Problems in the conduct and analysis of randomized clinical trials. Are we getting the right answers to the wrong questions?

To achieve the goal of validity, the randomized clinical trial has emerged as the scientific "gold standard" for evaluating therapies in clinical medicine. Regardless of how well randomized clinical trials are designed, however, problems often occur during the conduct of the trials that give rise to methodologic challenges in the analysis of results. Primarily two types of problems, changes in intended treatment and the failure to ascertain the study outcomes, occur during the conduct of randomized clinical trials.

Problems of comorbidity in mortality after prostatectomy.

Objective: In recent studies of patients with benign prostatic hyperplasia (BPH), men undergoing transurethral resection of the prostate (TURP) had higher long-term mortality than men undergoing open prostatectomy. We tested the hypothesis that the higher mortality for patients undergoing TURP could have occurred if these patients were older and sicker at the time of surgery than patients undergoing open prostatectomy.

Design And Setting: Retrospective cohort study at Yale-New Haven (Conn) Hospital.

The use of beta-agonists and the risk of death and near death from asthma.

Background: Morbidity and mortality from asthma appear to be increasing, and it has been suggested that medications used to treat asthma are contributing to this trend. We investigated a possible association between death or near death from asthma and the regular use of beta 2-agonist bronchodilators.

Methods: Using linked health insurance data bases from Saskatchewan, Canada, we conducted a matched case-control study of subjects drawn from a cohort of 12,301 patients for whom asthma medications had been prescribed between 1978 and 1987.

Synthetic recombinant vaccine expressing influenza haemagglutinin epitope in Salmonella flagellin leads to partial protection in mice.

The influenza virus haemagglutinin epitope 91-108, which is a conserved amino acid sequence in all type A H3 strains, was expressed in Salmonella flagellin, to evaluate its potential as a vaccine. For that purpose, a synthetic oligonucleotide comprising 54 bases coding for the corresponding sequence was inserted into the plasmid pLS408 and transformed into Escherichia coli JM101. Colonies containing the recombinant plasmid were used to transform Salmonella typhimurium LB5000 and were then transduced to a flagellin negative 'live vaccine' aroA mutant of Salmonella dublin.

Clinical complexity and epidemiologic uncertainty in case-control research. Fenoterol and asthma management.

Two recent epidemiologic case-control studies suggested that fenoterol, a selective beta-adrenergic agonist, was associated with an increase in the risk of asthma death. The results of these studies were criticized because of methodologic problems in the choice and selection of control subjects; the different methods used to gather exposure data in cases and control subjects; and because of inadequate classification and adjustment for asthma severity. In response to this controversy, a new study is underway, the Saskatchewan Asthma Epidemiology Project.

Social and clinical features as predictors of outcome in outpatient alcohol withdrawal.

Objective: To identify patient features--both social and clinical--that may be associated with treatment failure in outpatient alcohol withdrawal.

Design: A prospective observational cohort study of patients who underwent outpatient management of the alcohol withdrawal syndrome.

Setting: Community hospital-based outpatient alcohol treatment program.

Zidovudine (AZT) for treatment of patients infected with human immunodeficiency virus type 1. An evaluation of effectiveness in clinical practice.

To learn about the patterns of use and the effectiveness of zidovudine therapy in clinical practice, we conducted an observational cohort study of 86 patients with human immunodeficiency virus type 1 infection. All patients were followed up for at least 6 months after starting zidovudine (AZT) therapy. Of the 86 patients, 78 (91%) initially received full-dosage zidovudine (1200 mg/d), and eight received a reduced dosage (600 mg/d).

A prognostic system for transient ischemia or minor stroke.

Objective: To build a prognostic system for patients with carotid transient ischemic attack or minor stroke.

Design: Inception cohort study with 2-year follow-up.

Setting: Urban community teaching hospital.

Clarifying confusion: the confusion assessment method. A new method for detection of delirium.

Objective: To develop and validate a new standardized confusion assessment method (CAM) that enables nonpsychiatric clinicians to detect delirium quickly in high-risk settings.

Design: Prospective validation study.

Setting: Conducted in general medicine wards and in an outpatient geriatric assessment center at Yale University (site 1) and in general medicine wards at the University of Chicago (site 2).

Developing improved observational methods for evaluating therapeutic effectiveness.

Therapeutic efficacy is often studied with observational surveys of patients whose treatments were selected nonexperimentally. The results of these surveys are distrusted because of the fear that biased results occur in the absence of experimental principles, particularly randomization. The purpose of the current study was to develop and validate improved observational study designs by incorporating many of the design principles and patient assembly procedures of the randomized trial.

Treatment adherence and risk of death after a myocardial infarction.

