Showing papers on "Randomized controlled trial published in 1994"

Collaborative overview of randomized trials of antiplatelet therapy .1. prevention of death, myocardial-infarction, and stroke by prolonged antiplatelet therapy in various categories of patients

Abstract: Abstract Objective: To determine the effects of “prolonged” antiplatelet therapy (that is, given for one month or more) on “vascular events” (non-fatal myocardial infarctions, non-fatal strokes, or vascular deaths) in various categories of patients. Design: Overviews of 145 randomised trials of “prolonged” antiplatelet therapy versus control and 29 randomised comparisons between such antiplatelet regimens. Setting: Randomised trials that could have been available by March 1990. Subjects: Trials of antiplatelet therapy versus control included about 70 000 “high risk” patients (that is, with some vascular disease or other condition implying an increased risk of occlusive vascular disease) and 30 000 “low risk” subjects from the general population. Direct comparisons of different antiplatelet regimens involved about 10 000 high risk patients. Results: In each of four main high risk categories of patients antiplatelet therapy was definitely protective. The percentages of patients suffering a vascular event among those allocated antiplatelet therapy versus appropriately adjusted control percentages (and mean scheduled treatment durations and net absolute benefits) were: (a) among about 20 000 patients with acute myocardial infarction, 10% antiplatelet therapy v 14% control (one month benefit about 40 vascular events avoided per 1000 patients treated (2P< 0.00001)); (b) among about 20 000 patients with a past history of myocardial infarction, 13% antiplatelet therapy v 17% control (two year benefit about 40/1000 (2P<0.00001)); (c) among about 10 000 patients with a past history of stroke or transient ischaemic attack, 18% antiplatelet therapy v 22% control (three year benefit about 40/1000 (2P<0.00001)); (d) among about 20 000 patients with some other relevant medical history (unstable angina, stable angina, vascular surgery, angioplasty, atrial fibrillation, valvular disease, peripheral vascular disease, etc), 9% v 14% in 4000 patients with unstable angina (six month benefit about 50/1000 (2P<0.00001)) and 6% v 8% in 16 000 other high risk patients (one year benefit about 20/1000 (2P<0.00001)). Reductions in vascular events were about one quarter in each of these four main categories and were separately statistically significant in middle age and old age, in men and women, in hypertensive and normotensive patients, and in diabetic and non: diabetic patients. Taking all high risk patients together showed reductions of about one third in non-fatal myocardial infarction, about one third in non-fatal stroke, and about one sixth in vascular death (each 2P<0.00001). There was no evidence that non-vascular deaths were increased, so in each of the four main high risk categories overall mortality was significantly reduced. The most widely tested antiplatelet regimen was “medium dose” (75-325 mg/day) aspirin. Doses throughout this range seemed similarly effective (although in an acute emergency it might be prudent to use an initial dose of 160-325 mg rather than about 75 mg). There was no appreciable evidence that either a higher aspirin dose or any other antiplatelet regimen was more effective than medium dose aspirin in preventing vascular events. The optimal duration of treatment for patients with a past history of myocardial infarction, stroke, or transient ischaemic attack could not be determined directly because most trials lasted only one, two, or three years (average about two years). Nevertheless, there was significant (2P<0.00001) further benefit between the end of year 1 and the end of year 3, suggesting that longer treatment might well be more effective. Among low risk recipients of “primary prevention” a significant reduction of one third in non: fatal myocardial infarction was, however, accompanied by a non-significant increase in stroke. Furthermore, the absolute reduction in vascular events was much smaller than for high risk patients despite a much longer treatment period (4.4% antiplatelet therapy v 4.8% control; five year benefit only about four per 1000 patients treated) and was not significant (2P=0.09). Conclusions: Among a much wider range of patients at high risk of occlusive vascular disease than is currently treated routinely, some years of antiplatelet therapy - with aspirin 75-325 mg/day or some other antiplatelet regimen (provided there are no contraindications) - offers worthwhile protection against myocardial infarction, stroke, and death. Significant benefit is evident not only among patients with unstable angina, suspected acute myocardial infarction, or a past history of myocardial infarction, stroke, or transient ischaemic attack, but also among many other categories of high risk patients (such as those having vascular procedures and those with stable angina or peripheral vascular disease). There is as yet, however, no clear evidence on the balance of risks and benefits of antiplatelet therapy in primary prevention among low risk subjects.

A multifactorial intervention to reduce the risk of falling among elderly people living in the community.

Abstract: Background Since falling is associated with serious morbidity among elderly people, we investigated whether the risk of falling could be reduced by modifying known risk factors. Methods We studied 301 men and women living in the community who were at least 70 years of age and who had at least one of the following risk factors for falling: postural hypotension; use of sedatives; use of at least four prescription medications; and impairment in arm or leg strength or range of motion, balance, ability to move safely from bed to chair or to the bathtub or toilet (transfer skills), or gait. These subjects were given either a combination of adjustment in their medications, behavioral instructions, and exercise programs aimed at modifying their risk factors (intervention group, 153 subjects) or usual health care plus social visits (control group, 148 subjects). Results During one year of follow-up, 35 percent of the intervention group fell, as compared with 47 percent of the control group (P = 0.04). The adjusted...

