Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial.

AIMS/OBJECTIVE: Conflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and extra-skeletal effects of vitamin D supported the need for a definitive trial. The Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) trial aimed to assess the effects of TZDs (rosiglitazone and pioglitazone) on cardiovascular outcomes and the effects of vitamin D (cholecalciferol) on cancers and mortality. METHODS: A large multicentre 3 × 2 factorial double-blind placebo-controlled randomised trial recruited from outpatient primary care and specialty clinics in 33 countries. From June 2009 to July 2010, 1,332 people with type 2 diabetes and other cardiovascular risk factors aged ≥ 50 years whose HbA(1c) was 6.5-9.5% (48-80 mmol/mol) when using two or fewer glucose-lowering drugs were randomised by a central computer system to placebo (n = 541), rosiglitazone 4-8 mg/day (n = 399) or pioglitazone 30-45 mg/day (n = 392); 1,221 participants were randomised to placebo (n = 614) or vitamin D 1,000 IU/day (n = 607). Participants and all study personnel were blind to treatment allocation. The primary outcome for the TZD arm was the composite of myocardial infarction, stroke or cardiovascular death, and for the vitamin D arm it was cancer or all-cause death. All randomised participants were included in the primary analysis. RESULTS: From the study design, 16,000 people were to be followed for approximately 5.5 years. However, the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data. In the TZD arm, the cardiovascular outcome occurred in five participants (0.9%) in the placebo groups and three participants (0.4%) in the TZD groups (two allocated to pioglitazone, one to rosiglitazone). In the vitamin D arm, the primary outcome occurred in three participants (0.5%) in the placebo group and in two participants (0.3%) receiving vitamin D. Adverse events were comparable in all groups. CONCLUSIONS/INTERPRETATION: Uncertainty persists regarding the clinically relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial.

The combination oral and nutritional treatment of late-onset diabetes mellitus (CONTROL DM) trial results.

OBJECTIVE: To examine the effect of short-term improvements in glycaemic control on brachial artery endothelial function as a marker of cardiovascular health. METHODS: Persons with Type 2 diabetes who were poorly controlled on oral therapy were randomly assigned to monotherapy with repaglinide or combination therapy with repaglinide plus metformin. Brachial artery flow-mediated vasodilation was assessed by ultrasonography at randomization and following 16 weeks of therapy. The primary outcome was change in brachial artery endothelial function from baseline. Comparison of randomized groups was a secondary aim. RESULTS: Eighty-six participants were randomized, and 83 were followed to study completion. Post occlusion brachial artery vasodilation was 3.74% at baseline and 3.82% following 16 weeks of therapy (P = 0.77). The treatment effect was 0.08% (95% CI: -0.48%, 0.64%). No difference was seen between treatment groups (P = 0.69). Overall, A1C was reduced from 8.3% to 7.0%, with a greater reduction in the combination therapy group (from 8.4% to 6.7%) than in the monotherapy group (from 8.3% to 7.3%, p for difference between groups = 0.01). Statistically significant reductions were observed in fasting glucose, and plasminogen activator inhibitor-1. Statistically significant increases were observed for fasting insulin, uric acid, weight and BMI. CONCLUSIONS: Brachial artery endothelial function was not influenced by short-term improvements in glycaemic control. The CONTROL DM group was successful in lowering A1C. Future research should explore more intensive and longer-lasting improvements in glycaemic control on endothelial function. Some data previously published in abstract form (Diabetes 2001; 50 (Suppl. 2): A217).

The hemostatic effects of warfarin titration in post CABG patients in comparison to placebo treatment.

