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The Survival and Ventricular Enlargement (SAVE) Study demonstrated that long-term administration of the angiotensin-converting enzyme inhibitor captopril to recent survivors of myocardial infarction with left ventricular dysfunction resulted in a reduction in cardiovascular mortality and morbidity. Analysis of multiple subgroups demonstrated that baseline demongraphics (older age) and clinical characteristics (such as prior MI, history of diabetes or hypertension), that have previously been associated with a higher risk of cardiovascular events, were associated with greater end point event rates in SAVE regardless of therapy assignment at the time of randomization. The effectiveness of captopril therapy in reducing cardiovascular mortality and morbidity was examined in multiple subgroups. Although not all subgroups provided adequate statistical power, the benefits of captopril therapy were relatively uniform in the SAVE study. This indicates that the benefits were not confined to one particular subgroup and conversely that targeting of captopril therapy should be to the broadest group, as defined by SAVE entry criteria, to result in a reduction in cardiovascular mortality and morbidity. [ABSTRACT FROM PUBLISHER]

Objective: To evaluate treatment of mild hypertension using combinations of diet and low-dose pharmacologic therapies.Design: Multicenter, randomized, placebo-controlled clinical trial.Setting: Three university-based tertiary care centers.Patients: Patients (697) 21 to 65 years of age with diastolic blood pressure between 90 and 100 mm Hg as well as weight between 110% and 160% of ideal weight.Intervention: Patients were stratified by clinical center and race and were randomly assigned to one of three diets (usual, low-sodium and high-potassium, weight loss) and one of three agents (placebo, chlorthalidone, and atenolol).Measurements: Changes in measures of sexual problems, distress, and well-being after 6 months of therapy were analyzed.Main Results: Low-dose chlorthalidone and atenolol produced few side effects, except in men. Erection-related problems worsened in 28% (95% CI, 15% to 41%) of men receiving chlorthalidone and usual diet compared with 3% (CI, 0% to 9%) of those receiving placebo and usual diet (P = 0.009) and 11% (CI, 2% to 20%) of those receiving atenolol and usual diet (P greater than 0.05). The weight loss diet ameliorated this effect. The low-sodium diet with placebo was associated with greater fatigue (34%; CI, 23% to 45%) than was either usual diet (18%; CI, 10% to 27%; P = 0.04) or weight reduction (15%; CI, 7% to 23%; P = 0.009). The low-sodium diet with chlorthalidone increased problems with sleep (32%; CI, 22% to 42%) compared with chlorthalidone and usual diet (16%; CI, 8% to 24%; P = 0.04). The weight loss diet benefited quality of life most, reducing total physical complaints (P less than 0.001) and increasing satisfaction with health (P less than 0.001). Total physical complaints decreased in 57% to 76% of patients depending on drug and diet group, and were markedly decreased by weight loss.Conclusion: In general, low-dose antihypertensive drug therapy (with chlorthalidone or atenolol) improves rather than impairs the quality of life; however, chlorthalidone with usual diet increases sexual problems in men. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the 6-month change in cardiovascular (coronary heart disease) risk as a function of diet and drug therapy for mild hypertension.Design: Collaborative randomized, controlled clinical trial to assess the efficacy of alternative regimens in treating mild hypertension.Setting: Three university-based tertiary care centers-the Trial of Antihypertensive Interventions and Management (TAIM).Patients: Six hundred and ninety-two men and women ages 21 to 65 years with diastolic blood pressure between 90 and 100 mm Hg and weight between 110% and 160% of ideal weight.Measurements and Main Results: Patients stratified by clinical center and race were randomized into diet (usual, low sodium-high potassium, weight loss) and drug (placebo, chlorthalidone, and atenolol) groups resulting in nine diet plus drug combinations. The cardiovascular risk at 6-month follow-up was estimated relative to baseline in 692 participants using the Framingham Study model. Due to the blood pressure reduction, cardiovascular risk declined from baseline for all treatment groups (except the usual diet plus chlorthalidone group because of increased cholesterol levels). The relative cardiovascular risk at 6 months compared to baseline ranged from 0.83 in the weight loss plus atenolol subgroup to 1.03 in the usual diet plus chlorthalidone subgroup. The active drug plus weight loss groups showed the lowest relative cardiovascular risk at 6 months.Conclusions: Mild hypertension was generally reduced to desirable levels within 6 months by monotherapy. Evaluating blood pressure changes together with the risk factors indicated a differential effect on overall cardiovascular risk depending on the diet and drug used. Dietary therapy, particularly weight reduction, was important adjunctive treatment in reducing overall cardiovascular risk. [ABSTRACT FROM AUTHOR]

