Kenneth G. Berge

Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. SHEP Cooperative Research Group.

CONTEXT Heart failure is often preceded by isolated systolic hypertension, but the effectiveness of antihypertensive treatment in preventing heart failure is not known. OBJECTIVE To assess the effect of diuretic-based antihypertensive stepped-care treatment on the occurrence of heart failure in older persons with isolated systolic hypertension. DESIGN Analysis of data from a multicenter, randomized, double-blind, placebo-controlled clinical trial. PARTICIPANTS A total of 4736 persons aged 60 years and older with systolic blood pressure between 160 and 219 mm Hg and diastolic blood pressure below 90 mm Hg who participated in the Systolic Hypertension in the Elderly Program (SHEP). INTERVENTION Stepped-care antihypertensive drug therapy, in which the step 1 drug is chlorthalidone (12.5-25 mg) or matching placebo, and the step 2 drug is atenolol (25-50 mg) or matching placebo. MAIN OUTCOME MEASURES Fatal and nonfatal heart failure. RESULTS During an average of 4.5 years of follow-up, fatal or nonfatal heart failure occurred in 55 of 2365 patients randomized to active therapy and 105 of the 2371 patients randomized to placebo (relative risk [RR], 0.51; 95% confidence interval [CI], 0.37-0.71; P<.001; number needed to treat to prevent 1 event [NNT], 48). Among patients with a history of or electrocardiographic evidence of prior myocardial infarction (MI), the RR was 0.19 (95% CI, 0.06-0.53; P=.002; NNT, 15). Older patients, men, and those with higher systolic blood pressure or a history of or electrocardiographic evidence of MI at baseline had higher risk of developing heart failure. CONCLUSION In older persons with isolated systolic hypertension, stepped-care treatment based on low-dose chlorthalidone exerted a strong protective effect in preventing heart failure. Among patients with prior MI, an 80% risk reduction was observed.

The Effect of Treatment on Mortality in Mild Hypertension: Results of the Hypertension Detection and Follow-up Program

In the Hypertension Detection and Follow-up Program, 7825 (71.5 per cent) of the 10,940 participants had diastolic blood pressures averaging between 90 and 104 mm Hg on entry into the study and were designated Stratum 1. Half were referred to their usual source of care in the community (the referred-care group), and half were treated intensively in special clinics (the stepped-care group). Five-year mortality in the Stratum 1 patients given stepped care was 20.3 per cent lower than in those given referred care (P less than 0.01). Particularly noteworthy was the beneficial effect of stepped-care treatment on persons with diastolic pressures of 90 to 104 mm Hg who had no evidence of end-organ damage and were not receiving antihypertensive medication when they entered the study. This subgroup had 28.6 per cent fewer deaths at five years among those treated with stepped care than among those treated with referred care (P less than 0.01). These findings support a recommendation that in patients with mild hypertension, treatment should be considered early, before damage to end organs occurs.

Effect of atenolol and reserpine on selected events in the systolic hypertension in the elderly program (SHEP).

The effect of atenolol and reserpine on incidence of strokes, coronary heart disease (CHD), cardiovascular disease (CVD), and mortality was assessed in 4736 persons aged 60 years and older with isolated systolic hypertension. Participants were randomized to either chlorthalidone (2371), with step-up to atenolol, or reserpine if needed, or placebo (2365). The average baseline SBP/DBP was 170/77 mm Hg. In the active treatment group, step 1, dose 1 was chlorthalidone, 12.5 mg/day; dose 2 was 25 mg/day. For step 2, dose 1 was atenolol 25 mg/day (or reserpine 0.05 mg/day if atenolol was contraindicated); dose 2 was 50 mg/day (reserpine, 0.10 mg/day). During 4.5 years average follow-up, 32% (757) of the active treatment group were on atenolol, with an average exposure of two years and 8% (193) were on reserpine with an average exposure of 1.7 years. Overall there were 96 strokes, 140 CHD events and 289 CVD events among the 2365 active group participants. Using time-dependent lifetable regression with adjustment for several variables, the addition of either atenolol or reserpine to chlorthalidone did not substantially alter the risk ratios for chlorthalidone alone. The relative risk for CHD events for atenolol versus no atenolol was 1.04 (95% confidence interval: 0.58, 1.86) and for reserpine versus no reserpine was 0.93 (95% confidence interval: 0.29, 2.96). The relative risk for atenolol were 0.84 (95% confidence interval: 0.54, 1.30) for death, 1.34 (95% confidence interval: 0.80, 2.28) for stroke, and 1.07 (95% confidence interval: 0.71, 1.61) for CVD. For reserpine, the corresponding relative risks and confidence intervals were 0.65 (0.26, 1.59) for death, 0.27 (0.04, 2.26) for stroke, and 0.55 (0.20, 1.49) for CVD. Thus, the beneficial effects in several outcomes in Systolic Hypertension in the Elderly Program (SHEP) were due to the treatment regimen of lowering blood pressure based on low-dose chlorthalidone (plus atenolol or reserpine as required to meet blood pressure criteria). Additional (independent) benefits attributable to atenolol or to reserpine were not identified. However, a greater number of patients might have been necessary to adequately evaluate potential differential effects of these drugs, especially for reserpine.

Potassium-Sparing Effects of Triamterene in the Treatment of Hypertension

Triamterene (2,4,7-triamino-6-phenylpteridine) was employed alone and in combination with hydrochlorothiazide in the treatment of patients with group 1 and 2 hypertension. In 21 patients, triamterene alone had an inconsistent antihypertensive effect on the systolic blood pressure, which was minimal in most patients. In 16 patients the combination of triamterene and hydrochlorothiazide (2:1 by weight) reduced the systolic blood pressure slightly more than did hydrochlorothiazide alone. Triamterene alone or in combination with hydrochlorothiazide produced an increase in the concentration of potassium in serum. Side effects due to triamterene were similar to those noted with thiazide diuretics. In addition, five patients had a decreasein blood hemoglobin concentration, and two patients had reversible alterations in liver function during triamterene therapy. Triamterene may be a useful adjunct for thiazidetreated hypertensive patients by decreasing the likelihood of complicating hypokalemia.

Comparison of the treatment of hypercholesteremia with nicotinic acid, sitosterol, and safflower oil

Abstract In 10 patients with hypercholesteremia who were not restricted in amount or type of dietary fat, treatment with large oral doses of nicotinic acid (niacin) was more effective in lowering plasma cholesterol than was that with either safflower oil or sitosterol. The simultaneous administration of niacin and sitosterol was more effective than the use of either agent alone, and their combined effects were nearly additive. As compared with safflower oil or sitosterol in the treatment of hypercholesteremia, niacin has several practical advantages in that the drug is inexpensive, is simple to administer, and does not require alterations in the patients dietary habits. However, the safety of such long-term use of niacin must be established before this form of therapy can be regarded as other than an investigational procedure.

Perceptions of the coordinating center: As viewed by an advisory board

As an advisory group appointed by and directly accountable to the sponsoring agency, the advisory board has a unique relationship with the coordinating center. The coordinating center provides the data and analyses by which the board assesses progress and monitors safety of a trial. Although assessment of quality of performance of the units of the study is the direct concern of the coordinating center, corrective measures frequently become advisory board matters. Ideally, the relationship between the coordinating center and the advisory board is one of mutual trust and support in pursuit of the goal of a trial that is planned carefully, conducted with tight control of performance and safety, and reported accurately to the appropriate professional groups.