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PubMed2006

Transition from meeting abstract to full-length journal article for randomized controlled trials.

CONTEXT: Not all research presented at scientific meetings is subsequently published and, even when it is, there may be inconsistencies between these results and what is ultimately printed. Although late-breaking trials sessions are now integrated into several major scientific meetings and the results are often promptly and prominently communicated, no studies have examined the publication fate and degree of consistency between meeting abstracts or presentations and subsequent full-length article publications for randomized controlled trials (RCTs) presented at these sessions. OBJECTIVE: To compare RCT abstracts presented in the late-breaking trials session vs other sessions at a major scientific meeting and subsequent full-length publications. DESIGN: RCTs were identified by hand searching abstract proceedings booklets and related Web sites for the American College of Cardiology scientific meetings (1999-2002). Subsequent full-length articles were identified via electronic databases. MAIN OUTCOME MEASURES: Publication fate and degree of consistency between meeting abstract results and subsequent full-length publication results. RESULTS: The 86 late-breaking RCTs were significantly larger (median, 2737 patients vs 896; P<.001), were more likely to be preceded by a published design paper (27 [31%] vs 13 [13%]; P = .002), had higher quality scores when eventually published (mean Jadad score 2.69 vs 2.19; P = .01), and were less likely to report favorable results for the intervention than the 100 randomly chosen comparison RCTs presented in other sessions (50 [58%] vs 75 [75%]; P = .01; odds ratio 0.46; 95% confidence interval, 0.24-0.90). RCTs presented at the late-breaking trials sessions were significantly more likely to be published (79 [92%] vs 69 [69%]; P<.001) and appeared earlier after presentation (median 11.5 months vs 22.0 months; P<.001) than RCTs presented in other sessions, an association that persisted even after adjusting for sample size, conclusion of study, and RCT design: adjusted hazard ratio, 1.80 (95% confidence interval, 1.24-2.61). Sixty (41%) of the 148 RCTs that were subsequently published exhibited discrepancies between the efficacy estimate reported in the meeting abstract vs the one reported in the full-length article for the primary outcome. The mean change in effect was 0.44 SDs and in 20 cases (14%), the point estimate was statistically significant in only 1 member of the pair. The discrepancy rate was the same for late-breaking RCTs as for RCTs presented in other American College of Cardiology sessions (P = .92). CONCLUSIONS: Late-breaking trials were larger, more likely to be preceded by a design paper, and less likely to report positive results than RCTs presented at other sessions, but discrepancies between the meeting abstract results and subsequent full-length publication results were common even for late-breaking trials.

Abstracting and Indexing↗

PubMed2025

High-Dose vs Standard-Dose Influenza Vaccine and Cardiovascular Outcomes in Older Adults: A Prespecified Secondary Analysis of the DANFLU-2 Randomized Clinical Trial.

IMPORTANCE: The high-dose inactivated influenza vaccine (HD-IIV) has demonstrated superior protection against laboratory-confirmed influenza infection vs standard-dose IIV (SD-IIV); however, data regarding its effectiveness against cardiovascular (CV) outcomes are mainly from observational studies or specific high-risk groups. OBJECTIVE: To investigate the relative vaccine effectiveness (rVE) of HD-IIV vs SD-IIV against CV outcomes in the general older adult population in Denmark. DESIGN, SETTING, AND PARTICIPANTS: This was a prespecified secondary analysis of DANFLU-2, a pragmatic, open-label, individually randomized clinical trial (RCT) using nationwide administrative health registries in Denmark during the 2022/2023 to 2024/2025 influenza seasons. Older adults (age ≥65 years) were eligible for inclusion regardless of comorbidity. The trial design specified that if the primary end point was neutral, no hypothesis testing would be performed for secondary or exploratory end points. Data were analyzed from June 29 to August 12, 2025. INTERVENTIONS: Individual-level 1:1 randomization to HD-IIV or SD-IIV. Participants re-enrolling in additional seasons were rerandomized. MAIN OUTCOMES AND MEASURES: Severe CV outcomes were prespecified secondary and exploratory end points in the trial, occurring from 14 days after vaccination through May 31 the following year. RESULTS: A total of 332 438 participants (170 900 [51.4%] male; mean [SD] age, 73.7 [5.8] years) were randomized (166 218 to HD-IIV and 166 220 to SD-IIV), of whom 91 026 (27.4%) had a history of CV disease. HD-IIV did not significantly reduce the trial's primary end point of hospitalization for influenza or pneumonia. The incidence of hospitalization for any cardiorespiratory disease was lower in the HD-IIV group than the SD-IIV group (rVE, 5.7% [95% CI, 1.4% to 9.9%]; absolute difference, -0.13 [95% CI, -0.24 to -0.03] percentage points), and rVE did not differ by history of CV disease compared with no CV disease at baseline. Hospitalization for any CV disease occurred in fewer participants in the HD-IIV group than the SD-IIV group (rVE, 7.5% [95% CI, 1.5% to 12.5%]; absolute difference, -0.10 [95% CI, -0.18 to -0.02] percentage points) as did hospitalization for heart failure (rVE, 19.5% [95% CI, 3.3% to 33.1%]; absolute difference, -0.03 [95% CI, -0.06 to -0.01] percentage points). CONCLUSIONS AND RELEVANCE: This study found reduced incidence of cardiorespiratory hospitalization among those who received HD-IIV vs SD-IIV, driven by a lower incidence of CV hospitalizations, and particularly heart failure hospitalizations. These differences should be interpreted as exploratory findings in the setting of a large RCT with a neutral primary outcome. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05517174.

Aged↗

PubMed1996

Prognostic factors for patients with colon or rectal carcinoma treated with resection only. Five-year follow-up report.

