Fertility after uterine artery embolization of fibroids: a systematic review.

PURPOSE: The impact of uterine artery embolization (UAE) for the purpose of diminishing the effect of uterine fibroids on fertility is unclear. We have investigated the reported rates of pregnancy and miscarriage after treatment of uterine fibroids with UAE. MATERIALS AND METHODS: We searched for relevant information in PubMed and Embase for randomized controlled trials (RCT), controlled clinical trials, comparative before-after trials, cohort studies, case-control studies and case series where UAE treatment of premenopausal women was performed for uterine fibroids with and where a control intervention was included. The PRISMA guideline was used to do a systematic review using the main outcomes pregnancy rate and miscarriage rate. Risk of bias was assessed by the Cochrane risk of bias tool or by ROBINS-I. The quality of evidence was assessed by the GRADE approach. RESULTS: We included 17 studies (989 patients): 1 RCT, 2 cohort studies, and 14 case series. Pregnancy rates after UAE were 50% in the RCT and 51 and 69% in the cohort studies. Among the case series median pregnancy rate was 29%. Miscarriage rates were 64% in the RCT. Miscarriage rates at 56 and 34% were found in the cohort studies after UAE. The median miscarriage rate was 25% in the case series. CONCLUSION: Pregnancy rate was found to be lower and miscarriage rate higher after UAE than after myomectomy. However, we found very low quality of evidence regarding the assessed outcomes and the reported proportions are uncertain. There is a need for improved prospective randomized studies to improve the evidence base. Systematic review registration number: CRD42016036661.

Blinding in randomized clinical trials: imposed impartiality.

Blinding, or "masking," is a crucial method for reducing bias in randomized clinical trials. In this paper, we review important methodological aspects of blinding, emphasizing terminology, reporting, bias mechanisms, empirical evidence, and the risk of unblinding. Theoretical considerations and empirical analyses support the blinding of patients, health-care providers, and outcome assessors as to the trial intervention to which patients have been allocated. We encourage extensive pretrial testing of blinding procedures and explicit reporting of who was in the blinded condition and the methods used to ensure blinding.

The Osteoporosis Self-Assessment Tool versus alternative tests for selecting postmenopausal women for bone mineral density assessment: a comparative systematic review of accuracy.

SUMMARY: We performed a systematic review of studies comparing the Osteoporosis Self-Assessment Tool (OST) and other tests used to select women for bone mineral density (BMD) assessment. In comparative meta-analyses, we found that the accuracy of OST was similar to other tests that are based on information from the medical history. By contrast, assessment by quantitative ultrasonography at the heel was more accurate than OST in discriminating between women with high and low BMD. The methodological quality of the included studies was generally low. INTRODUCTION: Numerous tests are suggested for triaging postmenopausal women for bone mineral density (BMD) assessment by dual-energy X-ray absorptiometry. Previous studies suggest that OST, based on age and weight only, may be as accurate as more complex triage tests. We systematically compare the accuracy of OST and alternative triage tests in postmenopausal women. METHODS: We searched PubMed, Embase, Web of Science, citation lists, and conference proceedings. Our main measure of accuracy was the diagnostic odds ratio (DOR). We compared summary estimates of DOR (sDOR) for OST and alternative tests in pairwise meta-analyses by using the Moses-Littenberg approach. RESULTS: Summary estimates of DOR for OST and the clinical decision rules Simple Calculated Osteoporosis Risk Estimation (SCORE) and Osteoporosis Risk Assessment Instrument (ORAI) did not differ significantly in white women (relative sDOR: 0.57-1.17, all p >or= 0.11). By contrast, sDOR was higher for Stiffness Index assessed by calcaneal quantitative ultrasonography than for OST (relative sDOR: 1.9, p = 0.005). Studies were few in Asian and black women. Methodological quality, assessed with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist, was generally low. CONCLUSIONS: In white women, the accuracy of OST and alternative clinical decision rules was similar, whereas Stiffness Index was more accurate than OST. Low study quality renders transferability to clinical settings uncertain.