Effects of Smoking Intervention and the Use of an Inhaled Anticholinergic Bronchodilator on the Rate of Decline of FEV1: The Lung Health Study

Abstract: Objective. —To determine whether a program incorporating smoking intervention and use of an inhaled bronchodilator can slow the rate of decline in forced expiratory volume in 1 second (FEV1) in smokers aged 35 to 60 years who have mild obstructive pulmonary disease. Design. —Randomized clinical trial. Participants randomized with equal probability to one of the following groups: (1) smoking intervention plus bronchodilator, (2) smoking intervention plus placebo, or (3) no intervention. Setting. —Ten clinical centers in the United States and Canada. Participants. —A total of 5887 male and female smokers, aged 35 to 60 years, with spirometric signs of early chronic obstructive pulmonary disease. Interventions. —Smoking intervention: intensive 12-session smoking cessation program combining behavior modification and use of nicotine gum, with continuing 5-year maintenance program to minimize relapse. Bronchodilator: ipratropium bromide prescribed three times daily (two puffs per time) from a metered-dose inhaler. Main Outcome Measures. —Rate of change and cumulative change in FEV1over a 5-year period. Results. —Participants in the two smoking intervention groups showed significantly smaller declines in FEV1than did those in the control group. Most of this difference occurred during the first year following entry into the study and was attributable to smoking cessation, with those who achieved sustained smoking cessation experiencing the largest benefit. The small noncumulative benefit associated with use of the active bronchodilator vanished after the bronchodilator was discontinued at the end of the study. Conclusions. —An aggressive smoking intervention program significantly reduces the age-related decline in FEV1in middle-aged smokers with mild airways obstruction. Use of an inhaled anticholinergic bronchodilator results in a relatively small improvement in FEV1that appears to be reversed after the drug is discontinued. Use of the bronchodilator did not influence the long-term decline of FEV1. (JAMA. 1994;272:1497-1505)

Guidelines for the management of aneurysmal subarachnoid hemorrhage: A statement for healthcare professionals from a special writing group of the stroke council, American heart association

Abstract: Subarachnoid hemorrhage (SAH) is a common and frequently devastating condition, accounting for ≈5% of all strokes and affecting as many as 30 000 Americans each year.1,2 The American Heart Association (AHA) previously published “Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage.”3 Since then, considerable advances have been made in endovascular techniques, diagnostic methods, and surgical and perioperative management paradigms. Nevertheless, outcome for patients with SAH remains poor, with population-based mortality rates as high as 45% and significant morbidity among survivors.4–9 Several multicenter, prospective, randomized trials and prospective cohort analyses have influenced treatment protocols for SAH. However, rapid evolution of newer treatment modalities, as well as other practical and ethical considerations, has meant that rigorous clinical scientific assessment of the treatment protocols has not been feasible in several important areas. To address these issues, the Stroke Council of the AHA formed a writing group to reevaluate the recommendations for management of aneurysmal SAH. A consensus committee reviewed existing data in this field and prepared the recommendations in 1994.3 In an effort to update those recommendations, a systematic literature review was conducted based on a search of MEDLINE to identify all relevant randomized clinical trials published between June 30, 1994, and November 1, 2006 (search terms: subarachnoid hemorrhage , cerebral aneurysm , trial ; Table 1). Each identified article was reviewed by at least 2 members of the writing group. Selected articles had to meet one of the following criteria to be included: randomized trial or nonrandomized concurrent cohort study. Case series and nonrandomized historical cohort studies were reviewed if no studies with a higher level of evidence were available for a particular topic covered in the initial guidelines. These were chosen on the basis of sample size and the relevance of the particular studies to subjects that …

Treating anxiety disorders in children: Results of a randomized clinical trial.

Abstract: In this study a psychosocial treatment for 47 Ss (aged 9-13 years) with anxiety disorders was investigated. A 16-session cognitive-behavioral treatment was compared with a wait-list condition. Outcome was evaluated using child self-report, parent report, teacher report, cognitive assessment, and behavioral observations. Pretreatment-posttreatment changes and maintenance of gains at 1-year follow-up were examined. Results revealed that many treated Ss were found to be without a diagnosis at posttest and at follow-up and to be within normal limits on many measures. The child's perception of the therapeutic relationship and the therapist's perception of parental involvement were measured but were not related to outcome. Discussion focuses on characteristics of effective child therapy and the need for further research on treatment components and alternative treatment methods.