BACKGROUND: The prognostic factors and natural history of recurrence in patients with colorectal carcinoma who underwent curative resection and no other therapy were analyzed. METHODS: The object of analysis was the potentially curative resection only subgroup in the randomized clinical trial (RCT) that we performed. Cox's proportional hazards model was used mainly to analyze recurrence rates during the first 5 years after surgery. RESULTS: The analysis was performed on a subgroup of the RCT (279 patients with colon carcinoma and 293 patients with rectal carcinoma). Five-year disease free survival rates were 76.3% and 56.5% for colon and rectal carcinomas, respectively. The prognostic factors for recurrence for colon carcinoma patients were different from those with rectal carcinoma. For colon carcinoma, only Dukes stage was significant, whereas for rectal carcinoma, Dukes stage, age, location of the tumor, and serosal and venous invasion by cancer cells were prognostic factors. Log-transformed disease free survival rates were linear in Dukes Stage B and biphasic in Dukes Stage C for both colon and rectal carcinoma. The two phases in Dukes Stage C intersected at 2.85 and 3.04 years, respectively. The annual hazard value was high for the first 3 years in both colon and rectal carcinoma. CONCLUSIONS: We conclude that follow-up of patients with colorectal carcinoma who undergo potentially curative resection is of particular importance in the first 3 years after surgery. Furthermore, the usefulness of adjuvant chemotherapy can be adequately evaluated from data yielded during this postoperative period.

Chemotherapy, Adjuvant↗

PubMed1997

Rationale, objectives, and interpretation of randomized controlled trials.

A randomized controlled trial (RCT) is the most definitive tool for evaluation of the effectiveness of an intervention and can establish a cause-and-effect relationship between an intervention and an improved disease outcome. However, the undertaking of an RCT does not guarantee valid results, and the findings of RCTs of the same intervention are often discrepant. While many reported trials are of high quality, a significant number have deficiencies in design, conduct, analysis, or interpretation of results. Medical practitioners must become familiar with the methodology of RCTs in order to assess the validity of the reported findings and the relevance of the results to their own patients. Trialists must report sufficient information about the methods used so that readers can judge for themselves if the trial worked as planned.

Education, Medical↗

PubMed1997

The choice of pharmacoeconomic study design during drug development--part 2.

Pharmaceutical manufacturers are faced with the challenge of when and how to conduct pharmacoeconomic (PE) evaluations to satisfy formulary decision-makers. To illustrate the usefulness of decision analysis for strategic planning in drug development, a model was created to compare the cost-benefit of three PE design options: (1) add-on to a phase III safety and efficacy randomized controlled clinical trial (RCT), (2) stand-alone phase IIIb trial and (3) a phase IV observational study. Hypothetical data on the cost of performing each type of study, the probability of a conclusive PE evaluation and the 5-year sales potential of a cost-effective product were incorporated into the model. At a discount rate of 7%, the incremental net benefit of a phase IIIb PE study was 4.2 million Canadian dollars compared to a phase III RCT and 10.5 million Canadian dollars compared to a phase IV study. The incremental net benefit of a stand-alone phase IIIb trial compared to an add-on phase III design was negligible when the formulary percentage of total sales was 25% and the discount rate 10%. Although the data used to demonstrate the model were hypothetical, decision analysis can be a useful tool for preparing a sensible development strategy or uncovering deficiencies in an existing plant.

Journal Article↗

PubMed2001

Parameter solicitation for planning cost effectiveness studies with dichotomous outcomes.

When economic endpoints are included alongside clinical effectiveness measures in randomized clinical trials (RCT), they are summarized together by the incremental cost effectiveness ratio (ICER). Adding economic endpoints to an RCT complicates the planning of experiments because investigators must now solicit their beliefs about costs, but even more challenging, they must also specify their association with effectiveness. Solicitation of correlations between costs and effects can be unintuitive, and so potentially highly inaccurate. This is unfortunate because power is highly sensitive to the association between costs and effects. Mis-specification in this association may lead to substantially underpowered or overpowered studies. We show that when clinical effectiveness measures are dichotomous, specification of the correlation between costs and effects can be avoided by instead describing their association with a mixture model. This representation leads to simple and highly intuitive parameter specifications. It may also be used to generate realistic raw data that can be used to evaluate experiment power with simulation. We give particular attention to evaluating and interpreting power when Fieller's theorem method (FTM) is used to calculate confidence for, and test hypotheses about, the ICER. Data from a previously published clinical trial are used to demonstrate the use of this new method to calculate sample size for a cost effectiveness study.

Cost-Benefit Analysis↗

PubMed2000

Interventions for helping patients to follow prescriptions for medications.

BACKGROUND BACKGROUND: Efforts to assist patients with adherence to prescribed, self-administered medications might improve the benefits and efficiency of health care. OBJECTIVES OBJECTIVE: To update an ongoing review summarising the results of randomised controlled trials (RCTs) of interventions to help patients follow prescriptions for medications, focusing on trials that measured both adherence and clinical outcomes. SEARCH STRATEGY: Computerised searches to July 1998 in MEDLINE, CINAHL, The Cochrane Library, International Pharmaceutical Abstracts (IPA), PsychInfo, Sociofile, and HSTAR; bibliographies in articles on patient adherence; articles in the reviewers' personal collections; and contact with authors. SELECTION CRITERIA: Articles were selected if they reported an unconfounded RCT of an intervention to improve adherence with prescribed medications, measuring both medication adherence and treatment outcome, with at least 80% follow-up of each group studied and, for long-term treatments, at least six months follow-up for studies with positive initial findings. DATA COLLECTION AND ANALYSIS: Information on study design features, interventions and controls, and findings were extracted by one reviewer (PM) and a research assistant and confirmed by two of the other reviewers. The studies were too disparate to warrant meta-analysis. MAIN RESULTS: For short-term treatments, one study, of counselling and written information, showed an effect on adherence and clinical outcome. Ten of 19 interventions for long-term treatments reported in 17 RCTs were associated with improvements in adherence, but only nine interventions led to improvements in treatment outcomes. Almost all of the interventions that were effective for long-term care were complex, including combinations of more convenient care, information, counselling, reminders, self-monitoring, reinforcement, family therapy, and other forms of additional supervision or attention. Even the most effective interventions did not lead to large improvements in adherence and treatment outcomes. Two studies showed that telling patients about adverse effects of treatment did not affect their adherence. REVIEWER'S CONCLUSIONS: The full benefits of medications cannot be realised at currently achievable levels of adherence. Current methods of improving adherence for chronic health problems are mostly complex and not very effective. More studies of innovative approaches to assist patients to follow medication prescriptions are needed.