The relation of treatment adherence to mortality after a myocardial infarction was investigated among 2175 participants in the Beta Blocker Heart Attack Trial, which had data for measures of treatment adherence, clinical severity, and the psychological and social features that may influence post-infarction mortality. Overall, patients who did not adhere well to treatment regimen (ie, who took less than or equal to 75% of prescribed medication) were 2.6 times more likely than good adherers to die within a year of follow-up (95% confidence interval, 1.

Differences between women and men in survival after myocardial infarction. Biology or methodology?

To examine the impact of gender on survival after myocardial infarction, we performed a retrospective cohort study of 332 women and 790 men. Women who had a myocardial infarction were older and more often had hypertension, diabetes, previous heart failure, and impaired left ventricular function on admission. Cumulative 3-year mortality and in-hospital mortality rates were significantly higher in women than men, but mortality among hospital survivors was similar.

Does prophylaxis prevent postdental infective endocarditis? A controlled evaluation of protective efficacy.

Purpose: Despite the American Heart Association's (AHA) recommendations for antibiotic prophylaxis to prevent infective endocarditis, no controlled clinical evidence exists for the effectiveness of this intervention. The purpose of this case-control study was to determine whether antibiotic prophylaxis for a dental procedure reduces the risk of infective endocarditis in persons with high-risk cardiac lesions.

Patients And Methods: Cases consisted of eight subjects with high-risk lesions (six mitral, one aortic, one uncorrected tetralogy) whose first-time, native-valve infective endocarditis occurred within 12 weeks of a dental procedure and was diagnosed between 1980 and 1986.

Evidence against the association between alcohol use and ischemic stroke risk.

To examine the relationship between alcohol consumption and ischemic stroke risk, we used data from our case-control study of stroke risk. Eighty-nine patients admitted to the hospital with ischemic stroke documented by computed tomography of the head were matched to 178 controls. Alcohol use was defined by an estimate of customary use (heavy, moderate, light, or none).

New epidemiologic evidence confirming that bias does not explain the aspirin/Reye's syndrome association.

To determine the validity of the aspirin/Reye's syndrome association, we developed an epidemiologic investigation to assess the effects of five potential sources of bias. A case-control study incorporated procedures to avoid temporal precedence and susceptibility bias. These included classifying cases as having monophasic or biphasic patterns of illness and matching for severity of symptoms at zero-time.

The contributions of individual factors to thromboembolic stroke.

To determine the importance of individual factors to thromboembolic stroke (TES) risk, the authors performed a hospital-based case-control study. Ninety cases (56 men and 34 women, ages 15 to 65) discharged from the hospital between January 1981 and December 1984 with a diagnosis of TES supported by computed tomography were matched to 174 control patients (106 men and 68 women). Data on potential risk factors were obtained from the medical record and telephone interview.

The efficacy of atenolol in the outpatient management of the alcohol withdrawal syndrome. Results of a randomized clinical trial.

We conducted a randomized, double-blind, clinical trial of atenolol compared with placebo in the outpatient management of patients with the alcohol withdrawal syndrome. In addition to receiving customary therapy, 88 patients were randomly assigned to receive atenolol and 92 to receive placebo. Outcome during the next 14 days was assessed using two main measures: the patient's clinical course as assessed by an alcohol withdrawal severity index; and the occurrence of treatment failure (composite measure including return to drinking, dropouts, and withdrawal lasting longer than 5 days).

Scientific standards and the design of case-control research.

A new controversy has emerged over the results of a case-control study alleging a causal relationship between certain non-steroidal anti-inflammatory agents (NSAIAs) and the risks of agranulocytosis and aplastic anemia. After describing the methods and results of the International Agranulocytosis and Aplastic Anemia (IAAA) study, we review the distinctive methodologic challenges of this study and the requirements for avoiding bias, and then reconcile the study results with the principles of case-control design. As a result of our analysis, we believe that the IAAA study's most important and reliable finding is its documentation of the infrequent occurrences of aplastic anemia and agranulocytosis with analgesic use.

A controlled study of ischemic stroke risk in migraine patients.

To help resolve the uncertain relationship between migraine headache and ischemic stoke, we performed a hospital-based, case-control study. Eighty-nine cases ages 15-65 with a head computed tomography (CT) scan supported diagnosis of ischemic stroke were matched to 178 control subjects. Using information obtained by telephone interview, the patients were placed into three categories according to explicit criteria: classic migraine; common migraine; and no migraine headache.

An ecogenetic hypothesis for lung cancer in women.

Epidemiologic studies have established a strong association between cigarette smoking and lung cancer, but the risk estimates for women are less impressive than for men. We assessed the possible role of family history and its interrelationship with cigarette smoking as risk factors for lung cancer in women by conducting a case-control study. Among 112 cases, 7% had a primary family member with lung cancer compared with only 3% of 224 controls for an odds ratio of 2.