Recent large clinical trials have required screened patients to have serial measurements of an entry criteria variable, eliminating patients form further consideration if the average value is not in the eligibility range specified by the trial protocol. The increasing costs of large clinical trials required that they be executed efficiently. One way to improve efficiency would be to reduce the number of required screening measurements for a patient likely to be ineligible. A procedure is proposed that predicts the value of an average based on n measurements serially obtained on a patient during the screening phase when only m < n measurements are available. The employment of this procedure in a large clinical trial that uses low-density lipoprotein (LDL) cholesterol, total cholesterol, and triglycerides as entry criteria during the screening process is described. As a second example, this procedure is applied to population screening for lipid levels above a treatment threshold. The National Cholesterol Education Program recommends that the average of two LDL cholesterol measurements be used to determine whether LDL cholesterol is above 130 mg/dl, the threshold for treating patients with coronary heart disease. However, data from a sample of patients from a postinfarction population suggest that, if a single LDL cholesterol is above 146 mg/dl, the probability is greater than 95% that the average of the two LDL cholesterol measurements will be above 130 mg/dl.

Are newer types of antihypertensive agents, which are currently more costly to purchase on average, as good or better than diuretics in reducing coronary heart disease incidence and progression? Will lowering LDL cholesterol in moderately hypercholesterolemic older individuals reduce the incidence of cardiovascular disease and total mortality? These important medical practice and public health questions are to be addressed by the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind trial in 40,000 high-risk hypertensive patients. ALLHAT is designed to determine whether the combined incidence of fatal coronary heart disease (CHD) and nonfatal myocardial infarction differs between persons randomized to diuretic (chlorthalidone) treatment and each of three alternative treatments--a calcium antagonist (amlodipine), an angiotensin converting enzyme inhibitor (lisinopril), and an alpha-adrenergic blocker (doxazosin). ALLHAT also contains a randomized, open-label, lipid-lowering trial designed to determine whether lowering LDL cholesterol in 20,000 moderately hypercholesterolemic patients (a subset of the 40,000) with a 3-hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitor, pravastatin, will reduce all-cause mortality compared to a control group receiving "usual care." ALLHAT's main eligibility criteria are: 1) age 55 or older; 2) systolic or diastolic hypertension; and 3) one or more additional risk factors for heart attack (eg, evidence of atherosclerotic disease or type II diabetes). For the lipid-lowering trial, participants must have an LDL cholesterol of 120 to 189 mg/dL (100 to 129 mg/dL for those with known CHD) and a triglyceride level below 350 mg/dL. The mean duration of treatment and follow-up is planned to be 6 years. Further features of the rationale, design, objectives, treatment program, and study organization of ALLHAT are described in this article.

Isolated systolic hypertension has a higher prevalence with age and an associated excess cardiovascular risk. The Systolic Hypertension in the Elderly Program (SHEP) was a randomized, prospective, double blind clinical trial to assess the efficacy and safety of a antihypertensive regimen based on low dose diuretic therapy in reducing the five year combined incidence of fatal and nonfatal stroke. SHEP demonstrated a significant 36% reduction in stroke incidence. Also, 27% reduction in coronary heart disease incidence and a 32% reduction in major cardiovascular disease incidence were achieved. The benefits accrued to all subgroups identified based on baseline age, race, sex, blood pressure, serum cholesterol levels, and ECG abnormalities. A low-dose diuretic regimen should be the initial treatment of choice for most hypertensive patients, based on demonstrated reduction in risk for major cardiovascular events, its safety, acceptance by patients, and low cost.

