The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT): clinical center recruitment experience.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized clinical outcome trial of antihypertensive and lipid-lowering therapy in a diverse population (including substantial numbers of women and minorities) of 42,419 high-risk hypertensives aged > or = 55 years with a planned mean follow-up of 6 years. In this paper, we describe our experience in the identification, recruitment, and selection of clinical centers for this large simple trial capable of meeting the recruitment goals outlined for ALLHAT, and we highlight factors associated with clinical center performance. Over 135,000 recruitment brochures were mailed to physicians. Requests for information and application packets were received from 9351 (6.8%) interested investigators. A total of 1053 completed applications were received and 909 sites (86%) were eventually approved to join the trial. Of the approved sites, 278 either later declined participation or were never activated, and 8 were closed within a year for lack of enrollment. The final 623 randomizing centers exceeded the trial's recruitment goal to enroll at least 40,000 participants into the trial, although the recruitment period was extended 1.5 years longer than planned. Fewer than a quarter of the sites (22.6%) were recruited from academic medical centers or Department of Veterans Affairs Medical Centers. More than half of the sites (54.7%) were private solo or group practices, which contributed 53% of randomized participants. Community health centers comprised about 8% of the ALLHAT sites and 2.9% were part of health maintenance organizations. More than 22% of the principal investigators reported that they had no previous clinical research experience. In summary, ALLHAT was successful in recruiting a diverse group of clinical centers to achieve its patient recruitment goals.

Operational aspects of terminating the doxazosin arm of The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized, practice-based trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI). The double-blind, active-controlled component of ALLHAT was designed to determine whether the rate of the primary outcome-a composite of fatal coronary heart disease and nonfatal myocardial infarction-differs between diuretic (chlorthalidone) treatment and each of three other classes of antihypertensive drugs: a calcium antagonist (amlodipine), an angiotensin-converting enzyme inhibitor (lisinopril), and an alpha-adrenergic blocker (doxazosin) in high-risk hypertensive persons ages 55 years and older. In addition, 10,377 ALLHAT participants with mild to moderate hypercholesterolemia were also enrolled in a randomized, open-label trial designed to determine whether lowering serum LDL cholesterol with an HMG CoA reductase inhibitor (pravastatin) will reduce all-cause mortality as compared to a control group receiving "usual care." In January 2000, an independent data review committee recommended discontinuing the doxazosin treatment arm. The NHLBI director promptly accepted the recommendation. This article discusses the steps involved in the orderly closeout of one arm of ALLHAT and the dissemination of trial results. These steps included provisional preparations; the actual decision process; establishing a timetable; forming a transition committee; preparing materials and instructions; informing 65 trial officers and coordinators, 628 active clinics and satellite locations, 313 institutional review boards, over 42,000 patients, and the general public; reporting detailed trial results; and monitoring the closeout process. Control Clin Trials 2001;22:29-41

Ongoing and planned clinical trials of anti-arrhythmic drugs: an update.

Anti-arrhythmic drug therapy is frequently used for the control of ventricular arrhythmias in the setting of heart disease. These agents have been used in many randomised clinical trials in an attempt to demonstrate improved survival. However, most studies have been disappointing, showing little or no improvement in survival, and, in some cases, deterioration. This report reviews ongoing clinical trials designed to evaluate survival in specific patient populations.

The explosion of morbidity and mortality trials in hypertension.

The highlights of each generation of hypertension trials have been varied, but interrelated. The initial hypertension trials focused on middle-aged hypertensive individuals and later on the elderly, with emphasis on diastolic blood pressure and subsequently on systolic blood pressure. Past generations of trials elucidated whether and whom to treat. The current explosion of morbidity and mortality trials in hypertension largely seeks to learn what drugs should be used and to delineate what blood pressure goals should be targeted.

Use of the factorial design and quadratic response surface models to evaluate the fosinopril and hydrochlorothiazide combination therapy in hypertension.

The combination of angiotensin converting enzyme (ACE) inhibitor and thiazide diuretic has advantages over monotherapy for the treatment of hypertension. Previous study designs have often been inadequate to demonstrate the details of interactions between these antihypertensive agents. This study used a modified 4 x 4 factorial randomized, double-blind, placebo-controlled, parallel group design to study the efficacy of 17 different doses of fosinopril (Fos), a phosphinic acid derived ACE inhibitor, and hydrochlorothiazide (HCTZ) in 550 patients with mild to moderate hypertension. Data from these variables were fit to quadratic response surface models (QRSM) using polynomial functions in the doses of the two components. Using QRSM, seated systolic (SeSBP) and diastolic blood pressure (SeDBP) responses at 8 weeks were predicted for actual doses and interpolated for intermediate doses not studied. Fos and HCTZ alone and in combination produced a dose-related reduction in SeSBP and SeDBP. Using 10 mg Fos + 12.5 mg HCTZ reduced the adjusted mean SeDBP 6.3 mm Hg and 20 mg Fos + 12.5 mg HCTZ lowered the same measure 9.1 mm Hg. Coadministration of Fos and HCTZ produced an additive antihypertensive effect. This study of combination agents for hypertension using a factorial design with QRSM accurately predicts dose responses and is a valuable clinical trial methodology.