Henry Black, ed.
606 pp. New York: Marcel Dekker; 2001. $225.00. ISBN 0-8247-02700
Large, randomized clinical trials of treatments with blood pressure–lowering drug regimens have a long history that is usually dated from the Veterans Administration (since renamed the Department of Veterans Affairs) (VA) Cooperative Study on Antihypertensive Drugs, which reported results from 1967–1972. This useful book collects in one 660-page volume a good part of that history, including an attempt (in the last 5 chapters) to give a flavor of ongoing activity. In all cases, the chapters are authored by ≥1 of the clinical and/or coordinating center leaders of the particular trial and thus often give insights into the thinking behind the design, conduct, and interpretation, which is otherwise not easily available. The chapters on completed trials also collect in 1 place the information from many separate publications on the methods and results of the trials; eg, upwards of 30 study reports are cited in the Hypertension Detection and Follow-up Program (HDFP) chapter.
The book’s organization is approximately chronological, which provides the reader who troubles to start at the beginning the special pleasure of (re)discovering many groundbreaking and still relevant features of the early trials. For example, in the VA trial a 3-drug combination was used as initial treatment in the active group (achieving a mean on-treatment blood pressure of 135/87 mm Hg), a prerandomization compliance run-in was used with a biomarker-containing placebo, and an “oversight committee” of scientists not involved in the trial was used to monitor interim data. The sequence of chapter presentation also leads to grouping of related studies: early trials in rather select populations (VA, high risk; Public Health Service, low risk), large trials in highly representative populations with diastolic (mostly “mild”) hypertension (HDFP and the first Australian and British Medical Research Council [BMRC] trials), and trials in elderly patients (European Working Party trial, second BMRC trial, first Swedish Trial in Old Patients [STOP-Hypertension], and Systolic Hypertension in the Elderly Program, with the confirmatory Systolic Hypertension in Europe Trial following a few chapters later). The book also includes chapters on 2 multicenter but moderate-sized trials (<1000 patients) designed to compare, for blood pressure lowering and other “intermediate” outcomes, representatives of 5 to 6 different drug classes, formally against placebo but with an intent to provide data for drug selection. These trials (the Treatment of Mild Hypertension Study and the VA Cooperative Study on Monotherapy) paved the way for the recent and ongoing, larger direct comparison trials noted below.
Except for the last 2 mentioned, the foregoing trials were specifically designed to test the benefits for clinical end-points of blood pressure lowering by comparing 1 arm (2 each in the BMRC trials) assigned to initial systematic drug treatment, with a control arm receiving a placebo or no systematic treatment. The book includes chapters from 2 other kinds of trial designs that elucidate this general clinical question. One of these is the Hypertension Optimal Treatment study, the largest trial designed to compare effects of treatment regimens specifically targeted at reaching different levels of diastolic blood pressure. The other consists of trials of drugs that lower blood pressure but were selected primarily based on other effects for evaluation in patients with various manifest diseases: coronary heart disease (myocardial infarction), the β-Blocker Heart Attack Trial; congestive heart failure or left ventricular dysfunction, the Studies of Left Ventricular Dysfunction and the Survival and Ventricular Enlargement trial; and diabetes mellitus, the Captopril Type 1 Diabetic Nephropathy trial. There are those that would argue against such trials conducted with both hypertensive and nonhypertensive patients in a volume such as this, but it is difficult to contest the judgment that at least some of the benefits seen are attributable to blood pressure effects, and trials of this sort are included in the World Health Organization-International Society of Hypertension (WHO-ISH) Blood Pressure Lowering Treatment Trialists Collaboration (see chapter 25).
Although a few traditional trials such as the Oslo Hypertension Trial did not get into the book, it is in the case of the latter group of trials that the issue of inclusion really becomes problematic, because there are many trials of β-blockers and converting-enzyme inhibitors in patients with cardiac or renal disease. This problem of selection considerations (oddly, not addressed in the preface) persists with regard to the half-dozen direct-comparison trials, of which there are also many more than those included (as chapter 25 makes clear). Arguably, most of those included have some special, even unique, features, such as a focus on patients >70 years of age (STOP-Hypertension-2), evaluation of a nondihydropyridine calcium antagonist (Controlled Onset Verapamil Investigation of Cardiovascular Endpoints, CONVINCE), inclusion of an α-blocker arm and focus on African Americans (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, ALLHAT), and selection of a population exclusively with left ventricular hypertrophy (Losartan Intervention for Endpoint Reduction in Hypertension, LIFE). However, one suspects that publication deadlines constituted a major driving factor in what was left out.
The book has some additional deficiencies. There is no chapter providing an historical and conceptual overview, and the brief preface confuses random selection and random allocation of a study population, does not present a rigorous rationale for clinical rather than merely surrogate endpoint trials, and omits the important role of retrospective meta-analysis of clinical trials. There was an error in the preparation of copy for publication that resulted in omission of half of the ALLHAT clinics in the acknowledgments. (A complete list of ALLHAT clinical sites may be obtained from Sara Pressel [email@example.com] at the ALLHAT Clinical Trials Center).
Nevertheless, the editor and authors have performed a very valuable service in collecting between 2 covers an immense amount of information about a scientific era that has provided the treatment of hypertension with one of the firmest bases of evidence in all of medicine.