The Systolic Hypertension in the Elderly Program (SHEP), a randomized, double-masked, placebo-controlled trial of 4736 persons, was designed to assess the efficacy of antihypertensive drug treatment to reduce the risk of fatal and nonfatal strokes among people age 60 and over with isolated systolic hypertension. The statistical method used in interim monitoring of results was conditional power (or stochastic curtailment). The findings did not become conclusive until near the completion of the trial, and therefore SHEP was continued to its scheduled closing date. The trial demonstrated a 36% reduction in the incidence of stroke in the active treatment group (P = .0003). In addition to evaluating overall efficacy of treatment, the monitoring process considered such other issues as nonstroke outcomes, lag time between first report of stroke and final confirmation of stroke diagnosis, consistency of results across subgroups, and completeness of follow-up. The purpose of this article is to review these factors with primary emphasis on the statistical aspects.

Clinical trials often involve a variety of clinical and laboratory measures that are used as endpoints and sometimes two of these measures are combined in one endpoint. When the individual components of such a combined endpoint are 'time to event' measurements, the analysis is straightforward if each of the components is measured frequently and regularly over time. However, the analysis of the combined endpoint is more difficult when one component of the endpoint is right censored and the other is interval censored. This paper describes a statistic, based on a rank ordering of events for such a combined measure. The power of the test statistic is explored.

Recent clinical trials of primary and secondary prevention of cardiovascular disease have demonstrated that lowering plasma cholesterol decreases the incidence of coronary heart disease in patients with elevated plasma cholesterol. However, it is not known whether patients with established coronary artery disease and normal plasma cholesterol can be benefited. Several previous prevention trials reviewed in this report found that patients who had plasma cholesterol levels at baseline in the upper portion of the eligibility range (e.g., greater than 240 mg/dl) received greater benefit from hypolipidemic diet or drug therapy than patients who had lower plasma cholesterol levels at baseline. The recent availability of drugs that are more potent and less prone to cause adverse reactions than previous regimens permits this important question to be addressed. The Cholesterol and Recurrent Events trial is testing whether pravastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, will decrease the sum of fatal coronary heart disease and nonfatal myocardial infarction (MI) in patients who have recovered from a MI and who have normal total cholesterol levels. Fatal cardiovascular disease and total mortality are important secondary end points. The trial is enrolling 4,000 men and women from 80 centers throughout North America, age 21 to 75 years, who have survived MI for 3 to 20 months, who have plasma total cholesterol less than 240 mg/dl (6.2 mmol/liter) and low-density cholesterol of 115 to 174 mg/dl (3.0 to 4.5 mmol/liter), and who are representative of the general population of patients with MI. Patients are randomized to either active or inactive drug therapy. Active therapy consists of pravastatin, 40 mg/day, designed to achieve an average decrease in low-density lipoprotein cholesterol of approximately 30%, and an increase in high-density lipoprotein of 5%. The average duration of follow-up will be greater than or equal to 5 years. To protect against a lower than expected rate of recurrent events, the trial will be continued until a predetermined fixed number of coronary heart disease events occurs in the entire cohort so that the original sensitivity of the trial will be maintained.

The effect of dietary modification on continued blood pressure control after discontinuation of antihypertensive therapy has been studied. Participants who had been treated for 5 years in the Hypertension Detection and Follow-up Program were enrolled and randomly assigned to continue medication, discontinue medication with no dietary intervention, discontinue medication and reduce weight, discontinue medication and reduce sodium groups. Relapse of hypertension was slow, even without dietary modification. Both weight loss and sodium restriction slowed relapse. The severity of the hypertension and the number of drugs required for hypertension control had a marked effect on the rate of relapse. Relapse was slowest in the participants who had attained the lowest blood pressure on therapy.

One method for determining cause of death in a clinical trial is to use standard nosological coding of death certificates. In order to look at an alternative approach, the Hypertension Detection and Follow-up Program (HDFP) assessed underlying causes of death through the use of three physicians. These physicians were trained and standardized in the proper recording of cause of death on death certificates. Each physician completed a death certificate for each of the 768 deaths in the HDFP, utilizing all available information, including HDFP records, plus any additional hospital and autopsy records. The new standardized death certificates were then transmitted to a panel of three nosologists who coded the cause of death. The physician preparation procedure was compared with a procedure wherein a panel of three nosologists coded the original death certificate for the underlying cause of death. The procedures agreed on the three-digit International Classification of Disease, Adapted code in 60.1% of the cases. The agreement rate improved to 72.5% when disease codes were collapsed into broad disease categories utilized in the HDFP.