BACKGROUND: Since coronary artery bypass graft patients remain at risk of coronary artery and bypass graft occlusion after successful surgery, adjunct treatment regimens are under investigation. In a study of the patients of the multicenter Post Coronary Artery Bypass Graft (Post CABG) Trial, 1 mg warfarin was found to have no important effect on coagulation parameters. STUDY DESIGN: The effects of 1, 2 and 3 mg warfarin were evaluated at six-week intervals in 20 Post CABG Trial patients receiving titrated dose increases in comparison to 20 patients of similar age, gender and time from CABG treated with placebo. RESULTS: International normalized ratio (INR) values increased with warfarin dose increments for 1, 2, and 3 mg, respectively (0.95+/-0.16, 1.08+/-0.19, and 1.34+/-0.39) and in comparison to placebo treated patients (dosextreatment p<0.001). Factor VII coagulant activity decreased with warfarin titration (1 mg, 119.0+/-18.3 %; 2 mg, 100.6+/-32.8 %; 3 mg, 95.0+/-27.8 %) and in comparison to placebo (dosextreatment p=0.008). Levels of prothrombin fragment F1.2, tissue plasminogen activator, fibrinogen and von Willebrand factor were unchanged with warfarin dose increments and in comparison to placebo. CONCLUSIONS: At doses up to 3 mg, warfarin acts on the INR through a reduction of factor VII with no effect on the fibrinolytic system, fibrinogen or von Willebrand factor. At these doses F1.2 did not document reduced coagulation activity. The observations of this study were consistent with the decision in the Post CABG Trial to increase the warfarin dose above 1 mg to achieve a distinct effect of warfarin that was less than full anticoagulation.

Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke: the Systolic Hypertension in the Elderly Program (SHEP).

CONTEXT: The Systolic Hypertension in the Elderly Program (SHEP) demonstrated that treating isolated systolic hypertension in older patients decreased incidence of total stroke, but whether all types of stroke were reduced was not evaluated. OBJECTIVE: To investigate antihypertensive drug treatment effects on incidence of stroke by type and subtype, timing of strokes, case-fatality rates, stroke residual effects, and relationship of attained systolic blood pressure to stroke incidence. DESIGN: The SHEP study, a randomized, double-blind, placebo-controlled trial began March 1, 1985, and had an average follow-up of 4.5 years. SETTING AND PARTICIPANTS: A total of 4736 men and women aged 60 years or older with isolated systolic hypertension at 16 clinical centers in the United States. INTERVENTIONS: Patients were randomly assigned to receive treatment with 12.5 mg/d of chlorthalidone (step 1); either 25 mg/d of atenolol or 0.05 mg/d of reserpine (step 2) could be added (n = 2365); or placebo (n = 2371). MAIN OUTCOME MEASURES: Occurrence, type and subtype, and timing of first strokes and stroke fatalities; and change in stroke incidence for participants (whether in active treatment or placebo groups) reaching study-specific systolic blood pressure goal (decrease of at least 20 mm Hg from baseline to below 160 mm Hg) compared with participants not reaching goal. RESULTS: A total of 85 and 132 participants in the active treatment and placebo groups, respectively, had ischemic strokes (adjusted relative risk [RR], 0.63; 95% confidence interval [CI], 0.48-0.82); 9 and 19 had hemorrhagic strokes (adjusted RR, 0.46; 95% CI, 0.21-1.02); and 9 and 8 had strokes of unknown type (adjusted RR, 1.05; 95% CI, 0.40-2. 73), respectively. Four subtypes of ischemic stroke were observed in active treatment and placebo group participants, respectively, as follows: for lacunar, n = 23 and n = 43 (adjusted RR, 0.53; 95% CI, 0.32-0.88); for embolic, n = 9 and n = 16 (adjusted RR, 0.56; 95% CI, 0.25-1.27); for atherosclerotic, n = 13 and n = 13 (adjusted RR, 0. 99; 95% CI, 0.46-2.15); and for unknown subtype, n = 40 and n = 60 (adjusted RR, 0.64; 95% CI, 0.43-0.96). Treatment effect was observed within 1 year for hemorrhagic strokes but was not seen until the second year for ischemic strokes. Stroke incidence significantly decreased in participants attaining study-specific systolic blood pressure goals. CONCLUSIONS: In this study, antihypertensive drug treatment reduced the incidence of both hemorrhagic and ischemic (including lacunar) strokes. Reduction in stroke incidence occurred when specific systolic blood pressure goals were attained. JAMA. 2000;284:465-471

Hemostatic effects of 1 mg daily warfarin on post CABG patients. Post CABG Studies Investigators.

