University of Rochester Medical Center Participates in "Treating To New Targets" Study

Study Assesses Benefits of Reducing Cholesterol to Levels Lower Than Current Practice

August 18, 1998

The University of Rochester Medical Center will be one of the sites in a new multinational landmark research study that is being launched to investigate whether lowering LDL-cholesterol ("bad" cholesterol) to levels below current clinical practice can further reduce the chances of death or heart attack in patients with coronary heart disease. Enrollment in the study is slated to begin on September 8.

The study, known as Treating to New Targets (TNT), is designed to resolve an important issue in the science of cholesterol lowering; whether there is additional benefit in cardiovascular risk reduction by treating patients to more aggressive LDL-cholesterol goals. Patients will be treated with the cholesterol-lowering medication Lipitor? (atorvastatin calcium) tablets. Since the effect of Lipitor on cardiovascular morbidity and mortality is not known, this is one of the studies under way to determine its effect.

"We look forward to being part of this important study," said Thomas A. Pearson, M.D., Ph.D., lead investigator from the trial site. "Preliminary research has suggested that if we lower LDL-cholesterol beyond current clinical practice, we can achieve even greater cardiovascular benefits. TNT will help us determine the benefits of significantly reducing LDL levels to below 100mg/dL (2.6 mmol/L)."

The five-year trial will involve about 8,600 patients at approximately 250 sites in the United States, Canada, Europe, South Africa and Australia, making it one of the largest cardiovascular outcomes trials ever conducted with a cholesterol-lowering medication.

Large epidemiologic studies have established that low cholesterol levels are correlated with a reduced risk of cardiovascular morbidity and mortality. It was on the basis of these studies that regional guidelines on treating high cholesterol were developed. The joint European Society of Cardiology /European Artherosclerosis Society established its guidelines in 1993. In the U.S., the National Cholesterol Education Program (NCEP) released an update in 1993 of its original 1998 guidelines recommending a target LDL-cholesterol of 100 mg/dL (2.6 mmol/L) or less for patients with established coronary heart disease.

The TNT trial is the first study designed to examine whether the clinical benefit to patients treated to an LDL level of about 75 mg/dL (1.9 mmol/L) is greater than that seen in patients treated to an LDL level of about 100 mg/dL (2.6 mmol/L). The primary endpoint of the trial will be the incidence of coronary death or nonfatal myocardial infarction (heart attack) in each group.

The results of TNT could have important implications for the estimated 33 million people in the United States and Europe who suffer from heart disease.

The TNT trial is sponsored by Parke-Davis, a division of Warner-Lambert Company, and Pfizer Inc. Lipitor was discovered and developed by Parke-Davis and is marketed globally in collaboration with Pfizer.

In addition to TNT, Parke-Davis and Pfizer are sponsoring several other endpoint studies to address other important issues in lipid lowering. These include investigations of the clinical benefit of LDL-cholesterol reduction in patients with acute unstable angina, patients referred for revascularization procedures and those with Type II diabetes. Moreover, Parke-Davis and Pfizer are committed additionally to investigate the long-term comparative efficacy of atorvastatin in a future trial.

Lipitor is approved for marketing in 35 countries-in most countries it is indicated as an adjunct to diet and lifestyle changes for the reduction of elevated total cholesterol, LDL-cholesterol, apolipoprotein B and triglycerides in patients with high cholesterol when response to diet is inadequate.

Lipitor has been shown in clinical studies to produce reductions in LDL-cholesterol in patients with elevated cholesterol of 39% to 60% across the dose range of 10 to 80 mg. Reductions in triglycerides of 19% to 37% were reported in clinical trials across the same dose range.

Lipitor is generally well tolerated. Adverse reactions usually have been mild and transient, with fewer than 2 percent of patients being discontinued from clinical trials due to side effects related to atorvastatin. The rate of discontinuation was comparable to that of placebo. The most frequent adverse effects of atorvastatin are constipation, flatulence, dyspepsia and abdominal pain. It is recommended that liver function tests be performed before initiation of treatment, and after twelve weeks after initiation of therapy and any elevation in dose , and periodically thereafter. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of creatine phosphokinase (CPK).

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