Showing papers on "Randomized controlled trial published in 2003"

Methodological index for non-randomized studies (minors): development and validation of a new instrument.

Abstract: Background: Because of specific methodological difficulties in conducting randomized trials, surgical research remains dependent predominantly on observational or non-randomized studies. Few validated instruments are available to determine the methodological quality of such studies either from the reader's perspective or for the purpose of meta-analysis. The aim of the present study was to develop and validate such an instrument. Methods: After an initial conceptualization phase of a methodological index for non-randomized studies (MINORS), a list of 12 potential items was sent to 100 experts from different surgical specialities for evaluation and was also assessed by 10 clinical methodologists. Subsequent testing involved the assessment of inter-reviewer agreement, test-retest reliability at 2 months, internal consistency reliability and external validity. Results: The final version of MINORS contained 12 items, the first eight being specifically for non-comparative studies. Reliability was established on the basis of good inter-reviewer agreement, high test-retest reliability by the κ-coefficient and good internal consistency by a high Cronbach's α-coefficient. External validity was established in terms of the ability of MINORS to identify excellent trials. Conclusions: MINORS is a valid instrument designed to assess the methodological quality of non-randomized surgical studies, whether comparative or non-comparative. The next step will be to determine its external validity when used in a large number of studies and to compare it with other existing instruments.

The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials

Abstract: To comprehend the results of a randomised controlled trial (RCT), readers must understand its design, conduct, analysis, and interpretation. That goal can be achieved only through total transparency from authors. Despite several decades of educational efforts, the reporting of RCTs needs improvement. Investigators and editors developed the original CONSORT (Consolidated Standards of Reporting Trials) statement to help authors improve reporting by use of a checklist and flow diagram. The revised CONSORT statement presented here incorporates new evidence and addresses some criticisms of the original statement. The checklist items pertain to the content of the Title, Abstract, Introduction, Methods, Results, and Discussion. The revised checklist includes 22 items selected because empirical evidence indicates that not reporting this information is associated with biased estimates of treatment effect, or because the information is essential to judge the reliability or relevance of the findings. We intended the flow diagram to depict the passage of participants through an RCT. The revised flow diagram depicts information from four stages of a trial (enrollment, intervention allocation, follow- up, and analysis). The diagram explicitly shows the number of participants, for each intervention group, included in the primary data analysis. Inclusion of these numbers allows the reader to judge whether the authors have done an intention- to-treat analysis. In sum, the CONSORT statement is intended to improve the reporting of an RCT, enabling readers to understand a trial's conduct and to assess the validity of its results.

A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema.

Abstract: Background Lung-volume-reduction surgery has been proposed as a palliative treatment for severe emphysema. Effects on mortality, the magnitude and durability of benefits, and criteria for the selection of patients have not been established. Methods A total of 1218 patients with severe emphysema underwent pulmonary rehabilitation and were randomly assigned to undergo lung-volume-reduction surgery or to receive continued medical treatment. Results Overall mortality was 0.11 death per person-year in both treatment groups (risk ratio for death in the surgery group, 1.01; P=0.90). After 24 months, exercise capacity had improved by more than 10 W in 15 percent of the patients in the surgery group, as compared with 3 percent of patients in the medical-therapy group (P Conclusions Overall, lung-volume-reduction surgery increases the chance of improved exercise capacity but does not confer a survival advantage over medical therapy. It does yield a survival advantage for patients with both predominantly upper-lobe emphysema and low base-line exercise capacity. Patients previously reported to be at high risk and those with non-upper-lobe emphysema and high base-line exercise capacity are poor candidates for lung-volume-reduction surgery, because of increased mortality and negligible functional gain.

Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial.

Abstract: ContextPostmenopausal women have a greater risk than men of developing Alzheimer disease, but studies of the effects of estrogen therapy on Alzheimer disease have been inconsistent. On July 8, 2002, the study drugs, estrogen plus progestin, in the Women's Health Initiative (WHI) trial were discontinued because of certain increased health risks in women receiving combined hormone therapy.ObjectiveTo evaluate the effect of estrogen plus progestin on the incidence of dementia and mild cognitive impairment compared with placebo.Design, Setting, and ParticipantsThe Women's Health Initiative Memory Study (WHIMS), a randomized, double-blind, placebo-controlled clinical trial, began enrolling participants from the Women's Health Initiative (WHI) estrogen plus progestin trial in May 1996. Of the 4894 eligible participants of the WHI study, 4532 (92.6%) postmenopausal women free of probable dementia, aged 65 years or older, and recruited from 39 of 40 WHI clinical centers were enrolled in the WHIMS.InterventionParticipants received either 1 daily tablet of 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate (n = 2229), or a matching placebo (n = 2303).Main Outcome MeasuresIncidence of probable dementia (primary outcome) and mild cognitive impairment (secondary outcome) were identified through a structured clinical assessment.ResultsThe mean (SD) time between the date of randomization into WHI and the last Modified Mini-Mental State Examination (3MSE) for all WHIMS participants was 4.05 (1.19) years. Overall, 61 women were diagnosed with probable dementia, 40 (66%) in the estrogen plus progestin group compared with 21 (34%) in the placebo group. The hazard ratio (HR) for probable dementia was 2.05 (95% confidence interval [CI], 1.21-3.48; 45 vs 22 per 10 000 person-years; P = .01). This increased risk would result in an additional 23 cases of dementia per 10 000 women per year. Alzheimer disease was the most common classification of dementia in both study groups. Treatment effects on mild cognitive impairment did not differ between groups (HR, 1.07; 95% CI, 0.74-1.55; 63 vs 59 cases per 10 000 person-years; P = .72).ConclusionsEstrogen plus progestin therapy increased the risk for probable dementia in postmenopausal women aged 65 years or older. In addition, estrogen plus progestin therapy did not prevent mild cognitive impairment in these women. These findings, coupled with previously reported WHI data, support the conclusion that the risks of estrogen plus progestin outweigh the benefits.