Although coronary bypass graft surgery has increased the survival and quality of life of many individuals, patients remain at risk of restenosis and thrombotic occlusion of the coronary arteries and bypass grafts. In the screening period for participation in the multicenter Post Coronary Artery Bypass Graft (Post CABG) trial, the effects of 1 mg daily warfarin were evaluated using paired patient samples collected prior to and after at least 21 days of treatment. In stable patients (n = 40; 39 males 1 female; 51-74 years old) who previously had undergone coronary artery revascularization (1-10 years), no alterations in prothrombin time, international normalized ratio (INR), prothrombin fragment 1.2, or the hemostatic risk factors factor VII antigen and coagulant activity, von Willebrand's factor, fibrinogen, tPA, or PAI-1 were associated with the 1 mg daily warfarin treatment. The observations reported here supported the Post CABG Studies Steering Committee decision to treat patients with 1-4 mg warfarin daily adjusted to achieve INRs not to exceed 2. 0 consistent with low-intensity therapy.

Mass mailing and staff experience in a total recruitment program for a clinical trial: the SHEP experience. Systolic Hypertension in the Elderly Program. Cooperative Research Group.

The Systolic Hypertension in the Elderly Program (SHEP) staff contacted 447,921 screenees, of whom 11,919 (2.7%) were originally eligible and 4,736 (1.1%) maintained eligibility and were randomized. The total number of participants enrolled at the 16 clinical centers ranged from 133 to 559. The low yield of screenees to randomizations resulted from the study design, not from low levels of agreement to participate, and required the employment of a variety of recruitment strategies in a prudent overall plan. SHEP was one of the first clinical trials to use mass mailing as a primary strategy of recruitment. The study used mailing lists from seven generic sources. More than 3.4 million letters of invitation were mailed; they yielded an overall response rate of 4.3%. Motor vehicle and voter registration lists provided the greatest numbers of names. Mailings to members of health maintenance organizations (HMOs) and registrants of the Health Care Finance Administration (HCFA) provided the greatest response rates. Considerable variability in response rates existed among clinical centers using generically similar mailing lists. Generally, the number of hours spent on recruitment showed a positive, but not statistically significant, association with randomization yields. The recruitment yield was statistically significantly higher in clinics with experienced recruitment coordinators than in clinics with inexperienced ones (p = 0.0008). From these findings we conclude that mass mailing is an important strategy in an overall recruitment program, that the involvement of experienced recruitment staff is important, and that although the total time spent by staff on recruitment may also improve results, it matters less than the staff's level of recruiting experience.

Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: The Systolic Hypertension in the Elderly Program. SHEP Cooperative Research Group.

BACKGROUND: Previous studies often of short duration have raised concerns that antihypertensive therapy with diuretics and beta-blockers adversely alters levels of other cardiovascular disease risk factors. METHODS: The Systolic Hypertension in the Elderly Program was a community-based, multicenter, randomized, double-blind, placebo-controlled clinical trial of treatment of isolated systolic hypertension in men and women aged 60 years and older. This retrospective analysis evaluated development of diabetes mellitus in all 4736 participants in the Systolic Hypertension in the Elderly Program, including changes in serum chemistry test results in a subgroup for 3 years. Patients were randomized to receive placebo or treatment with active drugs, with the dose increased in stepwise fashion if blood pressure control goals were not attained: step 1, 12.5 mg of chlorthalidone or 25.0 mg of chlorthalidone; and step 2, the addition of 25 mg of atenolol or 50 mg of atenolol or reserpine or matching placebo. RESULTS: After 3 years, the active treatment group had a 13/4 mm Hg greater reduction in systolic and diastolic blood pressure than the placebo group (both groups, P<.001). New cases of diabetes were reported by 8.6% of the participants in the active treatment group and 7.5% of the participants in the placebo group (P=.25). Small effects of active treatment compared with placebo were observed with fasting levels of glucose (+0.20 mmol/L [+3.6 mg/dL]; P<.01), total cholesterol (+0.09 mmol/L [+3.5 mg/dL]; P<.01), high-density lipoprotein cholesterol (-0.02 mmol/L [-0.77 mg/dL]; P<.01) and creatinine (+2.8 micromol/L [+0.03 mg/dL]; P<.001). Larger effects were seen with fasting levels of triglycerides (+0.9 mmol/L [+17 mg/dL]; P<.001), uric acid (+35 micromol/L [+.06 mg/dL]; P<.001), and potassium (-0.3 mmol/L; P<.001). No evidence was found for a subgroup at higher risk of risk factor changes with active treatment. CONCLUSIONS: Antihypertensive therapy with low-dose chlorthalidone (supplemented if necessary) for isolated systolic hypertension lowers blood pressure and its cardiovascular disease complications and has relatively mild effects on other cardiovascular disease risk factor levels.