Drug Prescriptions↗

PubMed2005

Interventions to enhance medication adherence.

BACKGROUND: People who are prescribed self-administered medications typically take less than half the prescribed doses. Efforts to assist patients with adherence to medications might improve the benefits of prescribed medications, but also might increase their adverse effects. OBJECTIVES: To update a review summarizing the results of randomized controlled trials (RCTs) of interventions to help patients follow prescriptions for medications for medical problems, including mental disorders but not addictions. SEARCH STRATEGY: Computerized searches were updated to September 2004 without language restriction in MEDLINE, EMBASE, CINAHL, The Cochrane Library, International Pharmaceutical Abstracts (IPA), PsycINFO and SOCIOFILE. We also reviewed bibliographies in articles on patient adherence and articles in our personal collections, and contacted authors of original and review articles on the topic. SELECTION CRITERIA: Articles were selected if they reported an unconfounded RCT of an intervention to improve adherence with prescribed medications, measuring both medication adherence and treatment outcome, with at least 80% follow-up of each group studied and, for long-term treatments, at least six months follow-up for studies with positive initial findings. DATA COLLECTION AND ANALYSIS: Study design features, interventions and controls, and results were extracted by one reviewer and confirmed by at least one other reviewer. We extracted adherence rates and their measures of variance for all methods of measuring adherence in each study, and all outcome rates and their measures of variance for each study group, as well as levels of statistical significance for differences between study groups, consulting authors and verifying or correcting analyses as needed. MAIN RESULTS: For short-term treatments, four of nine interventions reported in eight RCTs showed an effect on both adherence and at least one clinical outcome, while one intervention reported in one RCT significantly improved patient compliance, but did not enhance the clinical outcome. For long-term treatments, 26 of 58 interventions reported in 49 RCTs were associated with improvements in adherence, but only 18 interventions led to improvement in at least one treatment outcome. Almost all of the interventions that were effective for long-term care were complex, including combinations of more convenient care, information, reminders, self-monitoring, reinforcement, counseling, family therapy, psychological therapy, crisis intervention, manual telephone follow-up, and supportive care. Even the most effective interventions did not lead to large improvements in adherence and treatment outcomes. Six studies showed that telling patients about adverse effects of treatment did not affect their adherence. AUTHORS' CONCLUSIONS: Improving short-term adherence is relatively successful with a variety of simple interventions. Current methods of improving adherence for chronic health problems are mostly complex and not very effective, so that the full benefits of treatment cannot be realized. High priority should be given to fundamental and applied research concerning innovations to assist patients to follow medication prescriptions for long-term medical disorders.

Drug Therapy↗

PubMed2000

Electroconvulsive therapy for schizophrenia.

BACKGROUND: Electroconvulsive therapy (ECT) involves the induction of a seizure (fit) for therapeutic purposes by the administration of a low frequency electrical stimulus shock via electrodes applied to the scalp. At present it is used for those with schizophrenia but its effects are unclear. OBJECTIVES: To determine whether electroconvulsive therapy (ECT) results in clinically meaningful benefit with regard to global improvement, hospitalisation, changes in mental state, behaviour and functioning in those with schizophrenia. SEARCH STRATEGY: Electronic searches of Biological Abstracts (1982-1996), EMBASE (1980-1996), Medline (1966-1996), PsycLIT (1974-1996) and SCISEARCH (1996) were undertaken. The references of all identified studies were investigated. SELECTION CRITERIA: All randomised controlled trials that compared ECT with placebo, 'sham ECT', non-pharmacological interventions and antipsychotics for people with schizophrenia, schizoaffective disorder or chronic mental disorder. DATA COLLECTION AND ANALYSIS: The reviewers extracted the data independently and analysed the data on an intention to treat basis. MAIN RESULTS: Less people with schizophrenia treated with ECT showed no improvement in general functioning when compared to those given placebo in the short term (OR 0.48 CI 99% 0.26-0.90). This effect, however, does not last. However, ECT is less effective than antipsychotic drug treatment for those with schizophrenia. Limited evidence exists to suggest that combining antipsychotic drugs and ECT increases the rate and extent of clinical improvement, in the short term, in one out of every five to six people. The evidence for the efficacy of ECT in the medium to long term is equivocal. Electroconvulsive therapy is also more effective than the now obsolete insulin coma treatment. REVIEWER'S CONCLUSIONS: There is some evidence to support the use of ECT for those with schizophrenia for short term relief of symptoms. Electroconvulsive therapy may be advocated as an adjunct to antipsychotic medication for those with schizophrenia who show a limited response to medication alone but the evidence for this is not strong. In fact in spite of more than five decades of widespread clinical use, the administration of ECT to those with schizophrenia lacks a strong research base.