Impact of allocation concealment on conclusions drawn from meta-analyses of randomized trials.

BACKGROUND: Randomized trials without reported adequate allocation concealment have been shown to overestimate the benefit of experimental interventions. We investigated the robustness of conclusions drawn from meta-analyses to exclusion of such trials. MATERIAL: Random sample of 38 reviews from The Cochrane Library 2003, issue 2 and 32 other reviews from PubMed accessed in 2002. Eligible reviews presented a binary effect estimate from a meta-analysis of randomized controlled trials as the first statistically significant result that supported a conclusion in favour of one of the interventions. METHODS: We assessed the methods sections of the trials in each included meta-analysis for adequacy of allocation concealment. We replicated each meta-analysis using the authors' methods but included only trials that had adequate allocation concealment. Conclusions were defined as not supported if our result was not statistically significant. RESULTS: Thirty-four of the 70 meta-analyses contained a mixture of trials with unclear or inadequate concealment as well as trials with adequate allocation concealment. Four meta-analyses only contained trials with adequate concealment, and 32, only trials with unclear or inadequate concealment. When only trials with adequate concealment were included, 48 of 70 conclusions (69%; 95% confidence interval: 56-79%) lost support. The loss of support mainly reflected loss of power (the total number of patients was reduced by 49%) but also a shift in the point estimate towards a less beneficial effect. CONCLUSION: Two-thirds of conclusions in favour of one of the interventions were no longer supported if only trials with adequate allocation concealment were included.

Blinded trials taken to the test: an analysis of randomized clinical trials that report tests for the success of blinding.

BACKGROUND: Blinding can reduce bias in randomized clinical trials, but blinding procedures may be unsuccessful. Our aim was to assess how often randomized clinical trials test the success of blinding, the methods involved and how often blinding is reported as being successful. METHODS: We analysed a random sample of blinded randomized clinical trials indexed in the The Cochrane Central Register of Controlled Trials and published in 2001. We identified 1599 blinded trials, and noted if they had conducted any test for the success of blinding. We also selected 200 trials randomly that did not report any such test, and sent a questionnaire to the corresponding authors asking them if they had conducted any tests. RESULTS: Thirty-one out of 1599 trials (2%) reported tests for the success of blinding. Test methods varied, and reporting was generally incomplete. Blinding was considered successful in 14 out of the 31 trials (45%) and unclear in 10 (32%). Of the seven trials (23%) reporting unsuccessful blinding the risk of a biased trial result was either not addressed or was discounted in six cases. We received 130 questionnaires from trial authors (65%) of which 15 (12%) informed that they had conducted, but not published, tests. CONCLUSIONS: Blinding is rarely tested. Test methods vary, and the reporting of tests, and test results, is incomplete. There is a considerable methodological uncertainty how best to assess blinding, and an urgent need for improved methodology and improved reporting.

Performance of the Osteoporosis Self-Assessment Tool in ruling out low bone mineral density in postmenopausal women: a systematic review.

UNLABELLED: The Osteoporosis Self-Assessment Tool (OST) is a simple test that may be of clinical value to rule-out low bone mineral density. We performed a systematic review to assess its performance in postmenopausal women. We included 36 studies. OST performed moderately in ruling-out femoral neck T-score or=0.28). Methodological study quality was generally low. CONCLUSIONS: The clinical usefulness of OST is uncertain. OST could be useful for ruling-out femoral neck T-score

Somatostatin analogues for acute bleeding oesophageal varices.

