John B. Kostis, MD, professor and chair, Department of Medicine; John G. Detwiler Professor of Cardiology; professor, Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School

In spite of recent trends revealing a 50% decrease in age adjusted cardiovascular disease mortality in the last 30 years, heart attack, stroke and hypertension are the most frequent causes of death in the U.S., and the number of persons with atherosclerotic disease has not declined significantly. The Myocardial Infarction Data Acquisition System (MIDAS), instituted by the Division of Cardiovascular Diseases and Hypertension at UMDNJ-Robert Wood Johnson Medical School, has monitored the occurrence, characteristics, invasive therapies and outcomes of all myocardial infarctions occurring in the state since 1986. Although a significant decline of fatal events has been observed in MIDAS, and the average age of occurrence has been postponed by approximately four years, there has been a corresponding increase in nonfatal events and approximately 40,000 myocardial infarctions or out-of-hospital coronary deaths have occurred annually in the state since 1986. This underscores the need for continuing emphasis on the prevention and treatment of atherosclerotic disease.

For more than 20 years it has been our belief that a global approach, focusing on all modifiable risk factors, including smoking, hyperlipidemia, hypertension, obesity and diabetes, is needed for successful primary or secondary prevention, and that focusing on individual risk factors is suboptimal. In this spirit, we have participated in the development and evaluation of non-pharmacological approaches and more than 100 drugs and devices used in patients at risk, and have designed, conducted, participated in and published clinical trials using these approaches. NIH and NIH-funded research by our group has highlighted the importance of lifestyle modification in improving the clinical condition of heart failure and in decreasing the need for antihypertensive therapy in older persons with hypertension. We have conducted many studies for the management of coronary artery disease. Some of this research includes: evaluating the usefulness of aspirin in the prevention of recurrent myocardial infarction; one of the earliest studies on stabilization and regression of coronary artery disease using cholesterol-lowering agents; and a clinical trial on the efficacy of beta-blockers in decreasing fatal and non-fatal coronary events in survivors of acute myocardial infarction.

Although clinical trials are the gold standard of evidence-based medicine, they have certain limitations, including their relatively short duration. Our group has conducted the extension of an important hypertension trial, the Systolic Hypertension in the Elderly Program (SHEP). This was an NIH-sponsored, placebo-controlled, double-blind, randomized, multi-center clinical trial testing the efficacy of diuretic-based, stepped-care antihypertensive drug treatment of isolated systolic hypertension (ISH) in decreasing morbid and mortal cardiovascular events in persons aged 60 years or older. The main criterion for inclusion was ISH, defined as a systolic blood pressure (BP) 160 to 219 mm Hg and a diastolic BP <90 mm Hg. Patients with insulin-dependent diabetes mellitus and those requiring diuretic therapy were excluded. Patients were treated in a randomized, double-blind fashion, using stepped-care therapy with chlorthalidone (a diuretic) 12.5-25.0 mg daily or matching placebo. If the BP remained above goal (decrease of systolic BP by >20 mm Hg and to <160 mm Hg), atenolol or reserpine was added. Potassium supplementation was recommended for any hypokalemia and was dictated by the protocol for confirmed serum potassium level less than 3.5 mEq/L.

The results of SHEP were a 36% reduction in stroke, 27% reduction in coronary heart disease and 49% reduction in heart failure with diuretic-based therapy compared to placebo. This study and other trials showed improved clinical outcomes with diuretic-based antihypertensive therapy, although these agents were associated with the development of diabetes in a significant proportion of patients. It has been proposed that the duration of clinical trials was too short to detect the adverse effects of diabetes. To answer this question, we studied the long-term mortality of the 4,732 participants. Our group, in collaboration with investigators from the University of Texas, undertook the SHEP extension study (SHEP-X) by ascertaining the vital status of participants using the National Death Index Plus for an average follow-up of 14.3 years. A total 1,987 (42%) of the original SHEP cohort were deceased at the end of the follow-up and approximately half of the deaths were due to cardiovascular causes. Cardiovascular mortality was significantly lower in the group randomized to chlorthalidone (19.0%) compared to placebo (21%, HR 0.854, 95% CI 0.751-0.972).

Seven hundred and ninety-nine SHEP participants had diabetes at baseline and an additional 427 developed diabetes during the first two years of treatment. The development of diabetes was more likely to occur in those randomized to chlorthalidone (258, 13%) than to those randomized to placebo (169, 8.7%, p<.0001). Participants who developed diabetes during diuretic therapy had lower fasting serum glucose at the second annual visit (136.1±30.8 mg/dl) than those who developed diabetes on placebo (143.8±49.0 mg/dl, p=0.055). Participants with diabetes at baseline had significantly higher mortality than those without diabetes at baseline (HR 1.633, CI 1.397-1.907 for the placebo group and HR 1.376, CI 1.161-1.631 in the active treatment group). Participants randomized to placebo who developed diabetes during the double-blind phase also had significantly higher mortality compared to those who did not develop diabetes (HR 1.348, CI 1.051-1.727). However, this effect was less pronounced and not statistically significant among participants who developed diabetes while on diuretic therapy. Diabetic participants (either at baseline or follow-up) who were randomized to active therapy had lower mortality during the extended follow-up than those randomized to placebo (HR 0.805, CI 0.680-0.952). This effect was more pronounced when cardiovascular mortality was considered (HR 0.688, CI 0.526-0.848).

In this study with very long follow-up, chlorthalidone-based treatment resulted in improved cardiovascular outcomes, especially among diabetics. Participants with diabetes associated with chlorthalidone had no significant increase in cardiovascular events and had a better prognosis than those with pre-existing diabetes. The persistence of the beneficial effect of antihypertensive therapy for about 15 years underscores the need for detection and early treatment of hypertension and other risk factors. Although this particular study involved a generic medication, similar research has been funded by many pharmaceutical companies including Pfizer, Inc., Merck, Bristol-Myers Squibb and Schering-Plough.

John B. Kostis, MD, is the John G. Detwiler Professor of Cardiology, professor of medicine and pharmacology, and chair in the Department of Medicine at RWJMS. He is also an adjunct professor of biomedical engineering at Rutgers University and chief of the medical service at Robert Wood Johnson University Hospital. A board-certified cardiologist with an active clinical practice, Dr. Kostis conducts cardiovascular research and teaches at the undergraduate, graduate and postgraduate levels. His research focuses on cardiovascular pharmacology, clinical trials and biomedical engineering and has been supported by the NIH, NIA and the pharmaceutical industry. He serves on the board of directors of the Robert Wood Johnson University Hospital, the board of the Educational Commission for Foreign Medical Graduates, the Executive Council of the American Society of Hypertension (treasurer) and is the president-elect of the Northeast Lipid Association. Dr. Kostis has been listed among the best doctors in New Jersey, New York and America. §