Electroconvulsive Therapy↗

PubMed2000

Corticosteroids for preventing relapse following acute exacerbations of asthma.

BACKGROUND: Acute asthma is responsible for many emergency department visits annually. Between 12-16% will relapse to require additional interventions within two weeks of ED discharge. Treatment of acute asthma is based on rapid reversal of bronchospasm and reducing airway inflammation and this review examines the evidence for using systemic corticosteroids to improve outcomes after discharge from the ED. OBJECTIVES: To determine the benefit of corticosteroids (oral, intramuscular, or intravenous) for the treatment of asthmatic patients discharged from an acute care setting (i.e. usually the emergency department) after assessment and treatment of an acute asthmatic exacerbation. SEARCH STRATEGY: The Cochrane Airways Group "Asthma and Wheez* RCT" register was searched using the terms: a) Asthma OR Wheez* b) Glucocorticoid OR Steroid* AND c) Exacerbat* OR Relapse* OR Emerg*. In addition, authors of all included studies were contacted to determine if unpublished studies which met the inclusion criteria were available. Bibliographies from included studies, known reviews and texts were also searched for additional citations. SELECTION CRITERIA: Only randomized controlled trials were eligible for selection. Studies were included in this review if they dealt with the outpatient treatment of asthmatic exacerbations using glucocorticoids at discharge and reported either relapse rate or PFTs. Two independent reviewers first identified potentially relevant studies and then selected articles for inclusion. Methodological quality was assessed independently by two reviewers. Agreement was assessed using kappa (k) statistics. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers; authors were contacted to verify the extracted data and clarify missing information. When author contact was unsuccessful, missing data were estimated from graphs where possible. Sensitivity, sub-group and overall analyses were performed using the Cochrane Review Manager. MAIN RESULTS: A search that yielded 229 references identified 169 (73%) original publications. Reviewers identified 8 studies for potential inclusion (k =0.76); 18 references were added by searching publication reference lists and contact with authors. Of these 26 articles, a total of 7 were included in the overview. Two studies used intramuscular corticosteroids, five studies used oral corticosteroids. Significantly fewer patients in the corticosteroid group relapsed to receive additional care in the first week (odds ratio (OR) 0.35; 95% confidence interval (CI): 0.17, 0.73). This favourable effect was maintained over the first 21 days (OR 0.33; 95% CI: 0.13, 0.82). Patients receiving corticosteroids had less need for beta-agonists (weighted mean difference (WMD) -3.3 activations/day; 95% CI: -5.5, -1.0). Changes in pulmonary function tests (SMD 0.045; 95% CI: -0.47, 0.56) and side effects (SMD 0.03; 95% CI : -0.38, 0.44) in the first 7-10 days, while rarely reported, showed no differences between the treatment groups. Statistically significant heterogeneity was identified for the side effect results; all other outcomes were homogeneous. It appears that IM corticosteroids are similarly efficacious to a 7-10 day tapering course of oral agents. From these results, as few as 13 patients need to be treated to prevent relapse to additional care after an exacerbation of asthma. REVIEWER'S CONCLUSIONS: A short course of corticosteroids following assessment for an acute exacerbation of asthma significantly reduces the number of relapses to additional care and decreases beta-agonist use without an apparent increase in side effects. Intramuscular corticosteroids appear as effective as oral agents.

Acute Disease↗

PubMed2000

Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants.

BACKGROUND: Nosocomial infections continue to be a significant cause of morbidity and mortality among preterm and/or low birth weight infants. Maternal transport of immunoglobulins to the fetus mainly occurs after 32 weeks gestation and endogenous synthesis does not begin until several months after birth. Administration of intravenous immunoglobulin provides IgG that can bind to cell surface receptors, provide opsonic activity, activate complement, promote antibody dependent cytotoxicity, and improve neutrophilic chemoluminescence. Intravenous immunoglobulin thus has the potential of preventing or altering the course of nosocomial infections. OBJECTIVES: To assess the effectiveness/safety of intravenous immunoglobulin (IVIG) administration (compared to placebo or no intervention) to preterm (< 37 weeks gestational age at birth) and/or low birth weight (LBW) (< 2500 g BW) infants in preventing nosocomial infections. SEARCH STRATEGY: Medline, Embase, Cochrane Library and Reference Update Databases were searched in November 1997 using keywords: immunoglobulin and infant-newborn and random allocation or controlled trial or randomized controlled trial (RCT). The reference lists of identified RCTs, personal files and Science Citation Index were searched. No language restrictions were applied. SELECTION CRITERIA: The criteria used to select studies for inclusion in this overview were: 1) DESIGN: RCTs in which administration of IVIG was compared to a control group that received a placebo or no intervention. 2) POPULATION: preterm (< 37 weeks gestational age) and/or LBW (<2500 g) infants. 3) INTERVENTION: IVIG for the prevention of bacterial/fungal infection during initial hospital stay (8 days or longer). (Studies that were primarily designed to assess the effect of IVIG on humoral immune markers were excluded as were studies in which the follow-up period was one week or less). 4) At least one of the following outcomes was reported: sepsis, any serious infection, death from all causes, death from infection, length of hospital stay, intraventricular haemorrhage (IVH), necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD). DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted information for each outcome reported in each study, and one researcher (AO) checked for any discrepancies and pooled the results. Relative risk (RR) and Risk Difference (RD) with 95% confidence intervals (CI) using the fixed effects model are reported. When a statistically significant RD was found the number needed to treat (NNT) was also calculated with 95% CIs. The results include all accepted studies in which the outcome of interest was reported. When statistically significant heterogeneity was found for an outcome, secondary (sensitivity) analyses were performed including only studies of the highest quality. MAIN RESULTS: Fifteen studies met inclusion criteria. These included 5,054 preterm and/or LBW infants and reported on at least one of the outcomes of interest for this systematic review. When all studies were combined there was a statistically significant reduction in sepsis, one or more episodes [RR 0.83 (95% CI 0.72, 0.97); RD -0.028 (95% CI -0.006, -0.051); NNT 36 (95% CI 20, 167)]. There was significant between-study heterogeneity. When, in a sensitivity analysis, the high quality studies were combined, the results remained significant [RR 0.78 (95% CI 0.62, 0.98); RD -0.031(95% CI -0.003, -0.059); NNT 32 (95% CI 17, 333]. For this analysis there was no statistically significant between-study heterogeneity. A statistically significant reduction was also found for any serious infection, one or more episodes, when all studies were combined [RR 0.85 (95% CI 0.75, 0. 95); RD -0.032 (95% CI -0.010, -0.054,); NNT 31 (95% CI 19, 100). There was statistically significant between-study heterogeneity. When, in a sensitivity analysis, the high quality studies were combined the results remained statistically significant [RR 0.80 (95% CI