The Finnish Diabetes Prevention Study (DPS) Lifestyle intervention and 3-year results on diet and physical activity

Abstract: OBJECTIVE —To describe the 1 ) lifestyle intervention used in the Finnish Diabetes Prevention Study, 2 ) short- and long-term changes in diet and exercise behavior, and 3 ) effect of the intervention on glucose and lipid metabolism. RESEARCH DESIGN AND METHODS —There were 522 middle-aged, overweight subjects with impaired glucose tolerance who were randomized to either a usual care control group or an intensive lifestyle intervention group. The control group received general dietary and exercise advice at baseline and had an annual physician’s examination. The subjects in the intervention group received additional individualized dietary counseling from a nutritionist. They were also offered circuit-type resistance training sessions and advised to increase overall physical activity. The intervention was the most intensive during the first year, followed by a maintenance period. The intervention goals were to reduce body weight, reduce dietary and saturated fat, and increase physical activity and dietary fiber. RESULTS —The intervention group showed significantly greater improvement in each intervention goal. After 1 and 3 years, weight reductions were 4.5 and 3.5 kg in the intervention group and 1.0 and 0.9 kg in the control group, respectively. Measures of glycemia and lipemia improved more in the intervention group. CONCLUSIONS —The intensive lifestyle intervention produced long-term beneficial changes in diet, physical activity, and clinical and biochemical parameters and reduced diabetes risk. This type of intervention is a feasible option to prevent type 2 diabetes and should be implemented in the primary health care system.

Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial.

Abstract: CONTEXT Depression and low perceived social support (LPSS) after myocardial infarction (MI) are associated with higher morbidity and mortality, but little is known about whether this excess risk can be reduced through treatment. OBJECTIVE To determine whether mortality and recurrent infarction are reduced by treatment of depression and LPSS with cognitive behavior therapy (CBT), supplemented with a selective serotonin reuptake inhibitor (SSRI) antidepressant when indicated, in patients enrolled within 28 days after MI. DESIGN, SETTING, AND PATIENTS Randomized clinical trial conducted from October 1996 to April 2001 in 2481 MI patients (1084 women, 1397 men) enrolled from 8 clinical centers. Major or minor depression was diagnosed by modified Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and severity by the 17-item Hamilton Rating Scale for Depression (HRSD); LPSS was determined by the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Social Support Instrument (ESSI). Random allocation was to usual medical care or CBT-based psychosocial intervention. INTERVENTION Cognitive behavior therapy was initiated at a median of 17 days after the index MI for a median of 11 individual sessions throughout 6 months, plus group therapy when feasible, with SSRIs for patients scoring higher than 24 on the HRSD or having a less than 50% reduction in Beck Depression Inventory scores after 5 weeks. MAIN OUTCOME MEASURES Composite primary end point of death or recurrent MI; secondary outcomes included change in HRSD (for depression) or ESSI scores (for LPSS) at 6 months. RESULTS Improvement in psychosocial outcomes at 6 months favored treatment: mean (SD) change in HRSD score, -10.1 (7.8) in the depression and psychosocial intervention group vs -8.4 (7.7) in the depression and usual care group (P<.001); mean (SD) change in ESSI score, 5.1 (5.9) in the LPSS and psychosocial intervention group vs 3.4 (6.0) in the LPSS and usual care group (P<.001). After an average follow-up of 29 months, there was no significant difference in event-free survival between usual care (75.9%) and psychosocial intervention (75.8%). There were also no differences in survival between the psychosocial intervention and usual care arms in any of the 3 psychosocial risk groups (depression, LPSS, and depression and LPSS patients). CONCLUSIONS The intervention did not increase event-free survival. The intervention improved depression and social isolation, although the relative improvement in the psychosocial intervention group compared with the usual care group was less than expected due to substantial improvement in usual care patients.

Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial.

