Search

Purpose: The Multiple Risk Factor Intervention Trial (MRFIT), a randomized clinical trial for the primary prevention of coronary heart disease, enrolled 12,866 men (including 8194 cigarette smokers) aged 35-57 years at 22 clinical centers across the United States. Participants were randomized either to special intervention (SI), which included an intensive smoking cessation program, or to usual care (UC). After 16 years of follow-up, lung cancer mortality rates were higher in the SI than in the UC group. Since rates of smoking cessation in SI were higher than those for UC for the 6 years of the trial, and since risk of lung cancer mortality is known to decline with smoking cessation, these results were unexpected. The purpose of the present study was to investigate hypotheses that could explain the higher observed lung cancer mortality rates in the SI as compared with the UC group., Methods: Analytic methods were employed to determine whether SI and UC participants differed either in baseline characteristics or in characteristics that changed during the trial and to determine whether these differences could explain the higher rates of lung cancer mortality among SI as compared to UC participants. Rates of mortality from coronary heart (CHD) were examined to explore the possibility that prevention of CHD death may have contributed to greater mortality due to lung cancer in the SI group., Results: From randomization through December 1990, 135 SI and 117 UC participants died from lung cancer. The relative difference between the SI and U groups adjusted for age and number of cigarettes smoked per day, was 1.17 (95% CI:0.92-1.51). The greatest difference between the SI and UC groups in lung cancer mortality rates occurred among the heaviest smokers at baseline who did not achieve sustained smoking cessation by year 2. In this group the rates of death from CHD were approximately the same among the SI and UC subjects. No differences in baseline characteristics were found between SI and UC smokers who did not achieve sustained cessation by year 2, and there were no differences in follow-up characteristics between the two study groups that could explain the difference in lung cancer mortality., Conclusions: None of the hypotheses proposed to explain the unexpected higher rates of lung cancer mortality among SI as compared with UC subjects were sustained by the data. Thus we conclude that the difference observed is due to chance, and that a longer period of sustained smoking cessation plus follow-up is necessary to detect a reduction in lung cancer mortality as a result of smoking cessation intervention in a randomized clinical trial.

We conducted a randomized, double-blind, placebo-controlled trial of oral potassium chloride supplementation (60 mmol/d) in 353 men and women with an initial average diastolic blood pressure between 80 and 89 mm Hg. In the active (n = 178) compared to the placebo (n = 175) treatment group, the urinary potassium level was significantly (p < 0.001) increased by an average of 44.0 and 42.3 mmol/24 h following 3 and 6 months of therapy, respectively. Compared to placebo, active treatment was associated with a small (mean = 1.8 mm Hg) but significant (p = 0.04) reduction in diastolic blood pressure following 3 months of therapy. Following 6 months, however, this apparent treatment effect had virtually disappeared (mean reduction in diastolic blood pressure = 0.3 mm Hg). There was no significant effect of potassium supplementation on systolic blood pressure at either follow-up visit. There was a significant, independent, dose-response relationship between change in both 24-hour urinary potassium excretion and urinary sodium-potassium ratio and the corresponding change in diastolic blood pressure (-1.49 mm Hg for the highest versus the lowest quartile of change in urinary potassium excretion.

Phase II of the Trials of Hypertension Prevention (TOHP) is a multicenter, randomized trial sponsored by the National Heart, Lung, and Blood Institute designed to test whether weight loss alone, sodium reduction alone, or the combination of weight loss and sodium reduction will decrease diastolic (DBP) and systolic blood pressure (SBP) as well as the incidence of hypertension (DBP > or = 90 mm Hg, SBP > or = 140 mm Hg, and/or use of antihypertensive medications) in subjects with high-normal DBP (83 to 89 mm Hg) and SBP less than 140 mm Hg at entry. These interventions were chosen for longer-term testing with end points including hypertension prevention as well as blood pressure (BP) change based on their demonstrated short-term efficacy in reducing BP in phase I of TOHP. The phase II study population is comprised of 2382 participants (1566 men and 816 women) who are 110 to 165% of desirable body weight, allocated at random to the four treatment arms using a 2 x 2 factorial design. The trial has 80% power to detect an overall treatment effect on DBP of 1.2 mm Hg for weight loss or sodium reduction and a difference of 1.6 mm Hg between the combined intervention and placebo groups. BP observers are blinded to participant treatment assignments. Participants will be followed for 3 to 4 years. This trial may have important public policy implications concerning the ability of life-style modifications to reduce BP and prevent the development of hypertension over the long term, thereby avoiding the need for drug therapy which while effective is costly and may have side effects.