Cross Infection↗

PubMed2004

Hormone replacement therapy in postmenopausal women: endometrial hyperplasia and irregular bleeding.

BACKGROUND: The decline in circulating oestrogen around the time of the menopause often induces unacceptable symptoms that affect the health and well being of women. Hormone replacement therapy (both unopposed oestrogen and oestrogen and progestogen combinations) is an effective treatment for these symptoms. In women with an intact uterus, unopposed oestrogen may induce endometrial stimulation and increase the risk of endometrial hyperplasia and carcinoma. The addition of progestogen reduces this risk but may cause unacceptable symptoms, bleeding and spotting which can affect adherence to therapy. OBJECTIVES: The objective of this review is to assess which hormone replacement therapy regimens provide effective protection against the development of endometrial hyperplasia and/or carcinoma with a low rate of abnormal vaginal bleeding. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group trials register (searched January 2003), The Cochrane Library (Issue 2, 2003), MEDLINE (1966 to January 2003), EMBASE (1980 to January 2003), Current Contents (1993 to January 2003), Biological Abstracts (1969 to 2002), Social Sciences Index (1980 to January 2003), PsycINFO (1972 to February 2003) and CINAHL (1982 to January 2003). The search strategy was developed by the Cochrane Menstrual Disorder and Subfertility Group. Attempts were also made to identify trials from citation lists of review articles and drug companies were contacted for unpublished data. In most cases, the corresponding author of each included trial was contacted for additional information. SELECTION CRITERIA: The inclusion criteria were randomised comparisons of unopposed oestrogen therapy, combined continuous oestrogen-progestogen therapy and sequential oestrogen-progestogen therapy with each other and placebo administered over a minimum treatment period of six months. Trials had to assess which regimen was the most protective against the development of endometrial hyperplasia/carcinoma and/or caused the lowest rate of irregular bleeding. DATA COLLECTION AND ANALYSIS: Sixty RCTs were identified. Of these 23 were excluded and seven remain awaiting assessment. The reviewers assessed the thirty included studies for quality, extracted the data independently and odds ratios for dichotomous outcomes were estimated. Outcomes analysed included frequency of endometrial hyperplasia or carcinoma, frequency of irregular bleeding and unscheduled biopsies or dilation and curettage, and adherence to therapy. MAIN RESULTS: Unopposed moderate or high dose oestrogen therapy when compared to placebo was associated with a significant increase in rates of endometrial hyperplasia with increasing rates at longer duration of treatment and follow up. Odds ratios ranged from (1 RCT; OR 5.4, 95% CI 1.4 to 20.9) for 6 months of treatment to (4 RCTs; OR 9.6, 95% CI 5.9 to 15.5) for 24 months treatment and (1 RCT; OR 15.0, 95% CI 9.3 to 27.5) for 36 months of treatment with moderate dose oestrogen (in the PEPI trial, 62% of those who took moderate dose oestrogen had some form of hyperplasia at 36 months compared to 2% of those who took placebo). Irregular bleeding and non adherence to treatment were also significantly more likely under these unopposed oestrogen regimens that increased bleeding with higher dose therapy. Although not statistically significant, there was a 3% incidence (2 RCTs) of hyperplasia in women who took low dose oestrogen compared to no incidence of hyperplasia in the placebo group. The addition of progestogens, either in continuous combined or sequential regimens, helped to reduce the risk of endometrial hyperplasia and improved adherence to therapy. At longer duration of treatment, continuous therapy was more effective than sequential therapy in reducing the risk of endometrial hyperplasia. There was evidence of a higher incidence of hyperplasia under long cycle sequential therapy (progestogen given every three months) compared to monthly sequential therapy (progestogen given every month). No increase in endometrial cancer was seen in any of t in any of the treatment groups during the duration (maximum of six years) of these trials. During the first year of therapy irregular bleeding and spotting was more likely in continuous combined therapy than sequential therapy. However, during the second year of therapy bleeding and spotting was more likely under sequential regimens. REVIEWERS' CONCLUSIONS: There is strong and consistent evidence in this review that unopposed oestrogen therapy, at moderate and high doses, is associated with increased rates of endometrial hyperplasia, irregular bleeding and consequent non adherence to therapy. The addition of oral progestogens administered either sequentially or continuously is associated with reduced rates of hyperplasia and improved adherence to therapy. Irregular bleeding is less likely under sequential than continuous therapy during the first year of therapy but there is a suggestion that continuous therapy over long duration is more protective than sequential therapy in the prevention of endometrial hyperplasia. Hyperplasia is more likely when progestogen is given every three months in a sequential regimen compared to a monthly progestogen sequential regimen.