Abstract: ContextAlthough low levels of high-density lipoprotein cholesterol (HDL-C) increase risk for coronary disease, no data exist regarding potential benefits of administration of HDL-C or an HDL mimetic. ApoA-I Milano is a variant of apolipoprotein A-I identified in individuals in rural Italy who exhibit very low levels of HDL. Infusion of recombinant ApoA-I Milano–phospholipid complexes produces rapid regression of atherosclerosis in animal models.ObjectiveWe assessed the effect of intravenous recombinant ApoA-I Milano/phospholipid complexes (ETC-216) on atheroma burden in patients with acute coronary syndromes (ACS).DesignThe study was a double-blind, randomized, placebo-controlled multicenter pilot trial comparing the effect of ETC-216 or placebo on coronary atheroma burden measured by intravascular ultrasound (IVUS).SettingTen community and tertiary care hospitals in the United States.PatientsBetween November 2001 and March 2003, 123 patients aged 38 to 82 years consented, 57 were randomly assigned, and 47 completed the protocol.InterventionsIn a ratio of 1:2:2, patients received 5 weekly infusions of placebo or ETC-216 at 15 mg/kg or 45 mg/kg. Intravascular ultrasound was performed within 2 weeks following ACS and repeated after 5 weekly treatments.Main Outcome MeasuresThe primary efficacy parameter was the change in percent atheroma volume (follow-up minus baseline) in the combined ETC-216 cohort. Prespecified secondary efficacy measures included the change in total atheroma volume and average maximal atheroma thickness.ResultsThe mean (SD) percent atheroma volume decreased by −1.06% (3.17%) in the combined ETC-216 group (median, −0.81%; 95% confidence interval [CI], −1.53% to −0.34%; P = .02 compared with baseline). In the placebo group, mean (SD) percent atheroma volume increased by 0.14% (3.09%; median, 0.03%; 95% CI, −1.11% to 1.43%; P = .97 compared with baseline). The absolute reduction in atheroma volume in the combined treatment groups was −14.1 mm3 or a 4.2% decrease from baseline (P<.001).ConclusionsA recombinant ApoA-I Milano/phospholipid complex (ETC-216) administered intravenously for 5 doses at weekly intervals produced significant regression of coronary atherosclerosis as measured by IVUS. Although promising, these results require confirmation in larger clinical trials with morbidity and mortality end points.

Effects of intravenous fluid restriction on postoperative complications: comparison of two perioperative fluid regimens: a randomized assessor-blinded multicenter trial.

Abstract: Objective: To investigate the effect of a restricted intravenous fluid regimen versus a standard regimen on complications after colorectal resection. Summary Background Data: Current fluid administration in major surgery causes a weight increase of 3‐ 6 kg. Complications after colorectal surgery are reported in up to 68% of patients. Associations between postoperative weight gain and poor survival as well as fluid overload and complications have been shown. Methods: We did a randomized observer-blinded multicenter trial. After informed consent was obtained, 172 patients were allocated to either a restricted or a standard intraoperative and postoperative intravenous fluid regimen. The restricted regimen aimed at maintaining preoperative body weight; the standard regimen resembled everyday practice. The primary outcome measures were complications; the secondary measures were death and adverse effects. Results: The restricted intravenous fluid regimen significantly reduced postoperative complications both by intention-to-treat (33% versus 51%, P 0.013) and per-protocol (30% versus 56%, P 0.003) analyses. The numbers of both cardiopulmonary (7% versus 24%, P 0.007) and tissue-healing complications (16% versus 31%, P 0.04) were significantly reduced. No patients died in the restricted group compared with 4 deaths in the standard group (0% versus 4.7%, P 0.12). No harmful adverse effects were observed. Conclusion: The restricted perioperative intravenous fluid regimen aiming at unchanged body weight reduces complications after elective colorectal resection.

Prevalence of Conventional Risk Factors in Patients With Coronary Heart Disease

Abstract: ContextIt is commonly suggested that more than 50% of patients with coronary heart disease (CHD) lack any of the conventional risk factors (cigarette smoking, diabetes, hyperlipidemia, and hypertension). This claim implies that other factors play a significant role in CHD and has led to considerable interest in nontraditional risk factors and genetic causes of CHD.ObjectiveTo determine the prevalence of the 4 conventional risk factors among patients with CHD.Design, Setting, and PatientsIn 2002-2003, we analyzed data for 122 458 patients enrolled in 14 international randomized clinical trials of CHD conducted during the prior decade. Patients included 76 716 with ST-elevation myocardial infarction, 35 527 with unstable angina/non–ST-elevation myocardial infarction, and 10 215 undergoing percutaneous coronary intervention.Main Outcome MeasuresPrevalence of each conventional risk factor and number of conventional risk factors present among patients with CHD, compared between men and women and by age at trial entry.ResultsAmong patients with CHD, at least 1 of the 4 conventional risk factors was present in 84.6% of women and 80.6% of men. In younger patients (men ≤55 years and women ≤65 years) and most patients presenting either with unstable angina or for percutaneous coronary intervention, only 10% to 15% of patients lacked any of the 4 conventional risk factors. This pattern was largely independent of sex, geographic region, trial entry criteria, or prior CHD. Premature CHD was related to cigarette smoking in men and cigarette smoking and diabetes in women. Smoking decreased the age at the time of CHD event (at trial entry) by nearly 1 decade in all risk factor combinations.ConclusionsIn direct contrast with conventional thinking, 80% to 90% of patients with CHD have conventional risk factors. Although research on nontraditional risk factors and genetic causes of heart disease is important, clinical medicine, public health policies, and research efforts should place significant emphasis on the 4 conventional risk factors and the lifestyle behaviors causing them to reduce the epidemic of CHD.

A randomized trial of aspirin to prevent colorectal adenomas

Abstract: Background Laboratory and epidemiologic data suggest that aspirin has an antineoplastic effect in the large bowel. Methods We performed a randomized, double-blind trial of aspirin as a chemopreventive agent against colorectal adenomas. We randomly assigned 1121 patients with a recent history of histologically documented adenomas to receive placebo (372 patients), 81 mg of aspirin (377 patients), or 325 mg of aspirin (372 patients) daily. According to the protocol, follow-up colonoscopy was to be performed approximately three years after the qualifying endoscopy. We compared the groups with respect to the risk of one or more neoplasms (adenomas or colorectal cancer) at least one year after randomization using generalized linear models to compute risk ratios and 95 percent confidence intervals. Results Reported adherence to study medications and avoidance of nonsteroidal antiinflammatory drugs were excellent. Follow-up colonoscopy was performed at least one year after randomization in 1084 patients (97 perc...

Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.

Abstract: Background Women who have had a spontaneous preterm delivery are at greatly increased risk for preterm delivery in subsequent pregnancies. The results of several small trials have suggested that 17 alpha-hydroxyprogesterone caproate (17P) may reduce the risk of preterm delivery. Methods We conducted a double-blind, placebo-controlled trial involving pregnant women with a documented history of spontaneous preterm delivery. Women were enrolled at 19 clinical centers at 16 to 20 weeks of gestation and randomly assigned by a central data center, in a 2:1 ratio, to receive either weekly injections of 250 mg of 17P or weekly injections of an inert oil placebo; injections were continued until delivery or to 36 weeks of gestation. The primary outcome was preterm delivery before 37 weeks of gestation. Analysis was performed according to the intention-to-treat principle. Results Base-line characteristics of the 310 women in the progesterone group and the 153 women in the placebo group were similar. Treatment with 1...

Evaluation of D-Dimer in the Diagnosis of Suspected Deep-Vein Thrombosis

Abstract: background Several diagnostic strategies using ultrasound imaging, measurement of d -dimer, and assessment of clinical probability of disease have proved safe in patients with suspected deep-vein thrombosis, but they have not been compared in randomized trials. methods Outpatients presenting with suspected lower-extremity deep-vein thrombosis were potentially eligible. Using a clinical model, physicians evaluated the patients and categorized them as likely or unlikely to have deep-vein thrombosis. The patients were then randomly assigned to undergo ultrasound imaging alone (control group) or to undergo d -dimer testing ( d -dimer group) followed by ultrasound imaging unless the d -dimer test was negative and the patient was considered clinically unlikely to have deep-vein thrombosis, in which case ultrasound imaging was not performed. results Five hundred thirty patients were randomly assigned to the control group, and 566 to the d -dimer group. The overall prevalence of deep-vein thrombosis or pulmonary embolism was 15.7 percent. Among patients for whom deep-vein thrombosis had been ruled out by the initial diagnostic strategy, there were two confirmed venous thromboembolic events in the d -dimer group (0.4 percent; 95 percent confidence interval, 0.05 to 1.5 percent) and six events in the control group (1.4 percent; 95 percent confidence interval, 0.5 to 2.9 percent; P=0.16) during three months of follow-up. The use of d -dimer testing resulted in a significant reduction in the use of ultrasonography, from a mean of 1.34 tests per patient in the control group to 0.78 in the d -dimer group (P=0.008). Two hundred eighteen patients (39 percent) in the d- dimer group did not require ultrasound imaging. conclusions Deep-vein thrombosis can be ruled out in a patient who is judged clinically unlikely to have deep-vein thrombosis and who has a negative d -dimer test. Ultrasound testing can be safely omitted in such patients.

A Randomized, Controlled Trial of the Use of Pulmonary-Artery Catheters in High-Risk Surgical Patients

Abstract: background Some observational studies suggest that the use of pulmonary-artery catheters to guide therapy is associated with increased mortality. methods We performed a randomized trial comparing goal-directed therapy guided by a pulmonary-artery catheter with standard care without the use of a pulmonary-artery catheter. The subjects were high-risk patients 60 years of age or older, with American Society of Anesthesiologists (ASA) class III or IV risk, who were scheduled for urgent or elective major surgery, followed by a stay in an intensive care unit. Outcomes were adjudicated by observers who were unaware of the treatment-group assignments. The primary outcome was in-hospital mortality from any cause. results Of 3803 eligible patients, 1994 (52.4 percent) underwent randomization. The baseline characteristics of the two treatment groups were similar. A total of 77 of 997 patients who underwent surgery without the use of a pulmonary-artery catheter (7.7 percent) died in the hospital, as compared with 78 of 997 patients in whom a pulmonary-artery catheter was used (7.8 percent) — a difference of 0.1 percentage point (95 percent confidence interval, i2.3 to 2.5). There was a higher rate of pulmonary embolism in the catheter group than in the standard-care group (8 events vs. 0 events, P=0.004). The survival rates at 6 months among patients in the standard-care and catheter groups were 88.1 and 87.4 percent, respectively (difference, i0.7 percentage point [95 percent confidence interval, i3.6 to 2.2]; negative survival differences favor standard care); at 12 months, the rates were 83.9 and 83.0 percent, respectively (difference, i0.9 percentage point [95 percent confidence interval, i4.3 to 2.4]). The median hospital stay was 10 days in each group. conclusions We found no benefit to therapy directed by pulmonary-artery catheter over standard care in elderly, high-risk surgical patients requiring intensive care.

A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma.