BACKGROUND: Somatostatin and its derivatives are often used for emergency treatment of bleeding oesophageal varices in patients with cirrhosis of the liver. OBJECTIVES: To study whether somatostatin or analogues improve survival or reduce the need for blood transfusions in patients with bleeding oesophageal varices. SEARCH STRATEGY: MEDLINE and The Cochrane Library were searched; last search in Febr 2004. Reference lists of articles, contacted authors. SELECTION CRITERIA: All randomised trials comparing somatostatin or analogues with placebo or no treatment in patients suspected of acute or recent bleeding from oesophageal varices. DATA COLLECTION AND ANALYSIS: The effect variables extracted were: mortality, blood transfusions, use of balloon tamponade, initial haemostasis and rebleeding. Intention-to-treat analyses including all randomised patients were conducted; a random effects analysis was preferred if there was significant heterogeneity between the trials (P < 0.10). The trials were divided in two quality groups; the better trials had concealed allocation of patients and were double-blind. MAIN RESULTS: We included 20 trials (2518 patients). The drugs did not reduce mortality significantly (relative risk 0.96, 95% confidence interval 0.74 to 1.24, for the high-quality trials, and 0.79 for low-quality trials). Units of blood transfused were 0.7 (0.3 to 1.2) less with drugs in the high-quality trials and 1.5 (0.9 to 2.0) less in the low-quality trials. Number of patients failing initial haemostasis was reduced, relative risk 0.67 (0.53 to 0.86). Number of patients with rebleeding was not significantly reduced for the high-quality trials, relative risk 0.82 (0.45 to 1.49) while it was substantially reduced in the low-quality trials, relative risk 0.35 (0.18 to 0.67). Use of balloon tamponade was rarely reported. AUTHORS' CONCLUSIONS: The effect corresponded to one half unit of blood saved per patient. It is doubtful whether this effect is worthwhile. The findings do not suggest a need for further placebo-controlled studies of the type reviewed here. A large placebo controlled trial enrolling thousands of patients is needed if one wishes to rule out the possibility that a worthwhile effect on mortality may have been overlooked.

Placebo interventions for all clinical conditions.

BACKGROUND: Placebo interventions are often claimed to improve patient-reported and observer-reported outcomes, but this belief is not based on evidence from randomised trials that compare placebo with no treatment. OBJECTIVES: To assess the effect of placebo interventions. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2002), MEDLINE (1966 to 2002), EMBASE (1980 to 2002), Biological Abstracts (1986 to 2002), and PsycLIT (1887 to 2002). We contacted experts on placebo research, and read references in the included trials. SELECTION CRITERIA: We included randomised placebo trials with a no-treatment control group investigating any health problem. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: Outcome data were available in 156 out of 182 included trials, investigating 46 clinical conditions. We found no statistically significant pooled effect of placebo in 38 studies with binary outcomes (4284 patients), relative risk 0.95 (95% confidence interval (CI) 0.89 to 1.01). The pooled relative risk for patient-reported outcomes was 0.95 (95% CI 0.88 to 1.03) and for observer-reported outcomes 0.91 (95% CI 0.81 to 1.03). There was heterogeneity (P=0.01) but the funnel plot was symmetrical. There was no statistically significant effect of placebo interventions in the four clinical conditions investigated in three trials or more: pain, nausea, smoking, and depression, but confidence intervals were wide. We found an overall effect of placebo treatments in 118 trials with continuous outcomes (7453 patients), standardised mean difference (SMD) -0.24 (95% CI -0.31 to -0.17). The SMD for patient-reported outcomes was -0.30 (95% CI -0.38 to -0.21), whereas no statistically significant effect was found for observer-reported outcomes, SMD -0.10 (95% CI -0.20 to -0.01). There was heterogeneity (P<0.001) and large variability in funnel plot results even for big trials. There was an apparent effect of placebo interventions on pain (SMD -0.25 (95% CI -0.35 to-0.16)), and phobia (SMD -0.63 (95% CI -1.17 to -0.08)); but also a substantial risk of bias. There was no statistically significant effect of placebo interventions in eight other clinical conditions investigated in three trials or more: nausea, smoking, depression, overweight, asthma, hypertension, insomnia and anxiety, but confidence intervals were wide. REVIEWERS' CONCLUSIONS: There was no evidence that placebo interventions in general have clinically important effects. A possible small effect on continuous patient-reported outcomes, especially pain, could not be clearly distinguished from bias.

Is the placebo powerless? Update of a systematic review with 52 new randomized trials comparing placebo with no treatment.