Endometrial Hyperplasia↗

PubMed2000

Risperidone versus typical antipsychotic medication for schizophrenia.

BACKGROUND: The 'conventional' neuroleptic drugs, such as haloperidol and chlorpromazine, are frequently used as the first line treatment for people with schizophrenia. However, about 5-25% of these people show poor response to these treatments and side effects often makes compliance with the 'older generation' of drug treatment problematic. Although the efficacy of these medications with respect to 'positive' symptoms is well described, little evidence exists that 'conventional' antipsychotic treatment has any effect on the 'negative' symptoms of schizophrenia. Risperidone is one of the 'new generation' neuroleptic compounds. As well as its reputed tendency to cause fewer movement disorders it is claimed that risperidone may improve negative symptoms. OBJECTIVES: To evaluate the effectiveness of risperidone for schizophrenia in comparison to 'conventional' neuroleptic drugs. SEARCH STRATEGY: Electronic searches of Biological Abstracts (1980-1997), Cochrane Schizophrenia Group's Register (1997), The Cochrane Library (1997, Issue1), EMBASE (1980-1997), MEDLINE (1966-1997), PsycLIT (1974-1997), and SCISEARCH (1997) were undertaken. References of all identified studies were searched for further trial citations. Pharmaceutical companies and authors of trials were contacted. SELECTION CRITERIA: All randomised trials comparing risperidone to any 'conventional' neuroleptic treatment for those with schizophrenia or other serious mental illnesses. DATA COLLECTION AND ANALYSIS: Citations and, where possible, abstracts were independently inspected by reviewers, papers ordered, re-inspected and quality assessed. Data were also independently extracted. Sensitivity analyses on dose of risperidone, haloperidol and duration of illness were undertaken for the primary outcomes of clinical improvement, side effects (movement disorders) and acceptability of treatment. For homogeneous dichotomous data the odds ratio (OR), 95% confidence interval (CI) and, where appropriate, the number needed to treat (NNT) were calculated on an intention-to-treat basis. MAIN RESULTS: Twelve short-term studies and two long term studies provided data on 3401 people. This review provides no evidence relating to the effect of risperidone on cognitive or social functioning, quality of life, employment status, discharge from hospital and relapse rates. Risperidone increases the odds of moderate clinical improvement (OR 0.65, CI 0.55-0.77, NNT 10, CI 7-16). It appears to have little or no additional effect on the positive and negative symptoms of schizophrenia but did have less tendency to cause movement disorders, largely in comparison with haloperidol (OR 0.43, CI 0.34-0.55, NNT 7, CI 5-10) for use of antiparkinsonian medication. Risperidone seems to be more acceptable to those with schizophrenia (OR 0.69 CI 0.57-0.83, NNT 15, CI 10-30, 30% baseline risk of dropping out). Those taking risperidone are also marginally less likely to experience somnolence (OR 0.78, CI 0. 61-0.99, NNT 22). Weight gain, however, is more likely with risperidone (OR 1.51 CI 1.14-2.00, NNT 13). Funnel plots show that smaller studies generally show greater benefit for risperidone than larger studies. A publication bias in favour of risperidone amongst the included studies may explain this effect. Sensitivity analyses on dose of risperidone (excluding those receiving 1 or 2 mg) did not materially change the results for the principal outcomes. Excluding data from those on higher doses of haloperidol (>10mg/day) does marginally change the results. Risperidone is less effective in achieving clinical improvement and preventing dropout but outcomes relating to movement disorders change little. REVIEWER'S CONCLUSIONS: Little can be concluded about the long term effects of risperidone and generalising results beyond a comparison with haloperidol would be imprudent. Risperidone may be more acceptable to those with schizophrenia and have marginal benefits in terms of limited clinical improvement and side

Antipsychotic Agents↗

PubMed2000

Cognitive behaviour therapy for schizophrenia.

BACKGROUND: Although medication is the mainstay of treatment for schizophrenia, always, some sort of informal or formal talking therapy is indicated. In cognitive behavioural therapy (CBT) links are made between the person's feelings and patterns of thinking which underpin their distress. OBJECTIVES: To review the effects of cognitive behaviour therapy (CBT) for those with schizophrenia compared to standard care, specific medication and non-intervention; also to review the effects of CBT for those with schizophrenia who are concurrently receiving standard care compared to no additional intervention to standard care, specific medication, additional drug interventions to standard care and other additional psychosocial interventions to standard care. SEARCH STRATEGY: Electronic searches of Biological Abstracts (1980-1998), CINAHL (1982-1998), The Cochrane Library (Issue 2, 1998), The Cochrane Schizophrenia Group's Register of Trials (August 1998), EMBASE (1980-1998), MEDLINE (1966-1998), PsycLIT (1887-1998), SIGLE (1990-1998), and Sociofile (1980-1998) were undertaken. All references of articles selected were searched for further relevant trials. SELECTION CRITERIA: Randomised trials of cognitive behaviour therapy for people with a diagnosis of schizophrenia, possible schizophrenia or mental illnesses where specific diagnoses have not been employed. Outcomes such as death, metal state, relapse, psychological well-being and acceptability of treatment were sought. DATA COLLECTION AND ANALYSIS: Studies were reliably selected and assessed for methodological quality. Data were extracted by two reviewers working independently. Dichotomous data were analysed on an intention-to-treat basis and continuous data with 70% completion rate are presented. MAIN RESULTS: Four small trials were identified. All presented data suggested that there was a difference favouring CBT plus standard care over standard care alone in terms of reducing relapse rates (short term OR 0.31 CI 0.1-0.98; medium term OR 0.38 CI 0.17-0.83; long term OR 0.46 CI 0.26-0.83, NNT 6 CI 3-30). These findings were supported within the trials by scale-derived data. CBT, however, did not keep more people in care than a standard approach and there is no data relating to the effect of CBT on compliance with medication. One study also presented data on the effects of CBT when compared to supportive psychotherapy. No effect statistically significantly favoured either group but all were suggestive that the trial may have been underpowered to find an effect in favour of CBT. REVIEWER'S CONCLUSIONS: The results of well conducted and reported ongoing trials are eagerly awaited. Currently, for those with schizophrenia willing to receive CBT, access to this treatment approach is associated with a substantially reduced risk of relapse. However, at present CBT is a fairly scarce commodity, often provided by highly skilled and experienced therapists. Therefore, its application in day to day practice may be restricted by the availability of suitable practitioners. Similarly, the present data provides little indication of how effective CBT procedures might be when they are applied by less experienced practitioners.

