Naltrexone in the treatment of alcohol dependence.

BACKGROUND: Although naltrexone, an opiate-receptor antagonist, has been approved by the Food and Drug Administration for the treatment of alcohol dependence, its efficacy is uncertain. METHODS: We conducted a multicenter, double-blind, placebo-controlled evaluation of naltrexone as an adjunct to standardized psychosocial treatment. We randomly assigned 627 veterans (almost all men) with chronic, severe alcohol dependence to 12 months of naltrexone (50 mg once daily), 3 months of naltrexone followed by 9 months of placebo, or 12 months of placebo. All patients were offered individual counseling and programs to improve their compliance with study medication and were encouraged to attend Alcoholics Anonymous meetings. RESULTS: There were 209 patients in each group; all had been sober for at least five days before randomization. At 13 weeks, we found no significant difference in the number of days to relapse between patients in the two naltrexone groups (mean, 72.3 days) and the placebo group (mean, 62.4 days; 95 percent confidence interval for the difference between groups, -3.0 to 22.8). At 52 weeks, there were no significant differences among the three groups in the percentage of days on which drinking occurred and the number of drinks per drinking day. CONCLUSIONS: Our findings do not support the use of naltrexone for the treatment of men with chronic, severe alcohol dependence.

Development for and results of the use of a gastroesophageal reflux disease activity index as an outcome variable in a clinical trial. VA Cooperative Study Group on Gastroesophageal Reflux Disease (GERD).

Due to the significant expense of obtaining frequent endoscopy and pH monitoring measures as outcome variables available for use in a multihospital clinical trial of gastroesophageal reflux disease, and the lack of a suitable inexpensive index of disease activity, evaluated for both reliability and validity, the study planning committee decided to develop an index of gastroesophageal reflux disease activity in a pilot study--to precede the clinical trial. In particular, the purpose of the pilot study was to find a reliable, valid, and inexpensive index of gastroesophageal reflux disease which could be obtained independently of the treating physician and used as an outcome variable in the clinical trial. This paper describes the pilot study and the statistical methodology used to derive and evaluate a gastroesophageal reflux disease activity index model. In addition, the results of the activity index's use in the subsequent clinical trial's longitudinal analyses are presented. Comparisons with the more expensive, and thus less frequently obtained, endoscopy and pH monitoring outcome variables are described.

Diagnostic inconsistencies in Barrett's esophagus. Department of Veterans Affairs Gastroesophageal Reflux Study Group.

BACKGROUND/AIMS: Few studies have compared the precision of various diagnostic tests used to determine the presence of Barrett's esophagus. The aim of this study was to compare the results of histological, endoscopic, and manometric tests for patients with Barrett's esophagus in two closely spaced examinations. METHODS: In a Veterans Administration Cooperative Study, 192 patients with complicated gastroesophageal reflux disease had esophageal manometry and endoscopy performed at baseline and after 6 weeks. At each examination, the endoscopist localized the most proximal level of Barrett's epithelium and the lower esophageal sphincter and obtained esophageal biopsy specimens. RESULTS: One hundred sixteen patients met the criteria for Barrett's esophagus on at least one of the two endoscopic examinations. Among patients with specialized columnar epithelium, 20% had specialized columnar epithelium found on only one of the two examinations. Although the mean lower esophageal sphincter level did not change, approximately 10% of patients had a change > or = 4 cm on endoscopy and manometry between examinations. This led to an apparent change in the diagnosis in 18% of patients with Barrett's esophagus. CONCLUSIONS: From one endoscopic examination to another, inconsistencies in the ability to detect specialized columnar epithelium are common. This may lead to substantial problems in establishing an accurate diagnosis of Barrett's esophagus.

Comparison of eligible randomized patients with two groups of ineligible patients: can the results of the VA Total Parenteral Nutrition clinical trial be generalized?

The recently reported VA Cooperative Study "A Randomized Clinical Trial of Total Parenteral Nutrition (TPN) in Malnourished Surgical Patients" randomized 395 pre-operative patients to TPN treatment or control. The study concluded that the use of perioperative TPN should be limited to the most severely malnourished patients. The study also followed 233 patients eligible for the study who refused to give informed consent for randomization (Eligible Refusers) as well as 1220 patients who were ineligible because they were not sufficiently malnourished (Index Group). Patients in the Index Group were determined to be significantly healthier than those in the two eligible groups of patients. Those in the Eligible Refuser group were shown to be slightly less malnourished than the Randomized Patients. The 395 patients randomized to the study (Randomized Patients) showed the highest rate of septic complications at 30 days and at 90 days (10% and 13% respectively) with rates for the Eligible Refusers slightly lower (8% and 9%) and Index Group rates still lower (4% and 4%). Nonseptic complication rates showed the same pattern (19% and 22% for the Randomized group, 12% and 12% for Eligible Refusers, and 10% and 10% for the Index Group). Because (a) the beneficial effect of TPN is attained only in severely malnourished patients, (b) there is increased risk of septic complications with TPN use in patients not severely malnourished, (c) Index Group patients, and presumably the population of patients from which they are drawn, are not severely malnourished, it follows that unless specifically indicated, TPN should not be used in nonseverely malnourished patients.

The "constant intake rate" assumption in interim recruitment goal methodology for multicenter clinical trials.

A primary concern of any multihospital clinical trial is the recruitment of a predetermined number of patients during a prespecified interval of time. In several recent papers a Poisson based model was used to estimate the time needed to recruit a predetermined number of patients and the probabilities of recruiting specified fractions of the sample during subintervals. The Poisson model requires the assumption that patients be recruited at a constant rate over the entire length of the interval. In this paper we test the adequacy of this model and assumption using patient intake data from nine multihospital VA clinical trials and propose an alternative Bayesian model.

White blood cell count and haematocrit as predictors of coronary recurrence after myocardial infarction.

Baseline white blood cell count (WCC) and haematocrit were examined in relation to recurrent coronary events and to all-cause mortality in 2026 persons enrolled in the first Persantin-Aspirin Reinfarction Study (PARIS-1) 2-60 months after myocardial infarction. WCC was strongly related to coronary recurrence (relative risk 3.5 for men with WCC greater than or equal to 9 X 10(9)/l vs men with WCC less than 5 X 10(9)/l) and total mortality (relative risk 2.6). No such relationships were found for haematocrit. WCC correlated also with cigarette-smoking, diuretic use, serum cholesterol and uric acid; however, the associations with coronary recurrence and total mortality persisted on multiple linear and logistic regression analysis including these variables and treatment group (p less than 0.001). WCC is therefore an easily-measured prognostic variable in survivors of myocardial infarction. Furthermore, we suggest that white blood cells may promote myocardial ischaemia by capillary plugging and/or release of toxic oxygen metabolites.