A Randomized Trial Comparing Perioperative Chemotherapy and Surgery With Surgery Alone in Resectable Stage IIIA Non-Small-Cell Lung Cancer

Abstract: BACKGROUND Patients with resectable stage IIIA non-small-cell lung cancer have a low survival rate following standard surgical treatment. Nonrandomized trials in which induction chemotherapy or a combination of chemotherapy and radiation prior to surgery were used to treat patients with regionally advanced primary cancers have suggested that survival is improved when compared with treatment by surgery alone. PURPOSE We performed a prospective, randomized study of patients with previously untreated, potentially resectable clinical stage IIIA non-small-cell lung cancer to compare the results of perioperative chemotherapy and surgery with those of surgery alone. METHODS This trial was designed to test the null hypothesis that the proportion of patients surviving 3 years is 12% for either treatment group against the alternate hypothesis that the 3-year survival rate would be 12% in the surgery alone group and 32% in the perioperative chemotherapy group. The estimated required sample size was 65 patients in each group. The trial was terminated at an early time according to the method of O'Brien and Fleming following a single unplanned interim analysis. The decision to terminate the trial was based on ethical considerations, the magnitude of the treatment effect, and the high degree of statistical significance attained. In total, 60 patients were randomly assigned between 1987 and 1993 to receive either six cycles of perioperative chemotherapy (cyclophosphamide, etoposide, and cisplatin) and surgery (28 patients) or surgery alone (32 patients). For patients in the former group, tumor measurements were made before each course of chemotherapy and the clinical tumor response was evaluated after three cycles of chemotherapy; they then underwent surgical resection. Patients who had documented tumor regression after preoperative chemotherapy received three additional cycles of chemotherapy after surgery. RESULTS After three cycles of preoperative chemotherapy, the rate of clinical major response was 35%. Patients treated with perioperative chemotherapy and surgery had an estimated median survival of 64 months compared with 11 months for patients who had surgery alone (P < .008 by log-rank test; P < .018 by Wilcoxon test). The estimated 2- and 3-year survival rates were 60% and 56% for the perioperative chemotherapy patients and 25% and 15% for those who had surgery alone, respectively. CONCLUSIONS In this trial, the treatment strategy using perioperative chemotherapy and surgery was more effective than surgery alone. IMPLICATIONS This clinical trial strengthens the validity of using perioperative chemotherapy in the management of patients with resectable stage IIIA non-small-cell lung cancer. Further investigation of the perioperative chemotherapy strategy in earlier stage lung cancer is warranted.

Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group.

Abstract: Objective. —To further define the safety and efficacy of recombinant human interleukin 1 receptor antagonist (rhIL-1ra) in the treatment of sepsis syndrome. Study Design. —Randomized, double-blind, placebo-controlled, multicenter, multinational clinical trial. Population. —A total of 893 patients with sepsis syndrome received an intravenous loading dose of rhIL-1ra, 100 mg, or placebo followed by a continuous 72-hour intravenous infusion of rhIL-1ra (1.0 or 2.0 mg/kg per hour) or placebo. Outcome Measure. —Twenty-eight—day all-cause mortality. Results. —There was not a significant increase in survival time for rhIL-1ra treatment compared with placebo among all patients who received the study medication (n=893; generalized Wilcoxon statistic, P =.22) or among patients with shock at study entry (n=713; generalized Wilcoxon statistic, P =.23), the two primary efficacy analyses specified a priori for this trial. Results from secondary analyses suggest an increase in survival time with rhIL-1ra treatment among patients with dysfunction of one or more organs (n=563; linear dose-response, P =.009). Retrospective analysis demonstrated an increase in survival time with rhIL-1ra treatment among patients with a predicted risk of mortality of 24% or greater (n=580; linear dose-response, P =.005) as well as among patients with both dysfunction of one or more organs and a predicted risk of mortality of 24% or greater (n=411; linear dose-response, P =.002). Conclusions. —There was not a statistically significant increase in survivial time for rhIL-1ra treatment compared with placebo among all patients who received the study medication or among patients with shock at study entry. Secondary and retrospective analyses of efficacy suggest that treatment with rhIL-1ra results in a dose-related increase in survival time among patients with sepsis who have organ dysfunction and/or a predicted risk of mortality of 24% or greater. ( JAMA . 1994;271:1836-1843)