Cognitive Behavioral Therapy↗

PubMed2000

Inhaled steroids for bronchiectasis.

BACKGROUND: Bronchiectasis is a progressive condition characterised by irreversible destruction and dilatation of airways, generally associated with chronic bacterial infection. The two distinct therapeutic goals are: symptom control and reduction in morbidity; and prevention of progression of the underlying disease. OBJECTIVES: To determine whether regular inhaled corticosteroids produce improvement in symptom control and whether they beneficially influence the natural history of the disease. SEARCH STRATEGY: The Cochrane Airways Group RCT register and Cochrane Controlled Clinical Trials Register were searched using the following search terms; bronchiectasis AND [corticosteroid* OR beclomethasone OR budesonide OR fluticasone OR triamcinolone OR flunisolide]. Bibliographies of each included RCT was searched for additional trials. Pharmaceutical companies that manufacture inhaled corticosteroids were also contacted. SELECTION CRITERIA: Only randomised double blind studies controlled trials were included. Patients with radiographic evidence of bronchiectasis were included, but patients with cystic fibrosis were excluded. DATA COLLECTION AND ANALYSIS: Data was extracted by one of the reviewers (FR). Continuous outcomes were analysed as effect sizes (weighted mean difference or as standardised mean difference with 95% confidence intervals). MAIN RESULTS: Only two trials on a total of 54 patients could be included. The studies were of 4 and 6 weeks duration. Inhaled corticosteroids had no significant effect on any of the outcomes included in this review, however there was a trend towards improving: FEV1, FVC, PEFR, RV and DLco. REVIEWER'S CONCLUSIONS: In bronchiectasis, regular use of inhaled corticosteroids may improve lung function. The available studies were too short and too small to provide any clear evidence to guide practice. Larger and longer studies should include rate of decline of lung function, exacerbation frequency, hospitalisations and healthy status as outcomes.

Administration, Inhalation↗

PubMed2000

Sucrose for analgesia in newborn infants undergoing painful procedures.

BACKGROUND: Management of pain for neonates is less than optimal. The administration of sucrose with and without non-nutritive sucking (pacifiers) has been the most frequently studied non-pharmacological intervention for relief of procedural pain in neonates. OBJECTIVES: To determine the efficacy, effect of dose, and safety of sucrose for relieving procedural pain as assessed by physiologic and/or behavioural indicators. SEARCH STRATEGY: Standard methods as per the Neonatal Collaborative Review Group. A MEDLINE search was carried out for relevant randomized controlled trials (RCTs) published from January 1966 - November 1, 1997; EMBASE from 1993-1997; Reference Update search on November 11, 1997 and search of the Cochrane Library Issue 4 on November 11, 1997. Key words and (MeSH) terms included, infant/newborn, pain, analgesia and sucrose. Personal files, bibliographies, the most recent relevant neonatal and pain journals and conference proceedings were searched manually. Unpublished studies were not included. Language restrictions were not imposed. SELECTION CRITERIA: RCTs in which term and/or preterm neonates undergoing heel lance, venepuncture or intramuscular injection (immunization) received sucrose or water/placebo or no intervention. DATA COLLECTION AND ANALYSIS: Trial quality was assessed according to the methods of the Neonatal Collaborative Review Group. Quality measures included; blinding of randomization, blinding of intervention, completeness of follow up and blinding of outcome measurement. Data were abstracted and independently checked for accuracy by the two investigators. The inconsistency in outcome measures and differences in the statistical reporting of results made meta-analysis impossible. We were not able to identify two studies in which the same physiologic and/or behavioral outcomes following a noxious stimulus (heel-lance, venepuncture, intramuscular injection) were measured and reported in an identical fashion using means and standard deviations (or standard errors). The results are therefore reported for each accepted study separately. MAIN RESULTS: Fifteen studies were identified for possible inclusion in this systematic review. Five studies were excluded; three RCTs were excluded as in these trials the number of infants randomized to treatment vs. placebo groups were not reported; one study was not an RCT, and in one RCT the neonates did not undergo a painful procedure. Ten RCTs were included in this review. Sucrose in a wide range of dosages was generally found to decrease univariate physiologic (heart rate) and behavioural (the mean percent time crying, total cry duration, duration of first cry, and facial action) pain indicators and multivariate [Premature Infant Pain Profile (PIPP)] pain outcomes in neonates undergoing heelstick or venepuncture. An optimal dose of sucrose to reduce pain associated with procedures in preterm and term neonates could not be identified through this systematic review. REVIEWER'S CONCLUSIONS: Sucrose reduces physiologic and/or behavioral indicators of stress/pain in neonates following procedural pain stimuli (heel lance, venepuncture, immunization). There was inconsistency in the dose of sucrose that was effective and an optimal dose to be used in preterm and/or term infants could not be identified. Considerations for future research are to describe the painful procedure and intervention in detail, to use appropriate sample size to show a statistically significant reduction in pain, to use a multidimensional conceptualization of pain, to select outcome measures that are reliable and valid pain indicators and to account for the variation in the infant's response and context in which the pain is experienced. The use of repeated administrations of sucrose in neonates needs to be investigated. Use of sucrose in neonates that are very low birth weight, unstable and/or ventilated also needs to be addressed. (ABSTRACT TRUNCATED)

Analgesics↗

PubMed2005

Corticosteroids for pulmonary sarcoidosis.