Abstract: A previous placebo-controlled trial has shown that biodegradable 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers (Gliadel wafers) prolong survival in patients with recurrent glioblastoma multiforme. A previously completed phase 3 trial, also placebo controlled, in 32 patients with newly diagnosed malignant glioma also demonstrated a survival benefit in those patients treated with BCNU wafers. Because of the small number of patients in that trial, a larger phase 3 trial was performed to confirm these results. Two hundred forty patients were randomized to receive either BCNU or placebo wafers at the time of primary surgical resection; both groups were treated with external beam radiation postoperatively. The two groups were similar for age, sex, Karnofsky performance status (KPS), and tumor histology. Median survival in the intent-to-treat group was 13.9 months for the BCNU wafer-treated group and 11.6 months for the placebo-treated group (log-rank P -value stratified by country = 0.03), with a 29% reduction in the risk of death in the treatment group. When adjusted for factors affecting survival, the treatment effect remained positive with a risk reduction of 28% ( P = 0.03). Time to decline in KPS and in 10/11 neuroperformance measures was statistically significantly prolonged in the BCNU wafer-treated group ( P

Effects of Computerized Physician Order Entry and Clinical Decision Support Systems on Medication Safety: A Systematic Review

Abstract: Background Iatrogenic injuries related to medications are common, costly, and clinically significant. Computerized physician order entry (CPOE) and clinical decision support systems (CDSSs) may reduce medication error rates. Methods We identified trials that evaluated the effects of CPOE and CDSSs on medication safety by electronically searching MEDLINE and the Cochrane Library and by manually searching the bibliographies of retrieved articles. Studies were included for systematic review if the design was a randomized controlled trial, a nonrandomized controlled trial, or an observational study with controls and if the measured outcomes were clinical (eg, adverse drug events) or surrogate (eg, medication errors) markers. Two reviewers extracted all the data. Discussion resolved any disagreements. Results Five trials assessing CPOE and 7 assessing isolated CDSSs met the criteria. Of the CPOE studies, 2 demonstrated a marked decrease in the serious medication error rate, 1 an improvement in corollary orders, 1 an improvement in 5 prescribing behaviors, and 1 an improvement in nephrotoxic drug dose and frequency. Of the 7 studies evaluating isolated CDSSs, 3 demonstrated statistically significant improvements in antibiotic-associated medication errors or adverse drug events and 1 an improvement in theophylline-associated medication errors. The remaining 3 studies had nonsignificant results. Conclusions Use of CPOE and isolated CDSSs can substantially reduce medication error rates, but most studies have not been powered to detect differences in adverse drug events and have evaluated a small number of "homegrown" systems. Research is needed to evaluate commercial systems, to compare the various applications, to identify key components of applications, and to identify factors related to successful implementation of these systems.

Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial.

Abstract: Context In the Women's Health Initiative trial of estrogen-plus-progestin therapy, women assigned to active treatment had fewer fractures. Objective To test the hypothesis that the relative risk reduction of estrogen plus progestin on fractures differs according to risk factors for fractures. Design, setting, and participants Randomized controlled trial (September 1993-July 2002) in which 16 608 postmenopausal women aged 50 to 79 years with an intact uterus at baseline were recruited at 40 US clinical centers and followed up for an average of 5.6 years. Intervention Women were randomly assigned to receive conjugated equine estrogen, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102). Main outcome measures All confirmed osteoporotic fracture events that occurred from enrollment to discontinuation of the trial (July 7, 2002); bone mineral density (BMD), measured in a subset of women (n = 1024) at baseline and years 1 and 3; and a global index, developed to summarize the balance of risks and benefits to test whether the risk-benefit profile differed across tertiles of fracture risk. Results Seven hundred thirty-three women (8.6%) in the estrogen-plus-progestin group and 896 women (11.1%) in the placebo group experienced a fracture (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.69-0.83). The effect did not differ in women stratified by age, body mass index, smoking status, history of falls, personal and family history of fracture, total calcium intake, past use of hormone therapy, BMD, or summary fracture risk score. Total hip BMD increased 3.7% after 3 years of treatment with estrogen plus progestin compared with 0.14% in the placebo group (P Conclusions This study demonstrates that estrogen plus progestin increases BMD and reduces the risk of fracture in healthy postmenopausal women. The decreased risk of fracture attributed to estrogen plus progestin appeared to be present in all subgroups of women examined. When considering the effects of hormone therapy on other important disease outcomes in a global model, there was no net benefit, even in women considered to be at high risk of fracture.

A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer.

Abstract: Background Experimental studies in animals and observational studies in humans suggest that regular aspirin use may decrease the risk of colorectal adenomas, the precursors to most colorectal cancers. Methods We conducted a randomized, double-blind trial to determine the effect of aspirin on the incidence of colorectal adenomas. We randomly assigned 635 patients with previous colorectal cancer to receive either 325 mg of aspirin per day or placebo. We determined the proportion of patients with adenomas, the number of recurrent adenomas, and the time to the development of adenoma between randomization and subsequent colonoscopic examinations. Relative risks were adjusted for age, sex, cancer stage, the number of colonoscopic examinations, and the time to a first colonoscopy. The study was terminated early by an independent data and safety monitoring board when statistically significant results were reported during a planned interim analysis. Results A total of 517 randomized patients had at least one colon...

A Comparison of Outcomes With Angiotensin-Converting--Enzyme Inhibitors and Diuretics for Hypertension in the Elderly

Abstract: Background Treatment of hypertension with diuretics, beta-blockers, or both leads to improved outcomes. It has been postulated that agents that inhibit the renin–angiotensin system confer benefit beyond the reduction of blood pressure alone. We compared the outcomes in older subjects with hypertension who were treated with angiotensin-converting–enzyme (ACE) inhibitors with the outcomes in those treated with diuretic agents. Methods We conducted a prospective, randomized, open-label study with blinded assessment of end points in 6083 subjects with hypertension who were 65 to 84 years of age and received health care at 1594 family practices. Subjects were followed for a median of 4.1 years, and the total numbers of cardiovascular events in the two treatment groups were compared with the use of multivariate proportional-hazards models. Results At base line, the treatment groups were well matched in terms of age, sex, and blood pressure. By the end of the study, blood pressure had decreased to a similar exte...

Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis

Abstract: ContextEstablishing relative benefit or harm from specific antihypertensive agents is limited by the complex array of studies that compare treatments. Network meta-analysis combines direct and indirect evidence to better define risk or benefit.ObjectiveTo summarize the available clinical trial evidence concerning the safety and efficacy of various antihypertensive therapies used as first-line agents and evaluated in terms of major cardiovascular disease end points and all-cause mortality.Data Sources and Study SelectionWe used previous meta-analyses, MEDLINE searches, and journal reviews from January 1995 through December 2002. We identified long-term randomized controlled trials that assessed major cardiovascular disease end points as an outcome. Eligible studies included both those with placebo-treated or untreated controls and those with actively treated controls.Data ExtractionNetwork meta-analysis was used to combine direct within-trial between-drug comparisons with indirect evidence from the other trials. The indirect comparisons, which preserve the within-trial randomized findings, were constructed from trials that had one treatment in common.Data SynthesisData were combined from 42 clinical trials that included 192 478 patients randomized to 7 major treatment strategies, including placebo. For all outcomes, low-dose diuretics were superior to placebo: coronary heart disease (CHD; RR, 0.79; 95% confidence interval [CI], 0.69-0.92); congestive heart failure (CHF; RR, 0.51; 95% CI, 0.42-0.62); stroke (RR, 0.71; 0.63-0.81); cardiovascular disease events (RR, 0.76; 95% CI, 0.69-0.83); cardiovascular disease mortality (RR, 0.81; 95% CI, 0.73-0.92); and total mortality (RR, 0.90; 95% CI, 0.84-0.96). None of the first-line treatment strategies–β-blockers, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers (CCBs), α-blockers, and angiotensin receptor blockers–was significantly better than low-dose diuretics for any outcome. Compared with CCBs, low-dose diuretics were associated with reduced risks of cardiovascular disease events (RR, 0.94; 95% CI, 0.89-1.00) and CHF (RR, 0.74; 95% CI, 0.67-0.81). Compared with ACE inhibitors, low-dose diuretics were associated with reduced risks of CHF (RR, 0.88; 95% CI, 0.80-0.96), cardiovascular disease events (RR, 0.94; 95% CI, 0.89-1.00), and stroke (RR, 0.86; 0.77-0.97). Compared with β-blockers, low-dose diuretics were associated with a reduced risk of cardiovascular disease events (RR, 0.89; 95% CI, 0.80-0.98). Compared with α-blockers, low-dose diuretics were associated with reduced risks of CHF (RR, 0.51; 95% CI, 0.43-0.60) and cardiovascular disease events (RR, 0.84; 95% CI, 0.75-0.93). Blood pressure changes were similar between comparison treatments.ConclusionsLow-dose diuretics are the most effective first-line treatment for preventing the occurrence of cardiovascular disease morbidity and mortality. Clinical practice and treatment guidelines should reflect this evidence, and future trials should use low-dose diuretics as the standard for clinically useful comparisons.

Metal-Protein Attenuation With Iodochlorhydroxyquin (Clioquinol) Targeting Aβ Amyloid Deposition and Toxicity in Alzheimer Disease: A Pilot Phase 2 Clinical Trial

Abstract: Background Alzheimer disease (AD) may be caused by the toxic accumulation of β-amyloid (Aβ). Objective To test this theory, we developed a clinical intervention using clioquinol, a metal-protein–attenuating compound (MPAC) that inhibits zinc and copper ions from binding to Aβ, thereby promoting Aβ dissolution and diminishing its toxic properties. Methods A pilot phase 2 clinical trial in patients with moderately severe Alzheimer disease. Results Thirty-six subjects were randomized. The effect of treatment was significant in the more severely affected group (baseline cognitive subscale score of the Alzheimer's Disease Assessment Scale, ≥25), due to a substantial worsening of scores in those taking placebo compared with minimal deterioration for the clioquinol group. Plasma Aβ 42 levels declined in the clioquinol group and increased in the placebo group. Plasma zinc levels rose in the clioquinol-treated group. The drug was well tolerated. Conclusion Subject to the usual caveats inherent in studies with small sample size, this pilot phase 2 study supports further investigation of this novel treatment strategy using a metal-protein–attenuating compound.

Effects of Rofecoxib or Naproxen vs Placebo on Alzheimer Disease Progression: A Randomized Controlled Trial