Recruitment for controlled clinical trials: literature summary and annotated bibliography.

This article is a literature summary and annotated bibliography of research on recruitment for controlled clinical trials published through 1995. It extends and revises a similar review published in this journal a decade ago. The current commentary focuses on intervening developments in recruitment, including diverse populations, HIV trials, primary prevention trials, recruitment strategies, overall planning and management, patient and physician attitudes, adherence, generalizability, and cost. Profound barriers may exist in the recruitment of diverse populations, involving language, cultural factors, beliefs about medical research, and the appropriateness of available protocols. Extensive literature exists on patient and physician barriers to participation. Trials in HIV-infected or AIDs-diagnosed individuals introduce special considerations, including issues of confidentiality, parallel track design, and populations difficult to define and track. Recruitment strategies such as patient registries, occupational screening, direct mail, and the media are now prominent in the literature. Successful planning and management of an overall recruitment plan include piloting strategies, monitoring recruitment by data tracking systems, and hiring quality staff. Generalizability of study results is influenced by the characteristics of participants and by their adherence to study protocol. With increasingly limited funding to conduct clinical trials, efforts to quantify and reduce recruitment costs are being made. While over 4000 titles were identified, primarily by MEDLINE literature search, the articles summarized emphasize data-supported and -confirmed conclusions, and broad coverage of disease areas. We annotate here 91 outstanding articles useful for formulation of overall recruitment approaches in clinical trials.

Prognostic significance of plasma norepinephrine in patients with asymptomatic left ventricular dysfunction. SOLVD Investigators.

BACKGROUND: Elevated plasma neurohormonal levels are associated with increased mortality rates in patients with symptomatic heart failure. A previous Studies of Left Ventricular Dysfunction (SOLVD) trial suggested that neurohumoral activation precedes the development of symptoms as demonstrated by increased neurohormonal levels in patients with asymptomatic left ventricular dysfunction. However, the significance of this early neurohumoral activation is unclear. The goals of this study were to determine the prognostic significance of the plasma concentrations of plasma norepinephrine (PNE) and atrial natriuretic peptide (ANP) and the renin activity (PRA) in patients with asymptomatic left ventricular dysfunction. METHODS AND RESULTS: PNE and PRA were measured before randomization in 514 patients with left ventricular ejection fractions < or = 35% who did not require treatment for congestive heart failure and were enrolled in the SOLVD Prevention Trial. Plasma ANP levels were measured in a subset of 241 patients owing to study design. Using the Cox proportional hazards model that included left ventricular ejection fraction, New York Heart Association functional class, age, sex, treatment assignment to placebo or enalapril, and cause of heart failure, we examined whether these neurohormones predicted all-cause mortality, cardiovascular mortality, hospitalization for heart failure, development of heart failure, or development of ischemic events (myocardial infarction or unstable angina). PNE was the strongest predictor of clinical events in this patient population. PNE levels above the median of 393 pg/mL were associated with a relative risk of 2.59 (P = .002) for all-cause mortality, 2.55 (P = .003) for cardiovascular mortality, 2.55 (P = .005) for hospitalization for heart failure, 1.88 (P = .002) for development of heart failure, 1.92 (P = .001) for ischemic events, and 2.59 (P = .005) for myocardial infarction. PNE remained the most powerful predictor for all-cause mortality and ischemic events when the analysis included only the patients with histories of ischemic left ventricular dysfunction. The increases in other neurohormonal levels were not useful in predicting the subsequent development of clinical events. CONCLUSIONS: Increased PNE levels in patients with asymptomatic left ventricular dysfunction appear to predict all-cause and cardiovascular mortalities and development of clinical events related to the onset of heart failure or acute ischemic syndromes. Thus, measurement of PNE may be a possible early marker for assessment of disease progression in patients with left ventricular dysfunction, and modulating the release or effect of PNE may lead to improved prognosis and/or a reduction in morbidity.