BACKGROUND: Pulmonary sarcoidosis is a common condition with an unpredictable course. Oral (OCS) or inhaled steroids (ICS) are widely used in its treatment, but there is no consensus about when and in whom therapy should be initiated, what dose should be given and for how long. Corticosteroids given for several months have deleterious side-effects so it is important to know whether they have any maintained benefit in pulmonary sarcoidosis. OBJECTIVES: To determine the randomised controlled trial (RCT) evidence for the benefit of corticosteroids (oral or inhaled) in the treatment of pulmonary sarcoidosis. SEARCH STRATEGY: MEDLINE, EMBASE and CENTRAL were searched using predefined terms. Bibliographies of retrieved RCTs and reviews were searched for additional RCTs. Pharmaceutical companies and authors of identified RCTs were contacted for other published and unpublished studies. Searches are current as of May 2004. SELECTION CRITERIA: Two reviewers independently assessed full text articles for inclusion based upon the following criteria: the study had to be a RCT or controlled clinical trial in adults with histological evidence of pulmonary sarcoidosis, treated with OCS (oral steroids) or ICS (oral steroids), compared with a control. DATA COLLECTION AND ANALYSIS: Study quality was assessed and data extracted independently by two reviewers. The primary outcome was CXR (chest x-ray). Outcomes were analysed as continuous and dichotomous outcomes, using standard statistical techniques. Heterogeneity was explored where it was identified. MAIN RESULTS: Twelve RCTs of variable quality involving 1051 participants met the inclusion criteria of the review. The oral steroid dose was equivalent to prednisolone 4-40 mg/day. OCS: there was an improvement in CXR over 3-24 months (Relative Risk (RR): 1.46 [1.01 to 2.09], 3 studies), but this finding requires cautious interpretation. No other significant differences were identified on secondary outcomes. ICS: Data were inadequate to perform meaningful analysis of data on CXR. Two studies showed no improvement in lung function, In one study there was an improvement in diffusing capacity in the treated group. There were no data on side-effects. In one study symptoms improved at the end of six months of treatment. AUTHORS' CONCLUSIONS: Oral steroids improved the chest X-ray and a global score of CXR, symptoms and spirometry over 3-24 months. However, there is little evidence of an improvement in lung function. There are limited data beyond two years to indicate whether oral steroids have any modifying effect on long-term disease progression. Oral steroids may be of benefit for patients with Stage 2 and 3 disease with moderate to severe or progressive symptoms or CXR changes.

Administration, Inhalation↗

PubMed2001

Heparins and mechanical methods for thromboprophylaxis in colorectal surgery.

BACKGROUND: Colorectal surgery implies higher risk of postoperative thromboembolic complications as deep venous thrombosis (DVT) and pulmonary embolism (PE) than general surgery. The best prophylaxis in general surgery is heparin and graded compression stockings. No systematic review on combination prophylaxis or on thrombosis prophylaxis in colorectal surgery has been published. OBJECTIVES: To compare the incidence of postoperative thromboembolism after colorectal surgery using prophylactic methods focussing on heparins and mechanical methods alone and in combinations. SEARCH STRATEGY: Electronic searches was performed in MEDLINE, EMBASE back to 1970. Abstract books from major congresses were handsearched as were reference lists from previously performed reviews. SELECTION CRITERIA: RCT or CCT comparing prophylactic interventions and/or placebo. Outcomes were ascending venography, 125 I-fibrinogen uptake test, ultrasound methods, pulmonary scintigraphy. Studies, using thermographic methods, other isotopic methods, plethysmographic methods, and purely clinical methods as the only diagnostic measure were excluded. 558 studies were identified - 477 were excluded. Only 3 of the identified studies focused exclusively on colorectal surgery. Studies of general surgery contain considerable numbers of colorectal patients. The authors of 66 studies in general and/or abdominal surgery were contacted for retrieving the results from the colorectal patients. Answers were received from very few. 19 studies entered this review. DATA COLLECTION AND ANALYSIS: All studies and all data extraction were performed independently by at least two of the authors. Outcome was deep venous thrombosis and/or pulmonary embolism. Analysis of bleeding complications were unfeasible. 12 meaningful outcomes were analysed by means of the fixed effects model with Peto Odds Ratios. MAIN RESULTS: Heparins versus no treatment: Any kind of heparincompared to no treatment or placebo (comparison 07.03, 11 studies). Heparin is better in preventing DVT and/or PE with a Peto Odds ratio at 0.32 (95% Confidence Interval 0.20-0.53) Unfractionated heparin versus low molecular weight heparin (comparison 08.03, 4 studies). The two treatments were found equally effective in preventing DVT and/or PE with a Peto Odds ratio 1.01 (95% Confidence Interval 0.67-1.52). Mechanical methods (comparison 10.3, 2 studies). The combination of graded compression stockings and LDH is better than LDH alone in preventing DVT and/or PE with a Peto Odds ratio at 4.17 (95% Confidence Interval 1.37-12.70). REVIEWER'S CONCLUSIONS: The optimal prophylaxis in colorectal surgery is the combination of graduated compression stockings and low-dose unfractionated heparin. The unfractionated heparin can be replaced with low molecular weight heparin.

Anticoagulants↗