Abstract: ContextLaboratory evidence that inflammatory mechanisms contribute to neuronal injury in Alzheimer disease (AD), along with epidemiological evidence, suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) may favorably influence the course of the disease.ObjectiveTo determine whether treatment with a selective cyclooxygenase (COX) -2 inhibitor (rofecoxib) or a traditional nonselective NSAID (naproxen) slows cognitive decline in patients with mild-to-moderate AD.DesignMulticenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to study medications.SettingForty ambulatory treatment centers affiliated with the Alzheimer's Disease Cooperative Study consortium.ParticipantsParticipants with mild-to-moderate AD (Mini-Mental State Examination score of 13-26) were recruited from December 1999 to November 2000 using clinic populations, referrals from community physicians, and local advertising. Stable use of cholinesterase inhibitors, estrogen, low-dose aspirin, and vitamin E was allowed. Participants with inflammatory diseases that might respond to the study medications were excluded. Of 474 participants screened, 351 were enrolled.InterventionsOnce-daily rofecoxib, 25 mg, or twice-daily naproxen sodium, 220 mg, or placebo.Main Outcome MeasuresThe primary outcome measure was the 1-year change in the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score. Secondary outcome measures included the Clinical Dementia Rating scale sum-of-boxes, the Neuropsychiatric Inventory, the Quality of Life-AD, and the time to attainment of significant end points (4-point decline from baseline ADAS-Cog score, 1-step worsening on the global Clinical Dementia Rating scale, 15-point decline on the ADCS activities of daily living inventory, institutionalization, or death).ResultsThe 1-year mean (SD) change in ADAS-Cog scores in participants treated with naproxen (5.8 [8.0]) or rofecoxib (7.6 [7.7]) was not significantly different from the change in participants treated with placebo (5.7 [8.2]). Results of secondary analyses showed no consistent benefit of either treatment. Fatigue, dizziness, and hypertension were more commonly reported in the active drug groups, and more serious adverse events were found in the active treatment group than in the placebo group.ConclusionThe results of this study indicate that rofecoxib or low-dose naproxen does not slow cognitive decline in patients with mild-to-moderate AD.

Reduction of Hospital Utilization in Patients With Chronic Obstructive Pulmonary Disease: A Disease-Specific Self-management Intervention

Abstract: Background Self-management interventions improve various outcomes for many chronic diseases. The definite place of self-management in the care of chronic obstructive pulmonary disease (COPD) has not been established. We evaluated the effect of a continuum of self-management, specific to COPD, on the use of hospital services and health status among patients with moderate to severe disease. Methods A multicenter, randomized clinical trial was carried out in 7 hospitals from February 1998 to July 1999. All patients had advanced COPD with at least 1 hospitalization for exacerbation in the previous year. Patients were assigned to a self-management program or to usual care. The intervention consisted of a comprehensive patient education program administered through weekly visits by trained health professionals over a 2-month period with monthly telephone follow-up. Over 12 months, data were collected regarding the primary outcome and number of hospitalizations; secondary outcomes included emergency visits and patient health status. Results Hospital admissions for exacerbation of COPD were reduced by 39.8% in the intervention group compared with the usual care group ( P = .01), and admissions for other health problems were reduced by 57.1% ( P = .01). Emergency department visits were reduced by 41.0% ( P = .02) and unscheduled physician visits by 58.9% ( P = .003). Greater improvements in the impact subscale and total quality-of-life scores were observed in the intervention group at 4 months, although some of the benefits were maintained only for the impact score at 12 months. Conclusions A continuum of self-management for COPD patients provided by a trained health professional can significantly reduce the utilization of health care services and improve health status. This approach of care can be implemented within normal practice.

Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial.

Abstract: ContextObservational studies have suggested that postmenopausal hormone treatment may improve cognitive function, but data from randomized clinical trials have been sparse and inconclusive The Women's Health Initiative Memory Study (WHIMS) is an ancillary study of the Women's Health Initiative (WHI) hormone therapy trials On July 8, 2002, the estrogen plus progestin therapy in the WHI trial was discontinued because of certain increased health risks for womenObjectiveTo determine whether estrogen plus progestin therapy protects global cognitive function in older postmenopausal womenDesign, Setting, and ParticipantsA randomized, double-blind, placebo-controlled clinical trial, WHIMS is an ancillary study of geographically diverse, community-dwelling women aged 65 years or older from 39 of 40 clinical centers within the WHI estrogen plus progestin trial that started in June 1995 Of 4894 eligible postmenopausal women aged 65 years or older and free of probable dementia at baseline, 4532 (926%) were enrolled in the estrogen plus progestin component of WHIMS A total of 4381 participants (967%) provided at least 1 valid cognitive function score between June 1995 and July 8, 2002InterventionsParticipants received either 1 daily tablet containing 0625 mg of conjugated equine estrogen with 25 mg of medroxyprogesterone acetate (n = 2145) or matching placebo (n = 2236)Main Outcome MeasureGlobal cognitive function measured annually with the Modified Mini-Mental State ExaminationResultsThe Modified Mini-Mental State Examination mean total scores in both groups increased slightly over time (mean follow-up of 42 years) Women in the estrogen plus progestin group had smaller average increases in total scores compared with women receiving placebo (P = 03), but these differences were not clinically important Removing women by censoring them after adjudicated dementia, mild cognitive impairment, or stroke, and nonadherence to study protocol, did not alter the findings Prior hormone therapy use and duration of prior use did not affect the interpretation of the results, nor did timing of prior hormone therapy initiation with respect to the final menstrual period More women in the estrogen plus progestin group had a substantial and clinically important decline (≥2 SDs) in Modified Mini-Mental State Examination total score (67%) compared with the placebo group (48%) (P = 008)ConclusionsAmong postmenopausal women aged 65 years or older, estrogen plus progestin did not improve cognitive function when compared with placebo While most women receiving estrogen plus progestin did not experience clinically relevant adverse effects on cognition compared with placebo, a small increased risk of clinically meaningful cognitive decline occurred in the estrogen plus progestin group

Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial.

