The Multiple Risk Factor Intervention Trial (MRFIT) revealed an unexpected subgroup finding: an association between diuretic treatment (especially with hydrochlorothiazide) and an increased rate of sudden death in hypertensive men with resting ECG abnormalities. The question is, does this finding result from random error, or does it represent a toxic response to hydrochlorothiazide? Our study is an effort to distinguish between these two possibilities by examining pathophysiologic mechanisms in men aged 35-70 who have the MRFIT- type ECG abnormalities and hypertension. After an initial set of cross- sectional measurements to compare the long term effects of prestudy diuretic regimens, 220 men were withdrawn from diuretics for a month of electrolyte supplementation and then randomized to 2 months of treatment with 1 of the following: (1) hydrochlorothiazide, (2) hydrochlorothiazide and oral potassium, (3) hydrochlorothiazide and oral potassium and magnesium, (4) hydrochlorothiazide and triamterene, (5) chlorthalidone or (6) placebo. The primary outcomes are the frequency and complexity of ventricular arrhythmias measured blindly on 24 hour continuous electrocardiographic monitoring (CEM), and serum and mononuclear cell potassium and magnesium levels (also measured blindly). 213 men completed the study and 70 wee re-randomized and passed through the study a second time. The HART grant produced a technically successful study with high rates of compliance and a relatively complete and error free data set, but with difficulty in recruiting enough men who met the restrictive entry criteria. The latter problem led us to continue entering subjects to the end of the 3 year grant period, and additional support is now requested for analyzing and publishing the results. The proposed 1-year renewal grant would also fund two things not covered in the original grant-analyzing quality of life assessments to compare the effects of the various treatment regimens and placebo, and reading our CEM's for silent myocardial ischemia to examine prevalence and nay association with ventricular arrhythmias. Approximately 60 million people in the United States have hypertension, and one of the most commonly prescribed drugs is hydrochlorothiazide. This study contribute information of great public health importance; does hydrochlorothiazide produce serum nad intracellular electrolyte disturbances that are associated with ventricular arrhythmias, and is any of 3 potassium-sparing hydrocholorothiaszide combination regimens less likely to have these adverse effects and therefore to be preferred for routine antihypertensive therapy?
| Siegel, D; Saliba, P; Haffner, S (1994) Glucose and insulin levels during diuretic therapy in hypertensive men. Hypertension 23:688-94 |
| Siegel, D; Cheitlin, M D; Seeley, D G et al. (1992) Silent myocardial ischemia in men with systemic hypertension and without clinical evidence of coronary artery disease. Am J Cardiol 70:86-90 |
| Siegel, D; Black, D M; Seeley, D G et al. (1992) Circadian variation in ventricular arrhythmias in hypertensive men. Am J Cardiol 69:344-7 |
| Siegel, D; Hulley, S B; Black, D M et al. (1992) Diuretics, serum and intracellular electrolyte levels, and ventricular arrhythmias in hypertensive men. JAMA 267:1083-9 |
| Chang, S W; Fine, R; Siegel, D et al. (1991) The impact of diuretic therapy on reported sexual function. Arch Intern Med 151:2402-8 |
| Siegel, D; Cheitlin, M D; Black, D M et al. (1990) Risk of ventricular arrhythmias in hypertensive men with left ventricular hypertrophy. Am J Cardiol 65:742-7 |
