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INVEST Trial Shows Verapamil Treatment Equal to Gold Standard

Abbott Park, Ill, April 2, 2003 — Results from a study evaluating more than 22,000 high risk patients with cardiovascular disease demonstrated that treatment involving a verapamil-based strategy was equal to a gold standard beta blocker strategy in reducing mortality, heart attacks, or strokes. In the INVEST study, women represented more than half of all participants, and for the first time in a large study, all of the patients had both hypertension and coronary artery disease. Coronary artery disease (CAD) is the leading cause of death worldwide.

Results from INVEST (INternational VErapamil SR — Trandolapril STudy) also showed that nearly three-quarters of the patients were able to achieve the goals set forth under stringent treatment guidelines for controlling blood pressure. Preliminary results from the study also suggest that patients in the verapamil-based treatment arm were less likely to develop type-2 diabetes than those in the beta-blocker-based (atenolol) treatment arm. The primary outcomes of the landmark INVEST trial were presented today by principal investigator Carl J. Pepine, M.D., MACC, professor of medicine and chief of the division of cardiovascular medicine, University of Florida, president, American College of Cardiology, as a late-breaking clinical trial at the 52nd Annual Scientific Sessions of the American College of Cardiology. INVEST was supported by Abbott Laboratories.

"Up to now, physicians who cared for patients with both hypertension and coronary artery disease commonly treated these patients with beta blockers. These findings from INVEST provide physicians with new clinical evidence supporting an important alternative in treating these high-risk patients," said Pepine.

About INVEST INVEST represents the second-largest cardiovascular outcomes trial in total patients studied. INVEST was unique in that it used an Internet-based system to enroll patients, collect data, distribute drugs, and monitor the study. INVEST included patients from 15 countries and enrolled patients age 50 years and older with documented hypertension and CAD. The mean patient age was 66 years old. Fifty-two percent of the patients were women, 36 percent of the patients were Hispanic, and 13 percent were Black. In addition to hypertension and CAD, the majority of patients involved in the study had one or more risk factors including: diabetes, high cholesterol, overweight, smoking history, prior history of myocardial infarction and chronic angina. INVEST began in September 1997, and the study was completed in February 2003. On average, patients in INVEST were followed for 2.7 years.

INVEST was a community-based trial for physicians who often see patients with both hypertension and CAD. The study compared two treatment regimens available for use in clinical practice: verapamil, a non-dihydropyridine calcium channel blocker (NDP-CCB) vs. atenolol, a beta-blocker (BB). The study was powered to evaluate if both treatment strategies were equivalent in preventing significant adverse outcomes. In order to reach target blood pressure goals, physicians were allowed to sequentially add anti-hypertensive medications to both treatment arms. Blood pressure goals were based on the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) guidelines that recommend blood pressure goals of 140/90 mmHg or below for hypertensive patients and 130/85 mmHg or below for hypertensive patients with diabetes or renal disease. The verapamil arm allowed for the addition of the angiotensin converting enzyme (ACE) inhibitor trandolapril or use of the co-formulated tablet containing both verapamil SR and trandolapril. The diuretic hydrochlorothiazide (HCTZ) could then be added if needed. The BB arm allowed for the addition of HCTZ and then trandolapril, as required. ACE inhibitor therapy was recommended for all patients with diabetes, renal disease, or heart failure, regardless of treatment strategy. Across the entire study, the majority of the patients (70%) required more than one medication to reach target blood pressure goals, showing that a single medication was insufficient to control blood pressure in this patient population.

Previous hypertension trials demonstrated that achieving blood pressure control ( Based on JNC VI estimates, only 51 percent of patients treated with antihypertensive medications are controlled to target blood pressure of "Abbott is pleased to sponsor research that provides the medical community with new information on how to aggressively manage blood pressure in patients with coronary artery disease," said Jeffrey M. Leiden, M.D., Ph.D., chief scientific officer, and president and chief operating officer, Pharmaceutical Products Group, Abbott Laboratories.

Additional Results In a questionnaire, more patients in the verapamil arm responded that they felt good or excellent (p=0.01) at 24 months.

The adverse events reported were similar in frequency between treatment strategies. However, dyspnea, lightheadedness, symptomatic bradycardia, and wheezing were reported more frequently in BB patients, whereas constipation and cough were reported more frequently in the verapamil patients.

Diabetes INVEST provided additional insight into the potential impact of different antihypertensive medications on the development of diabetes. Preliminary analysis of these data revealed differences between the treatment strategies. Patients in the verapamil group were 13 percent less likely to develop diabetes during follow-up vs. patients in the beta-blocker group.

"These findings may have important public health implications and warrant further investigation," said Pepine.

The JNC VI, the American Diabetes Association (ADA) and the National Kidney Foundation (NKF) recommend adding an NDP-CCB to an ACE inhibitor in the hypertensive diabetic patient.

About Hypertension and Coronary Artery Disease More than 50 million Americans have hypertension and millions remain undiagnosed. Hypertension is a condition that results from abnormally elevated blood pressure inside the veins and arteries. Hypertension is a risk factor for coronary heart disease, diabetes, kidney disease and pregnancy complications. Hypertension can eventually damage important organs such as the heart, brain, eyes or kidneys.

Some 12 million Americans suffer from CAD, the most common form of heart disease. Each year, more than 500,000 Americans die of heart attacks caused by CAD. Coronary artery disease is a narrowing of the small blood vessels that supply blood and oxygen to the heart (coronary arteries). CAD usually results from the build up of fatty material and plaque (atherosclerosis). As the coronary arteries narrow, the flow of blood to the heart can slow or stop. The disease can cause chest pain (angina), shortness of breath, a heart attack or other symptoms.

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