Abstract: ContextTreatment strategies for cystic fibrosis (CF) lung disease include antibiotics, mucolytics, and anti-inflammatory therapies. Increasing evidence suggests that macrolide antibiotics might be beneficial in patients with CF.ObjectiveTo determine if an association between azithromycin use and pulmonary function exists in patients with CF.Design and SettingA multicenter, randomized, double-blind, placebo-controlled trial conducted from December 15, 2000, to May 2, 2002, at 23 CF care centers in the United States.ParticipantsOf the 251 screened participants with a diagnosis of CF, 185 (74%) were randomized. Eligibility criteria included age 6 years or older, infection with Pseudomonas aeruginosa for 1 or more years, and a forced expiratory volume in 1 second (FEV1) of 30% or more. Participants were stratified by FEV1 (≥60% predicted vs <60% predicted), weight of less than 40 kg vs 40 kg or more, and CF center.InterventionThe active group (n = 87) received 250 mg (weight <40 kg) or 500 mg (weight ≥40 kg) of oral azithromycin 3 days a week for 168 days; placebo group (n = 98) received identically packaged tablets.Main Outcome MeasuresChange in FEV1 from day 0 to completion of therapy at day 168 and determination of safety. Secondary outcomes included pulmonary exacerbations and weight gain.ResultsThe azithromycin group had a mean 0.097-L (SD, 0.26) increase in FEV1 at day 168 compared with 0.003 L (SD, 0.23) in the placebo group (mean difference, 0.094 L; 95% confidence interval [CI], 0.023-0.165; P = .009). Nausea occurred in 17% more participatns in the azithromycin group (P = .01), diarrhea in 15% more (P = .009), and wheezing in 13% more (P = .007). Participants in the azithromycin group had less risk of experiencing an exacerbation than participants in the placebo group (hazard ratio, 0.65; 95% CI, 0.44-0.95; P = .03) and weighed at the end of the study an average 0.7 kg more than participants receiving placebo (95% CI, 0.1-1.4 kg; P = .02).ConclusionAzithromycin treatment was associated with improvement in clinically relevant end points and should be considered for patients with CF who are 6 years or older and chronically infected with P aeruginosa.

Systematic Review of Herbs and Dietary Supplements for Glycemic Control in Diabetes

Abstract: OBJECTIVE —To conduct a systematic review of the published literature on the efficacy and safety of herbal therapies and vitamin/mineral supplements for glucose control in patients with diabetes. RESEARCH DESIGN AND METHODS —We conducted an electronic literature search of MEDLINE, OLDMEDLINE, Cochrane Library Database, and HealthSTAR, from database inception to May 2002, in addition to performing hand searches and consulting with experts in the field. Available clinical studies published in the English language that used human participants and examined glycemic control were included. Data were extracted in a standardized manner, and two independent investigators assessed methodological quality of randomized controlled trials using the Jadad scale. RESULTS —A total of 108 trials examining 36 herbs (single or in combination) and 9 vitamin/mineral supplements, involving 4,565 patients with diabetes or impaired glucose tolerance, met the inclusion criteria and were analyzed. There were 58 controlled clinical trials involving individuals with diabetes or impaired glucose tolerance (42 randomized and 16 nonrandomized trials). Most studies involved patients with type 2 diabetes. Heterogeneity and the small number of studies per supplement precluded formal meta-analyses. Of these 58 trials, the direction of the evidence for improved glucose control was positive in 76% (44 of 58). Very few adverse effects were reported. CONCLUSIONS —There is still insufficient evidence to draw definitive conclusions about the efficacy of individual herbs and supplements for diabetes; however, they appear to be generally safe. The available data suggest that several supplements may warrant further study. The best evidence for efficacy from adequately designed randomized controlled trials (RCTs) is available for Coccinia indica and American ginseng. Chromium has been the most widely studied supplement. Other supplements with positive preliminary results include Gymnema sylvestre , Aloe vera , vanadium, Momordica charantia , and nopal.

The clinical importance of changes in outcome scores after treatment for chronic low back pain

Abstract: When measuring treatment effect in chronic low back pain with multi-item outcome instruments, it is necessary, both for clinical decision-making and research purposes, to understand the clinical importance of the outcome scores. The aims of the present study were three-fold. Firstly, it aimed to estimate the minimal clinically important difference of three multi-item outcome instruments (the Oswestry Disability Index, the General Function Score and the Zung Depression Scale) and of the visual analogue scale (VAS) of back pain. Secondly, it aimed to estimate the error of measurement of these instruments; and its third aim was to describe the clinical meaning of score change. The study population consisted of 289 patients treated surgically or non-surgically in a randomised controlled trial. The minimal clinically important difference was estimated with patient global assessment as the external criterion. It was compared with the standard error of measurement of the instruments. The individual items of the instruments were compared for score changes related to improvement and deterioration. The standard error of measurement of the Oswestry Disability Index, the General Function Score and the Zung Depression Scale was 4, 6 and 3 units, respectively. The 95% tolerance interval was 10, 16 and 8 units, respectively. The minimal clinically important difference was 10, 12 and 8–9 units, respectively, thus not significantly exceeding the tolerance interval. The minimal clinically important difference of VAS back pain was 18–19 units, well exceeding the 95% tolerance interval, which was 15 units. Improvement after treatment for chronic low back pain tends to occur to a greater extent in sleep disturbance, ability to do usual things and psychological irritability, but to a lesser extent in the ability to sit, stand and lift. We conclude that the VAS of back pain is responsive enough to detect the minimal clinically important difference, whereas the smallest acceptable score changes of the Oswestry Disability Index, the General Function Score and the Zung Depression Scale may require an increase to exceed the 95% tolerance interval when used for clinical decision making and for power calculation. Despite improvement after treatment, the ability to sit, stand and lift, remain notable problems.