Efficacy of Divalproex vs Lithium and Placebo in the Treatment of Mania

Abstract: Objective. —To compare the effectiveness of divalproex sodium with that of lithium and placebo in patients with acute mania. Design. —Randomized, double-blind, parallel-group study of treatment outcomes in patients with manic-depressive illness. Patients. —A total of 179 hospitalized, acutely manic patients meeting the Research Diagnostic Criteria for manic disorder, approximately half of whom had been nonresponsive to lithium previously, were studied at nine university-affiliated hospitals. Interventions. —After a minimum 3-day washout period, random assignment for 21 days to divalproex, lithium, or placebo in a 2:1:2 ratio. Dosage of divalproex and lithium was increased if tolerated to a target concentration of 1041 μmol/L (150 μg/ mL) or 1.5 mmol/L (conventionally expressed as milliequivalents per liter), respectively. Main Outcome Measures. —Primary outcome measures were changes in the Mania Rating scale derived from the Schedule for Affective Disorders and Schizophrenia. Results. —Intent-to-treat analysis for efficacy was based on data from 68, 35, and 73 patients in the divalproex, lithium, and placebo groups, respectively. Groups were initially comparable except that all eight patients with four or more manic episodes in the previous year were in the divalproex group. In 30%, 33%, and 51% of the above groups, treatment was prematurely terminated due to lack of efficacy, with fewer premature terminations from divalproex than placebo (P=.017). The proportions of patients improving at least 50% were higher for divalproex and lithium groups than for the placebo group: 48% for divalproex (P=.004) and 49% for lithium (P=.025) vs 25% for placebo. Divalproex was as effective in rapid-cycling manic patients as in other patients. Conclusions. —Both divalproex and lithium were significantly more effective than placebo in reducing the symptoms of acute mania. The efficacy of divalproex appears to be independent of prior responsiveness to lithium. (JAMA. 1994;271:918-924)

Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy.

Abstract: PURPOSETo examine long-term cause-specific mortality in patients irradiated for breast cancer as part of a randomized clinical trial.PATIENTS AND METHODSWe studied all available information from randomized trials initiated before 1975 in which radiotherapy was the randomized option and surgery was the same for both treatment arms. Eight such trials were identified.RESULTSThe increased all-cause mortality rate in 10-year survivors previously reported is no longer significant, although a numerical difference in favor of non-irradiated patients remains. This result was strongly influenced by the earliest trials, and more recent trials have found a nonsignificant net benefit in overall mortality associated with radiation therapy. An excess of cardiac deaths was apparent in both early and more recent trials (P < .001), but this was offset by a reduced number of deaths due to breast cancer, especially in more recent trials.CONCLUSIONThe reduction of breast cancer deaths suggests that radiation therapy may have ...

The importance of placebo effects in pain treatment and research.

Abstract: Objective. —To estimate the importance and implications of placebo effects in pain treatment and research from the existing literature, with emphasis on their magnitude and duration, the conditions influencing them, and proposed explanations. Data Sources. —English-language articles and books identified through MEDLINE (1980 through 1993) and PsycLIT (1967 through 1993) database searching, bibliography review, and expert consultation. Study Selection. —Articles were included if they pertained to the review objectives. Results. —Placebo response rates vary greatly and are frequently much higher than the often-cited one third. Placebos have time-effect curves, and peak, cumulative, and carryover effects similar to those of active medications. As with medication, surgery can produce substantial placebo effects, and this possibility is commonly overlooked in case series reports on back surgery. Individuals are not consistent in their placebo responses, and a placebo-responder personality has not been identified. Models advanced to explain placebo effects emphasize the role of anxiety, expectations, and learning. Conclusions. —Placebo effects influence patient outcomes after any treatment, including surgery, that the clinician and patient believe is effective. Placebo effects plus disease natural history and regression to the mean can result in high rates of good outcomes, which may be misattributed to specific treatment effects. The true causes of improvements in pain after treatment remain unknown in the absence of independently evaluated randomized controlled trials. ( JAMA . 1994;271:1609-1614)

Randomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome.

Abstract: The impact of a new therapy that includes pressure-controlled inverse ratio ventilation followed by extracorporeal CO2 removal on the survival of patients with severe ARDS was evaluated in a randomized controlled clinical trial. Computerized protocols generated around-the-clock instructions for management of arterial oxygenation to assure equivalent intensity of care for patients randomized to the new therapy limb and those randomized to the control, mechanical ventilation limb. We randomized 40 patients with severe ARDS who met the ECMO entry criteria. The main outcome measure was survival at 30 days after randomization. Survival was not significantly different in the 19 mechanical ventilation (42%) and 21 new therapy (extracorporeal) (33%) patients (p = 0.8). All deaths occurred within 30 days of randomization. Overall patient survival was 38% (15 of 40) and was about four times that expected from historical data (p = 0.0002). Extracorporeal treatment group survival was not significantly different from other published survival rates after extracorporeal CO2 removal. Mechanical ventilation patient group survival was significantly higher than the 12% derived from published data (p = 0.0001). Protocols controlled care 86% of the time. Average PaO2 was 59 mm Hg in both treatment groups. Intensity of care required to maintain arterial oxygenation was similar in both groups (2.6 and 2.6 PEEP changes/day; 4.3 and 5.0 FIO2 changes/day). We conclude that there was no significant difference in survival between the mechanical ventilation and the extracorporeal CO2 removal groups. We do not recommend extracorporeal support as a therapy for ARDS. Extracorporeal support for ARDS should be restricted to controlled clinical trials.