Results of the primary outcome measure and clinical events from the Asymptomatic Carotid Artery Progression Study.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have proven to be more effective in reducing levels of low density lipoprotein (LDL) cholesterol and to be better tolerated than other lipid-lowering compounds. Most of the trials evaluating the effects of these new agents on progression of atherosclerosis have not included individuals asymptomatic for cardiovascular disease and who have LDL cholesterol levels at or below the limits established by the National Cholesterol Education Program for initiating treatment. The Asymptomatic Carotid Artery Progression Study (ACAPS) tested the effect of the HMG-CoA reductase inhibitor, lovastatin, on early-stage carotid atherosclerosis (as detected by B-mode ultrasonography) in 919 asymptomatic men and women, 40-79 years of age, who had LDL cholesterol levels between the 60th and 90th percentiles. Participants randomized into this double-blind, placebo-controlled, factorially designed study received lovastatin (20-40 mg/day) or lovastatin-placebo and warfarin (1 mg/day), or warfarin-placebo over a 3-year period. The progression of the mean maximum intimal-medial thickness (IMT) over 12 walls of both carotid arteries represented the primary outcome. Lovastatin treatment was associated with a reduction in progression of mean maximum IMT (p < 0.001). Levels of LDL cholesterol were reduced by 28% (43.5 mg/dl [11.25 mmol/liter]) in the lovastatin group within 6 months (p < 0.0001) and remained stable throughout the follow-up period, whereas these levels remained essentially unchanged in the lovastatin-placebo group. The difference in incidence of major cardiovascular events for patients in the lovastatin-placebo group was significant: 5 versus 14, respectively (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Tolerability of enalapril initiation by patients with left ventricular dysfunction: results of the medication challenge phase of the Studies of Left Ventricular Dysfunction.

Although converting-enzyme inhibitors are useful for the treatment of congestive heart failure (CHF), there are concerns about adverse reactions especially on initiation of therapy. In the Studies of Left Ventricular Dysfunction, enalapril, 2.5 mg twice per day was given on an open-label outpatient basis for 7 days (mean 6.1, range 2 to 7, and median 7) as a prerandomization drug challenge to 7487 patients with left ventricular dysfunction (ejection fraction < or = 0.35). Four hundred forty-four (5.93%) patients reported side effects, including symptoms attributed to hypotension (in 166 patients [2.2%]). The majority (346 [77.9%] of 444 and 129 [77.7%] of 166 with symptoms attributed to hypotension) of patients who reported side effects were willing to participate in the study and to continue receiving enalapril. Thus only 98 (1.3%) of 7487 patients (0.5% because of symptoms attributed to hypotension) were not willing to continue because of side effects. Women and patients of CHF class III or IV were more likely to report side effects. In conclusion, enalapril is well tolerated by patients with left ventricular dysfunction; treatment can be initiated on an outpatient basis in the majority of patients.

Plasma lipid effects of three common vegetable oils in reduced-fat diets of free-living adults.

We compared plasma lipid changes due to the polyunsaturated fatty acids (PUFAs) in partially hydrogenated soybean oil, corn oil, and sunflower oil fed in reduced-fat diets (22-26% of total energy). Each oil was the dominant fat in isoenergetic diets of centrally prepared foods consumed by 26 male and 35 female normolipidemic, free-living individuals. Test diets were consumed double-blind, alternating with self-selected diets for 5 wk each. The ranges of proportions of total fat were: 4.7-9.7% polyunsaturated fat, 8.9-14.2% monounsaturated fat and 5.4-7.4% saturated fat. All three diets lowered (P < 0.0001) total cholesterol (11%), LDL cholesterol (13%), and HDL cholesterol (10%), without triglyceride changes. We conclude that PUFAs at approximately 6% of total energy result in clinically relevant plasma cholesterol-lowering and that the proportion of polyunsaturated fat must be an important consideration when planning reduced-fat, reduced-saturated-fat diets.

Conclusions and implications of the systolic hypertension in the elderly program.

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.

Statistical considerations in monitoring the Systolic Hypertension in the Elderly Program (SHEP).

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.

Methodological issues facing studies of atherosclerotic change.