To provide further understanding of the decline in stroke mortality in the United States, data from 16 randomized controlled trials of hypertension treatment and stroke published to date are pooled. The overall weighted average blood pressure reduction was 13/6 mm Hg. The pooled odds ratio was 0.61 (95% confidence interval: 0.55, 0.68), indicating approximately a 39% (32 to 45%) reduction in stroke occurrence. Percent reduction was somewhat higher in studies of mild-moderate hypertension (47%) and somewhat lower in studies of the elderly (35%). There was no differential effect by gender (reductions of 37% for women, 34% for men) or by race (32% for blacks, 37% for whites). The magnitudes of reductions for fatal (41%) and nonfatal (37%) strokes, and for diuretics and beta-blockers (odds ratio diuretic versus beta-blocker, 0.86; 95% CI: 0.69, 1.08) were similar. Implications for the decline in stroke mortality in the United States are discussed.

Phase I of the Trials of Hypertension Prevention (TOHP) was a National Heart, Lung, and Blood Institute-sponsored, 3-year, national, multicenter, randomized, controlled trial designed to test the feasibility and efficacy of three life-style (weight loss, sodium restriction, and stress management) and four nutrition supplement (calcium, magnesium, fish oil, and potassium) interventions aimed at lowering diastolic blood pressure in those whose blood pressure was initially in the high normal range (80 to 89 mm Hg). A total of 2182 volunteers were recruited and allocated to the various treatment arms, such that each hypothesis was tested with a power of 85% or higher to detect a diastolic blood pressure treatment effect of 2 mm Hg. The four nutrition supplement interventions were delivered in a double-blinded fashion and the three life-style interventions, single (observed) -blinded. Phase I was designed to provide a rigorous test of short-term lowering of blood pressure for each of the seven treatments chosen and provides the basis for planning of a subsequent long-term trial of hypertension prevention.

Since 1987, four randomized controlled clinical trials with 872 nonhypertensive subjects have produced results on weight-reducing interventions, involving decreased caloric intake and/or increased expenditure, for effects on blood pressure (BP). The Hypertension Prevention Trial maintained a 3.5-kg net weight loss through 36 months with intake reduction alone. This program decreased BP by 2.4/1.8 mm Hg (systolic/diastolic) compared to controls, but both weight loss and blood pressure changes were smaller when combined with decreased sodium intake. A Stanford University trial achieved weight losses of 7.4 and 5.1 kg over 12 months with diet and exercise, respectively. Effects on clinic BP were in the range of 1.5 to 3.0 mm Hg and did not differ by intervention approach. The sole trial in children, conducted at University of Michigan, found similar weight loss (about 7 kg) and BP effects from limiting caloric intake over 20 weeks, regardless of inclusion of an exercise program; the latter did, however, result in greater reductions in percent body fat, heart rate, and serum insulin levels. The Primary Prevention of Hypertension trial tested a multifactor intervention including reductions in weight (mean, 2.7 kg), sodium and alcohol intake, and increased physical activity. During a 5-year period, clinic BP was reduced by 2.0/1.9 mm Hg, and the incidence of hypertension, by 52%. It is concluded that weight loss, however achieved, lowers BP in overweight nonhypertensive persons, and probably can contribute substantially to reducing the incidence of hypertension. Whether there are independent effects additive to weight loss from increasing physical activity and reducing sodium intake remains unknown.