A Case-Management System for Coronary Risk Factor Modification after Acute Myocardial Infarction

Abstract: Objective: To evaluate the efficacy of a physician-directed, nurse-managed, home-based case-management system for coronary risk factor modification. Design: Randomized clinical trial in which patie...

Randomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome

Abstract: The impact of a new therapy that includes pressure-controlled inverse ratio ventilation followed by extracorporeal CO 2 removal on the survival of patients with severe ARDS was evaluated in a randomized controlled clinical trial. Computerized protocols generated around-the-clock instructions for management of arterial oxygenation to assure equivalent intensity of care for patients randomized to the new therapy limb and those randomized to the control, mechanical ventilation limb. We randomized 40 patients with severe ARDS who met the ECMO entry criteria. The main outcome measure was survival at 30 days after randomization

Comprehensive Discharge Planning for the Hospitalized Elderly: A Randomized Clinical Trial

Abstract: Objective To study the effects of a comprehensive discharge planning protocol, designed specifically for the elderly and implemented by nurse specialists, on patient and caregiver outcomes and cost of care. Design Randomized clinical trial. Setting Hospital of the University of Pennsylvania. Patients 276 patients and 125 caregivers. Patients were 70 years and older and were placed in selected medical and surgical cardiac diagnostic-related groups. Measurements Group differences in patient outcomes (length of initial hospital stay, length of time between initial hospital discharge and readmission, and rehospitalization rates) and charges for care (charges for initial hospitalization, rehospitalizations, health services after discharge, and nurse specialist services) were measured 2, 6, and 12 weeks after discharge. Results From the initial hospital discharge to 6 weeks after discharge, patients in the medical intervention group had fewer readmissions, fewer total days rehospitalized, lower readmission charges, and lower charges for health care services after discharge. No differences in these outcomes were found between the surgical intervention and control groups during this period. Conclusions Study findings support the need for comprehensive discharge planning designed for the elderly and implemented by nurse specialists to improve their outcomes after hospital discharge and to achieve cost savings. The findings also suggest that this intervention had its greatest effect in delaying or preventing rehospitalization of patients in the medical intervention group during the first 6 weeks after discharge.

Impact of Follow-up Testing on Survival and Health-Related Quality of Life in Breast Cancer Patients: A Multicenter Randomized Controlled Trial

Abstract: Objective. —To assess prospectively the impact on survival and health-related quality of life of two follow-up protocols in patients with early breast cancer. Design. —Randomized controlled clinical trial. Setting. —Multicenter study involving 26 general hospitals in Italy. Patients. —A consecutive sample of 1320 women younger than 70 years with stage I, II, and III unilateral primary breast cancer. Intervention. —Patients were randomly assigned to an intensive surveillance, which included physician visits and performance of bone scan, liver echography, chest roentgenography, and laboratory tests at predefined intervals (n=655), or to a control regimen (n=665), in which patients were seen by their physicians at the same frequency but only clinically indicated tests were performed. Both groups received a yearly mammogram aimed at detecting contralateral breast cancer. Main Outcome Measures. —Primary end points were overall survival and health-related quality of life. Results. —Compliance to the two follow-up protocols was more than 80%. At a median follow-up of 71 months, no difference was apparent in overall survival with 132 deaths (20%) in the intensive group and 122 deaths (18%) in the control group. No significant differences were apparent in time to detection of recurrence between the two groups. Measurements of health-related quality of life (ie, overall health and quality-of-life perception, emotional well-being, body image, social functioning, symptoms, and satisfaction with care) at 6,12, 24, and 60 months of follow-up did not show differences by type of care received. Conclusions. —Results of this trial support the view that a protocol of frequent laboratory tests and roentgenography after primary treatment for breast cancer does not improve survival or influence health-related quality of life. Routine use of these tests should be discouraged. (JAMA. 1994;271:1587-1592)

Bayesian Approaches to Randomized Trials

Abstract: Statistical issues in conducting randomized trials include the choice of a sample size, whether to stop a trial early and the appropriate analysis and interpretation of the trial results. At each of these stages, evidence external to the trial is useful, but generally such evidence is introduced in an unstructured and informal manner. We argue that a Bayesian approach allows a formal basis for using external evidence and in addition provides a rational way for dealing with issues such as the ethics of randomization, trials to show treatment equivalence, the monitoring of accumulating data and the prediction of the consequences of continuing a study

Preventing Falls Among Community-Dwelling Older Persons: Results From a Randomized Trial

Abstract: A randomized trial of falls prevention program that addressed home safety, exercise, and behavioral risks was conducted with 3,182 independently living HMO members age 65 and older. The intervention decreased the odds of falling by 0.85, but only reduced the average number of falls among those who fell by 7%. The effect was strongest among men age 75 and older. The likelihood of avoiding falls requiring medical treatment was not significantly affected by the intervention. We conclude that the intervention dose was not of sufficient intensity or duration to have a marked protective effect on older persons. Future research should focus on more intensive intervention approaches because serious falls do not appear to be amendable to low-intensity environment/behavioral efforts. Language: en

