-daily dihydropydridine CCB, indicated for the treatment of mild-to-moderate hypertension. SULAR is generally well-tolerated. The most frequently occurring adverse experiences with SULAR include peripheral edema and headache. These are generally mild and only occasionally lead to patient withdrawal from treatment.
Calcium Channel Blocker Studies Results from STEPHY(3) II demonstrate that CCBs did not increase the risk of fatal or nonfatal cancer over three years in an elderly European population Ú65 years.(4) Recently, experimental data postulated an increased risk of cancer with use of CCBs. STEPHY II assessed the relationship between the three-year incidence of fatal or nonfatal cancer and the use of CCBs. The incidence of fatal cancer was 2.2% for patients on CCBs and 2.1% for those not on CCBs; the incidence of nonfatal cancer was 12% for those on CCBs and 11% for those not on CCBs (both differences not significant).
Additional new data from the CAMI(5) database support the safety of CCBs in the long-term treatment of postmyocardial infarction (MI) patients, in contrast to recent studies raising concerns regarding their safety in patients with coronary artery disease.(6) Cardiovascular event rates post-MI were compared in 4,133 consecutive acute MI patients who may or may not have received CCBs. No significant difference was found in cardiac events in patients on CCBs (n=450) compared to those (n=2,346) not on CCBs (21.6% vs 25.2%, p=0.105). In addition, there was a trend toward a beneficial effect produced on heart rate-lowering CCBs. The exposure analysis confirmed that there was no increase in events in the CCB-treated group.
Also, intraveneous nisoldipine echocardiography (Nis-E) has been shown to be a new tool for predicting the recovery of regional left ventricular (LV) function after coronary revascularization in patients with chronic ischemic dysfunction.(7) The potential value of Nis-E in detecting hibernating myocardium has not been tested, even though clinical studies have shown that nisoldipine, a highly vasoselective dihydropyridine calcium antagonist, can improve contractility, possibly through an increase in coronary blood flow, LV afterload reduction or improved calcium handling in the ischemic myocardium. Nis-E was completed in all 35 patients studied without significant side effects or development of echocardiography or ECG signs of ischemia. The sensitivity, specificity and positive and negative predictive values of Nis-E for predicting recovery of regional LV function were 88%, 73%, 86%, and 77%, respectively, suggesting that Nis-E is safe and can be used for identifying myocard! ial hibernation. Nisoldipine is not approved in the United States for treatment of ischemia or myocardial hibernation.
Finally, data from an in vitro study show nisoldipine to be the most potent of four agents tested in protecting against the endothelial cell injury induced either by 3-morpholinosydnonimine (SIN-1) or peroxynitrite (PN), even outperforming vitamin E.(8) Nitric oxide (NO) and superoxide anion (
--O2-), which are known to be generated by inflammatory cells under certain pathological conditions, may be cytotoxic to the endothelial cell due to PN formation. In this study, the effects of nisoldipine on NO +
--O2-, or PN mediated endothelial cell injury were assessed and compared with nicardipine, nifedipine, and Trolox (water soluble vitamin E). All agents (1-20 µM) were able to attenuate the PN-mediated endothelial cell injury, with the following order of efficacy: nisoldipine > vitamin E > nicardipine >> nifedipine. The protective mechanism is most likely through a lipophilic 'chain-breaking' action against the 'OH-like species' released from PN or SIN-1, which might dir! ectly mediate the oxidative endothelial cell cytotoxic effects.
Zeneca Pharmaceuticals is a business unit of Zeneca Inc., a $3.1 billion bioscience business with approximately 7,200 employees in the United States. Zeneca Inc. is a wholly-owned subsidiary of the U.K.-based Zeneca Group PLC (NYSE:ZEN), a major $9 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) Assessment of Treatment with Lisinopril and Survival. (2) Use of medications varies markedly among countries participating in an international CHF trial. Massie BM et al, University of California, San Francisco, CA. (3) Starnberg Study on Epidemiology of Parkinsonism and Hypertension in the Elderly. (4) Calcium channel blockers do not increase the risk of fatal or non-fatal cancer in an elderly European population: Results from STEPHY II. Trenkwalder PRA et al, Stanford University, Stanford, CA. (5) Canadian Acute Myocardial Infarction (6) Are calcium channel blockers post myocardial infarction safe? The CAMI Experience. Stewart DJ et al, St Michael's Hospital, Toronto, ON, Canada. (7) Nisoldipine echocardiography: A new tool for predicting recovery of regional left ventricular function after coronary revascularization in patients with chronic ischemic dysfunction. Sheiban I et al, IRCCS H San Raffaele, Milan, Italy. (8) Protective effects of nisoldipine (Nis) against nitric oxide (NO) + superoxide anion (
--02-) or peroxynitrite (PN) mediated endothelial cell injury. Mak IT et al, George Washington University, Washington, DC.
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