BACKGROUND: The association between coronary heart disease and lesions of the coronary arteries has led to investigations of different interventions on atherosclerotic change. Currently, B-mode ultrasound of the peripheral arterial vessels, rather than arteriography of the coronary arteries, provides the most accurate evaluation of atherosclerotic disease extent in the patient. METHODS AND RESULTS: When measuring the effect of risk factor modification on atherosclerotic change, it is important to select appropriate methods and end points for quantifying disease and evaluating subsequent change. Measurements must be valid, precise, and reliable and require appropriate a priori definitions of end points and their change. Consistent methodology within studies is crucial. Multiple measurements and data reduction methods can increase the efficiency of comparisons and merit careful consideration. Missing data arising from nonvisualization of sites complicate analyses. Identifying both covariates of atherosclerotic change and possible confounding interventions require monitoring biochemical, physiological, and/or clinical variables and making inferences from these. CONCLUSIONS: To strengthen the rationale for use of B-mode ultrasonography in assessing the natural history of atherosclerosis, four methodological issues must be addressed: evaluation of primary end points using composite and/or individual measurements of atherosclerotic assessment from the carotid arteries, evaluation of new methodology that may allow assessment of the anatomy of specific lesions and/or their potential for rupture, development of methods making complementary use of both angiographic measurements of lumen diameter and ultrasound assessment of the arterial wall, and concrete demonstration of a direct link between increasing intimal-medial thickness and subsequent clinical events. The use of a continuous variable (intimal-medial thickness) in ultrasound studies offers cost/benefit advantages; this methodology continues to evolve.

Recruitment strategies in the studies of left ventricular dysfunction (SOLVD): strategies for screening and enrollment in two concurrent but separate trials. The SOLVD Investigators.

SOLVD was a double-masked, placebo-controlled trial whose initial sample size goal was to randomize 6100 participants into two concurrent trials: treatment and prevention. The objective was to determine if participants with severe left ventricular dysfunction (left ventricular ejection fraction < or = 35%, with congestive heart failure (2569) and participants without overt heart failure (4228) had improved survival with angiotensin-converting enzyme inhibitors. Participants were identified from cardiac catheterization, echocardiography and radionuclide laboratories, and inpatient units. The treatment trial recruitment goal was attained 13 months ahead of schedule while recruitment for the prevention trial was extended 11 months beyond the scheduled time. Recruitment of relatively asymptomatic participants with a low ejection fraction in a hospital-based trial necessitated novel strategies. Coronary care units and clinics for follow-up of acute cardiac conditions, not typically employed in studies of chronic diseases, were useful recruitment sources. Different approaches to encourage participation also needed to be employed. Expanding selected entry criteria was evaluated and the success of varying strategies was reviewed. The authors recommend tailoring of strategies to the target population, staffing flexibility, principal investigator involvement, and broad entry criteria in recruitment activities.

Effectiveness of low-dose colestipol therapy in patients with moderate hypercholesterolemia.

Recommended doses of bile-acid binding resins have an established hypocholesterolemic effect, but data on responses to low doses, especially in women and subjects with moderate hypercholesterolemia, are sparse. A double-blind, placebo-controlled, randomized trial of 3 low doses of colestipol hydrochloride was conducted in women and men with moderate hypercholesterolemia. Men and women with plasma low-density lipoprotein (LDL) cholesterol concentrations greater than 4 mmol/liter (155 mg/dl) and triglyceride concentrations less than 2.82 mmol/liter (250 mg/dl) were recruited for the study. Eligible patients (54 women and 98 men) were placed on the American Heart Association step I diet 6 weeks before randomization. Participants were subsequently assigned to 1 of 4 drug treatment groups (placebo, and 5, 10 and 15 g/day of colestipol in 2 divided doses) for an additional 12 weeks. Of the 152 patients randomized, 141 completed all aspects of the study. For the treatment groups--placebo, and 5, 10 and 15 g of colestipol--LDL cholesterol reductions (mmol/liter) were observed respectively (n = 141): 0.10 +/- 0.49 (2.7%), 0.65 +/- 0.41 (16.3%), 0.98 +/- 0.36 (22.8%) and 1.17 +/- 0.47 (27.2%) (p less than 0.001). Similar changes were observed in total cholesterol and apolipoprotein B concentrations. The apolipoprotein B/LDL cholesterol ratio increased significantly with increasing colestipol dosage. Modest but insignificant changes in plasma triglyceride levels occurred, and high-density lipoprotein cholesterol levels remained unchanged. A dose of 5 g/day of colestipol achieved 51% of the LDL cholesterol reduction noted with 15 g/day. Low-dose colestipol therapy is effective in the treatment of patients with moderate hypercholesterolemia.(ABSTRACT TRUNCATED AT 250 WORDS)