Correcting for non-compliance in randomized trials using structural nested mean models

Abstract: In a randomized trial designed to study the effect of a treatment of interest on the evolution of the mean of a time-dependent outcome variable, subjects are assigned to a treatment regime, or, equivalently, a treatment protocol. Unfortunately, subjects often fail to comply with their assigned regime. From a public health point of view, the causal parameter of interest will often be a function of the treatment differences that would have been observed hadcontrary to fact, all subjects remained on protocol. This paper considers the identification and estimation of these treatment differences based on a new class of structural models, the multivariate structural nested mean models, when reliable estimates of each subject's actual treatment are available. Estimates of “actual treatment” might, for example, be obtained by measuring the amount of “active drug” in the subject's blood or urine at each follow-up visit or by pill counting techniques. In addition, we discuss a natural extension of our methods to ob...

Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus

Abstract: Background Essential mixed cryoglobulinemia is frequently associated with hepatitis C virus (HCV) infection. A beneficial effect of interferon alfa therapy has been reported, but we do not know whether the antiviral activity of the drug affects the clinical and biochemical manifestations of disease. Methods In a prospective randomized, controlled trial, we studied 53 patients with HCV-associated type II cryoglobulinemia. A group of 27 patients received recombinant interferon alfa-2a thrice weekly at a dose of 1.5 million units for a week and then 3 million units thrice weekly for the following 23 weeks. The 26 control patients did not receive anything apart from previously prescribed treatments. All patients were then followed for an additional 24 to 48 weeks. Results Interferon was usually well tolerated, but it was permanently discontinued in two patients because of atrial fibrillation and depression. Two of the 26 patients in the control group were lost to follow-up. After the treatment period, serum H...

Statistical Power, Sample Size, and Their Reporting in Randomized Controlled Trials

Abstract: Objective. —To describe the pattern over time in the level of statistical power and the reporting of sample size calculations in published randomized controlled trials (RCTs) with negative results. Design. —Our study was a descriptive survey. Power to detect 25% and 50% relative differences was calculated for the subset of trials with negative results in which a simple two-group parallel design was used. Criteria were developed both to classify trial results as positive or negative and to identify the primary outcomes. Power calculations were based on results from the primary outcomes reported in the trials. Population. —We reviewed all 383 RCTs published inJAMA, Lancet, and theNew England Journal of Medicinein 1975, 1980, 1985, and 1990. Results. —Twenty-seven percent of the 383 RCTs (n=102) were classified as having negative results. The number of published RCTs more than doubled from 1975 to 1990, with the proportion of trials with negative results remaining fairly stable. Of the simple two-group parallel design trials having negative results with dichotomous or continuous primary outcomes (n=70), only 16% and 36% had sufficient statistical power (80%) to detect a 25% or 50% relative difference, respectively. These percentages did not consistently increase overtime. Overall, only 32% of the trials with negative results reported sample size calculations, but the percentage doing so has improved over time from 0% in 1975 to 43% in 1990. Only 20 of the 102 reports made any statement related to the clinical significance of the observed differences. Conclusions. —Most trials with negative results did not have large enough sample sizes to detect a 25% or a 50% relative difference. This result has not changed over time. Few trials discussed whether the observed differences were clinically important. There are important reasons to change this practice. The reporting of statistical power and sample size also needs to be improved. (JAMA. 1994;272:122-124)

[Effects of frequent ultrasound during pregnancy: a randomised controlled trial].

Abstract: Despite widespread application of ultrasound imaging and Doppler blood flow studies, the effects of their frequent and repeated use in pregnancy have not been evaluated in controlled trials. From 2834 women with single pregnancies at 16-20 weeks gestation, 1415 were selected at random to receive ultrasound imaging and continuous-wave Doppler flow studies at 18, 24, 28, 34, and 38 weeks gestation (the intensive group) and 1419 to receive single ultrasound imaging at 18 weeks (the regular group). Outcome data was obtained from 99% of women who entered the study. The only difference between the two groups was significantly higher intrauterine growth restriction in the intensive group, when expressed both as birthweight < 10th centile (relative risk 1.35; 95% confidence interval 1.09 to 1.67; p = 0.006) and birthweight < 3rd centile (relative risk 1.65; 95% confidence intervals 1.09 to 2.49; p = 0.020). While it is possible that this finding was a chance effect, it is also plausible that frequent exposure to ultrasound may have influenced fetal growth. Repeated prenatal ultrasound imaging and Doppler flow examinations should be restricted to those women to whom the information is likely to be of clinical benefit.