BACKGROUND: It is widely believed that placebo interventions induce powerful effects. We could not confirm this in a systematic review of 114 randomized trials that compared placebo-treated with untreated patients. AIM: To study whether a new sample of trials would reproduce our earlier findings, and to update the review. METHODS: Systematic review of trials that were published since our last search (or not previously identified), and of all available trials. RESULTS: Data was available in 42 out of 52 new trials (3212 patients). The results were similar to our previous findings. The updated review summarizes data from 156 trials (11 737 patients). We found no statistically significant pooled effect in 38 trials with binary outcomes, relative risk 0.95 (95% confidence interval 0.89-1.01). The effect on continuous outcomes decreased with increasing sample size, and there was considerable variation in effect also between large trials; the effect estimates should therefore be interpreted cautiously. If this bias is disregarded, the pooled standardized mean difference in 118 trials with continuous outcomes was -0.24 (-0.31 to -0.17). For trials with patient-reported outcomes the effect was -0.30 (-0.38 to -0.21), but only -0.10 (-0.20 to 0.01) for trials with observer-reported outcomes. Of 10 clinical conditions investigated in three trials or more, placebo had a statistically significant pooled effect only on pain or phobia on continuous scales. CONCLUSION: We found no evidence of a generally large effect of placebo interventions. A possible small effect on patient-reported continuous outcomes, especially pain, could not be clearly distinguished from bias.

Placebo treatment versus no treatment.

BACKGROUND: Placebo interventions are often believed to improve patient reported and observer reported outcomes, but this belief is not based on evidence from randomised trials that compare placebo with no treatment. OBJECTIVES: To assess the effect of placebo interventions. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register (The Cochrane Library, issue 3, 1998), MEDLINE (Jan 1966 to Dec 1998), EMBASE (Jan 1980 to Dec 1998), Biological Abstracts (Jan 1986 to Dec 1998), PsycLIT (Jan 1887 to Dec 1998). Experts on placebo research were contacted and references in the included trials were read. SELECTION CRITERIA: Randomised placebo trials with a no-treatment control group investigating any health problem were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. MAIN RESULTS: Outcome data were available in 114 out of 130 included trials, investigating 40 clinical conditions. Outcomes were binary in 32 trials (3795 patients) and continuous in 82 (4730 patients). We found no statistically significant pooled effect of placebo in studies with binary outcomes, relative risk 0.95 (95 per cent confidence interval 0.88 to 1.02). The pooled relative risk for subjective (patient reported) outcomes was 0.95 (0.86 to 1.05) and for objective (observer reported) outcomes 0.91 (0.80 to 1.04). There was statistically significant heterogeneity (P < 0.03), but no evidence of sample size bias (P = 0.56). We found an overall positive effect of placebo treatments in trials with continuous outcomes, standardised mean difference -0.28 (95 per cent confidence interval -0.38 to -0.19). The standardised mean difference for subjective outcomes was -0.36 (-0.47 to -0.25), whereas no statistically significant effect was found for objective outcomes, standardised mean difference -0.12 (-0.27 to 0.03). There was statistically significant heterogeneity (P < 0.001), and evidence of sample size bias (P = 0.05). There was no statistically significant effect of placebo interventions in eight out of nine clinical conditions investigated in three trials or more (nausea, relapse in prevention of smoking and depression, overweight, asthma, hypertension, insomnia and anxiety), but confidence intervals were wide. There was a modest apparent analgesic effect of placebo interventions, standardised mean difference -0.27 (-0.40 to -0.15), but also a substantial risk of bias. REVIEWER'S CONCLUSIONS: There was no evidence that placebo interventions in general have clinically important effects. A possible moderate effect on subjective continuous outcomes, especially pain, could not be clearly distinguished from bias.

Low agreement among 24 doctors using the Neer-classification; only moderate agreement on displacement, even between specialists.