This paper presents a computer program for estimating transition probabilities between states in a stochastic model for an illness-death process which incorporates time-dependent covariates. Parameters are estimated by the method of maximum likelihood using the Newton-Raphson iterative procedure. The program provides the standard normal deviate statistics as well as the value of the maximum of the likelihood function which can be used on repeated applications to test hypotheses concerning coefficients associated with covariates. Although this program is demonstrated by using a model with two 'illness' states and two 'death' states, it is also suitable for analyzing data with models involving fewer states, such as the analysis of survival time with covariates assuming a proportional hazard model.

The Systolic Hypertension in the Elderly Program (SHEP) is a randomized double-blind placebo-controlled trial to determine if antihypertensive treatment of isolated systolic hypertension (ISH) [systolic blood pressure (SBP) greater than or equal to 160 mmHg, diastolic blood pressure (DBP) less than 90 mmHg] reduces the 5 year incidence of fatal and nonfatal stroke. Between March 1, 1985 and January 15, 1988, 4736 persons (target 4800) with ISH, age 60 years and over, were enrolled. Potential participants met blood pressure (BP) and age criteria. Those on antihypertensive medication prior to enrollment without documented diastolic hypertension had their medication tapered and discontinued, and then met BP criteria (33% of cohort). Stepped-care therapy with chlorthalidone and atenolol (alternative, reserpine) or matching placebos was initiated as first and second steps. At baseline the trial population was 43.1% male, 56.9% female; 13.9% black, 86.1% non-black. Also, the mean age was 71.6 years; the mean SBP was 170.3 mmHg and the mean DBP was 76.6 mmHg; 59.8% had codeable resting electrocardiographic abnormalities. The trial is now in follow-up phase with scheduled termination in 1991.

The effects of propranolol on lipids and lipoproteins were investigated in survivors of a recent myocardial infarction who were enrolled in the double-blind Beta-Blocker Heart Attack Trial. Nonfasting serum samples were obtained in more than 2800 patients assigned randomly to either propranolol or placebo. The propranolol-treated group had high-density lipoprotein cholesterol levels 3-4 mg/dl less and triglyceride concentrations 30-40 mg/dl higher than the placebo group. These effects occurred in men and women in all age categories.

This paper presents a computer program for estimating transition rates between states in a two-compartment Markov process, where the rates are functions of covariates. Parameters are estimated by the method of maximum likelihood using the Newton-Raphson iterative procedure. The program provides statistics for testing hypotheses concerning regression coefficients and calculates observed versus expected values in order to assess the fit of the model to the data.

The Trial of Antihypertensive Interventions and Management was a multicenter randomized, placebo-controlled trial designed to assess the effectiveness of various combinations of pharmacologic and dietary interventions in the treatment of mild hypertension (diastolic blood pressure 90-100 mmHg). The primary outcome was blood pressure change between baseline and 6 months. The study consisted of a 3 X 3 factorial design wherein participants were randomly allocated to nine drug-diet treatment groups. Drugs included placebo, diuretic, and beta-blocker. Diets were usual, weight loss, and low sodium/high potassium. The basic strategy was to address clinical questions of interest by comparing mean blood pressure changes of selected drug-diet combinations. This paper describes the study including experimental design, sample size considerations, statistical analysis, organizational structure, and baseline findings.

The Hypertension Detection and Follow-up Program (HDFP) findings demonstrate the predictive value of baseline systolic blood pressure (SBP) and of pulse pressure (PB) in five-year mortality from all causes. Grouping participants into four SBP strata revealed an approximately two-fold increase in age-adjusted mortality rate from SBP stratum I to SBP stratum IV. This effect remained after the contributions of other risk factors were controlled by multivariate analysis. In contrast, baseline diastolic blood pressure (DBP) had little demonstrable effect on mortality in this particular population. The predictive power of pulse pressure was similar to that of SBP. The group mean SBP of every stratum fell progressively during the trial, the change being of greater magnitude in the stepped care (SC) group than in the referred care (RC) group. Also, the reduction in all-cause mortality associated with SC treatment was observed at all levels of baseline SBP. An analysis using life table regression with SBP as a time-dependent variable showed that the postrandomization reduction in SBP was a significant factor in reducing mortality. Similarly, reduced DBP was also contributory. Prospective studies are required to answer definitively the question of the efficacy of treatment of systolic hypertension. Nevertheless, the present analysis of the HDFP data, despite design limitations, supports the advisability of reducing elevated systolic blood pressure.