Intensive Diagnostic Follow-up After Treatment of Primary Breast Cancer: A Randomized Trial

Abstract: Objective. —To evaluate the effectiveness of early detection of intrathoracic and bone metastases in reducing mortality in breast cancer patients. Design. —Randomized clinical trial allocating breast cancer patients to two alternative follow-up protocols (intensive vs clinical) for at least 5 years. Setting. —Twelve breast clinics (referral centers) in different areas in Italy. Patients. —A total of 1243 consecutive patients (either premenopausal or postmenopausal) surgically treated for unilateral invasive breast carcinoma with no evidence of metastases. The two study groups were well balanced in terms of clinical and prognostic characteristics. Intervention. —Patients in both treatment groups had physical examination and mammography, while patients of the intensive follow-up group had, in addition, chest roentgenography and bone scan every 6 months. Main Outcome Measures. —Vital status at 5 years was the main outcome; information was available for all except five patients (0.4%). Relapse-free survival was also analyzed. Results. —Overall, 393 recurrences (104 local and 289 distant) were observed during the study. Increased detection of isolated intrathoracic and bone metastases was evident in the intensive follow-up group compared with the clinical follow-up group (112 vs 71 cases), while no difference was observed for other sites and for local and/or regional recurrences. The 5-year relapse-free survival rate was significantly higher for the clinical follow-up group, with patients in the intensive follow-up group showing earlier detection of recurrences. No difference in 5-year overall mortality (18.6% vs 19.5%) was observed between the two follow-up groups. Conclusions. —Periodic chest roentgenography and bone scan allow earlier detection of distant metastases, but anticipated diagnosis appears to be the only effect of intensive follow-up, and no impact on prognosis is evident after 5 years. Periodic intensive follow-up with chest roentgenography and bone scan should not be recommended as a routine policy. (JAMA. 1994;271:1593-1597)

Concorde: MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection

Abstract: Concorde is a double-blind randomised comparison of two policies of zidovudine treatment in symptom-free individuals infected with human immunodeficiency virus (HIV): (a) immediate zidovudine from the time of randomisation (Imm); and (b) deferred zidovudine (Def) until the onset of AIDS-related complex (ARC) or AIDS (CDC group IV disease) or the development of persistently low CD4 cell counts if the clinician judged that treatment was indicated. Between October, 1988, and October, 1991, 1749 HIV-infected individuals from centres in the UK, Ireland, and France were randomly allocated to zidovudine 250 mg four times daily (877 Imm) or matching placebo (872 Def). Follow-up was to death or Dec 31,1992 (total 5419 person-years; medians 3·3 years) and only 7% of the 1749 had not had a full clinical assessment after July 1, 1992. Of those allocated to the Def group, 418 started zidovudine at some time during the trial, 174 (42%) of them at or after they were judged by the clinician to have developed ARC or AIDS (nearly all confirmed subsequently) and most of the remainder on the basis of low CD4 cell counts. Those in the Imm group spent 81% of the time before ARC or AIDS on zidovudine compared with only 16% for those in the Def group. Despite the large difference in the amount of zidovudine between the two groups and the fact that the number of clinical endpoints (AIDS and death) in Concorde (347) outnumbers the total of those in all other published trials in symptom-free and early symptomatic infection, there was no statistically significant difference in clinical outcome between the two therapeutic policies. The 3-year estimated survival probabilities were 92% (95% Cl 90-94%) in Imm and 94% (92-95%) in Def (log-rank p=0·13), with no significant differences overall or in subgroup analyses by CD4 cell count at baseline. Similarly, there was no significant difference in progression of HIV disease: 3-year progression rates to AIDS or death were 18% in both groups, and to ARC, AIDS, or death were 29% (Imm) and 32% (Def) (p=0·18), although there was an indication of an early but transient clinical benefit in favour of Imm in progression to ARC, AIDS, or death. However, there was a clear difference in changes in CD4 cell count over time in the two groups. Median changes from baseline at 3 months were + 20 cells/µL (Imm) and -9 cells/µL (Def), a difference of 29 cells/µL (95% Cl 16-42; p < 0·0001) which persisted for up to 3 years. Thus such persistent differences in CD4 cell count do not necessarily imply long-term differences in clinical outcome. 6 participants had life-threatening adverse events that were judged to be possibly drug related: 4 occurred on trial capsules before unblinding (3 on zidovudine, 1 on placebo) and 2 occurred on open zidovudine. Despite a daily dose of 1 g of zidovudine, the frequency of severe haematological and other adverse events on trial therapy was low but significantly higher in the Imm group: 16 Imm and 2 Def participants stopped trial drug for haematological events and the estimated proportions with haemoglobin dropping below 10 g/dL were 5% and 1%, respectively, at 1 year and 8% and 2%, respectively, at 3 years. Another 83 (9%) Imm and 36 (4%) Def participants stopped for other adverse events, predominantly gastrointestinal or neurological symptoms (headaches) or malaise. The results of Concorde do not encourage the early use of zidovudine in symptom-free HIV-infected adults. They also call into question the uncritical use of CD4 cell counts as a surrogate endpoint for assessment of benefit from long-term antiretroviral therapy.

Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial.

Abstract: Objectives:To evaluate the safety, pharmacokinetics, and efficacy of human recombinant interleukin-1 receptor antagonist (IL-lra) in the treatment of patients with sepsis syndrome.Design:Prospective, open-label, placebo-controlled, phase II, multicenter clinical trial using three different doses of

Imipramine in Patients with Chest Pain Despite Normal Coronary Angiograms

Abstract: Background Ten to 30 percent of patients undergoing cardiac catheterization because of chest pain are found to have normal coronary angiograms. Because these patients may have a visceral pain syndrome unrelated to myocardial ischemia, we investigated whether drugs that are useful in chronic pain syndromes might also be beneficial in such patients. Methods Sixty consecutive patients underwent cardiac, esophageal, psychiatric, and pain-sensitivity testing and then participated in a randomized, double-blind, placebo-controlled three-week trial of clonidine at a dose of 0.1 mg twice daily (20 patients), imipramine at a dose of 50 mg nightly with a morning placebo (20 patients), or placebo twice daily (20 patients); this treatment phase was compared with an identical period of twice-daily placebo for all patients (placebo phase). Results Thirteen (22 percent) of the 60 patients had ischemic-appearing electrocardiographic responses to exercise, 22 of the 54 tested (41 percent) had abnormal esophageal motility, ...

Assessing the quality of randomization from reports of controlled trials published in obstetrics and gynecology journals.

Abstract: Objective. —To assess the methodologic quality of approaches used to allocate participants to comparison groups in randomized controlled trials from one medical specialty. Design. —Survey of published, parallel group randomized controlled trials. Data Sources. —All 206 reports with allocation described as randomized from the 1990 and 1991 volumes of four journals of obstetrics and gynecology. Main Outcome Measures. —Direct and indirect measures of the adequacy of randomization and baseline comparisons. Results. —Only 32% of the reports described an adequate method for generating a sequence of random numbers, and only 23% contained information showing that steps had been taken to conceal assignment until the point of treatment allocation. A mere 9% described both sequence generation and allocation concealment. In reports of trials that had apparently used unrestricted randomization, the differences in sample sizes between treatment and control groups were much smaller than would be expected due to chance. In reports of trials in which hypothesis tests had been used to compare baseline characteristics, only 2% of reported test results were statistically significant, lower than the expected rate of 5%. Conclusions. —Proper randomization is required to generate unbiased comparison groups in controlled trials, yet the reports in these journals usually provided inadequate or unacceptable information on treatment allocation. Additional analyses suggest that nonrandom manipulation of comparison groups and selective reporting of baseline comparisons may have occurred. ( JAMA . 1994;272:125-128)

Treatment of septic shock with human monoclonal antibody HA-1A. A randomized, double-blind, placebo-controlled trial. CHESS Trial Study Group

Abstract: Objective To compare the effectiveness of 100 mg of HA-1A and placebo in reducing the 14-day all-cause mortality rate in patients with septic shock and gram-negative bacteremia in the Centocor: HA-1A Efficacy in Septic Shock (CHESS) trial, and to assess the safety of 100 mg of HA-1A given to patients with septic shock who did not have gram-negative bacteremia. Design Large, simple, group-sequential, randomized, double-blind, multicenter, placebo-controlled trial. Setting 603 investigators at 513 community and university-affiliated hospitals in the United States. Patients Within 6 hours before enrollment, the patients had been in shock with a systolic blood pressure of less than 90 mm Hg after adequate fluid challenge or had received vasopressors to maintain blood pressure. These episodes of shock began within 24 hours of enrollment. A presumptive clinical diagnosis of gram-negative infection as the cause of the shock episode and a commitment from the patients' physicians to provide full supportive care were required. Measurements Blood cultures were obtained within 48 hours of enrollment, and death at day 14 after treatment was recorded. Adverse events occurring within 14 days after enrollment were also tabulated. Results 2199 patients were enrolled; 621 (28.2%) met all enrollment criteria, received HA-1A or placebo, and had confirmed gram-negative bacteremia. Mortality rates in this group were as follows: placebo, 32% (95 and HA-1A, 33% (109 of 328) (P = 0.864, Fisher exact test, two-tailed; 95% CI for the difference, -6.2% to 8.6%). Mortality rates in the patients without gram-negative bacteremia were as follows: placebo, 37% (292 of 793) and HA-1A, 41% (318 of 785) (P = 0.073, Fisher exact test, one-tailed; CI, -0.8% to 8.8%). Conclusions In this trial, HA-1A was not effective in reducing the 14-day mortality rate in patients with gram-negative bacteremia and septic shock. These data do not support using septic shock as an indication for HA-1A treatment. If HA-1A is effective in reducing the mortality rate in patients dying from endotoxemia, these patients must be identified using other treatment criteria.