Twenty-four orthopaedic surgeons classified 42 pairs of radiographs according to the Neer system for proximal humeral fractures. Mean kappa value for inter-observer agreement was 0.27 (95% CI 0.26-0.28) with no clinically significant difference between orthopaedic residents ( n=9), fellows ( n=6) and specialists ( n=9). Mean kappa for agreement of displacement versus non-displacement was 0.41 (95% CI 0.39-0.43) overall, and 0.50 (95% CI 0.45-0.56) within the specialist group. The agreement found in our study is unsatisfactory from a clinical perspective.

Improved interobserver variation after training of doctors in the Neer system. A randomised trial.

We investigated whether training doctors to classify proximal fractures of the humerus according to the Neer system could improve interobserver agreement. Fourteen doctors were randomised to two training sessions, or to no training, and asked to categorise 42 unselected pairs of plain radiographs of fractures of the proximal humerus according to the Neer system. The mean kappa difference between the training and control groups was 0.30 (95% CI 0.10 to 0.50, p = 0.006). In the training group the mean kappa value for interobserver variation improved from 0.27 (95% CI 0.24 to 0.31) to 0.62 (95% CI 0.57 to 0.67). The improvement was particularly notable for specialists in whom kappa increased from 0.30 (95% CI 0.23 to 0.37) to 0.79 (95% CI 0.70 to 0.88). These results suggest that formal training in the Neer system is a prerequisite for its use in clinical practice and research.

Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment.

BACKGROUND: Placebo treatments have been reported to help patients with many diseases, but the quality of the evidence supporting this finding has not been rigorously evaluated. METHODS: We conducted a systematic review of clinical trials in which patients were randomly assigned to either placebo or no treatment. A placebo could be pharmacologic (e.g., a tablet), physical (e.g., a manipulation), or psychological (e.g., a conversation). RESULTS: We identified 130 trials that met our inclusion criteria. After the exclusion of 16 trials without relevant data on outcomes, there were 32 with binary outcomes (involving 3795 patients, with a median of 51 patients per trial) and 82 with continuous outcomes (involving 4730 patients, with a median of 27 patients per trial). As compared with no treatment, placebo had no significant effect on binary outcomes (pooled relative risk of an unwanted outcome with placebo, 0.95; 95 percent confidence interval, 0.88 to 1.02), regardless of whether these outcomes were subjective or objective. For the trials with continuous outcomes, placebo had a beneficial effect (pooled standardized mean difference in the value for an unwanted outcome between the placebo and untreated groups, -0.28; 95 percent confidence interval, -0.38 to -0.19), but the effect decreased with increasing sample size, indicating a possible bias related to the effects of small trials. The pooled standardized mean difference was significant for the trials with subjective outcomes (-0.36; 95 percent confidence interval, -0.47 to -0.25) but not for those with objective outcomes. In 27 trials involving the treatment of pain, placebo had a beneficial effect (-0.27; 95 percent confidence interval, -0.40 to -0.15). This corresponded to a reduction in the intensity of pain of 6.5 mm on a 100-mm visual-analogue scale. CONCLUSIONS: We found little evidence in general that placebos had powerful clinical effects. Although placebos had no significant effects on objective or binary outcomes, they had possible small benefits in studies with continuous subjective outcomes and for the treatment of pain. Outside the setting of clinical trials, there is no justification for the use of placebos.

The uncontrollable placebo effect.

OBJECTIVE: To analyse the role of the control group in the methodology of clinical placebo effect evaluating trials. SETTING: Department of Medical Philosophy and Clinical Theory, University of Copenhagen. METHODS: A theoretical methodological analysis. RESULTS: At least with present trial designs, it is impossible, with certainty, to exclude a potential placebo effect from the so-called control group. The placebo effect, in other words, is uncontrollable. CONCLUSION: I suggest that the notions of control group and placebo treatment group are replaced by the notions of "placebo effect maximising group" and "placebo effect minimising group", thus stressing the fact that what such trials measure is a relative effect, and an underestimation of the absolute placebo effect. The illusion of absolute placebo effect evaluation must be acknowledged when articles referring to empirical trials on the placebo effect are interpreted.