Adequate Generation Of Allocation Sequence Research Articles

High versus standard blood pressure target in hypertensive high-risk patients undergoing elective major abdominal surgery: a study protocol for the HISTAP randomized clinical trial

BackgroundThe intraoperative period is often characterized by hemodynamic instability, and intraoperative hypotension is a common complication. The optimal mean arterial pressure (MAP) target in hypertensive patients is still not clear. We hereby describe the protocol and detailed statistical analysis plan for the high versus standard blood pressure target in hypertensive high-risk patients undergoing elective major abdominal surgery: the HISTAP randomized clinical trial. The HISTAP trial aims at addressing whether the use of a higher intraoperative MAP target in high-risk hypertensive surgical patients scheduled for elective abdominal surgery would improve postoperative outcomes, as compared to the standard and recommended perioperative MAP, by using a composite outcome including a 30-day mortality from surgical intervention and at least one major organ dysfunction or new onset of sepsis and septic shock occurring 7 days after surgery.MethodsThe HISTAP trial is an investigator-initiated, pragmatic, parallel-grouped, randomized, stratified, analyst-blinded trial with adequate allocation sequence generation, and allocation concealment. We will allocate 636 patients to a MAP target ≥ 80 mmHg (treatment group) or to a MAP target ≥65 mmHg (control group). The primary outcome is a composite outcome including a 30-day mortality from the operation and major organ complications. Secondary outcomes are mortality at 30 days, intensive care unit (ICU) length of stay, ICU readmission, Sequential Organ Failure Assessment (SOFA) scores recorded up to postoperative day 7, overall intraoperative fluid balance, vasopressors use, and the need for reoperation. An unadjusted χ2 test will be used for the primary outcome analysis. A Cox proportional hazards model will be used to adjust the association between the primary outcome and baseline covariates.ConclusionsThe HISTAP trial results will provide important evidence to guide clinicians’ choice regarding the intraoperative MAP target in high-risk hypertensive patients scheduled for elective abdominal surgery.

Methodological reporting quality of randomized controlled trials in three spine journals from 2010 to 2012.

To elucidate the methodological reporting quality of randomized controlled trials (RCTs) in three spine journals from 2010 to 2012. In this study, we summarized the methodological report of RCTs in three major spine journals, including the Spine Journal, Spine and the European Spine Journal from 2010 to 2012. The methodological reporting quality, including the allocation sequence generation, allocation concealment, blinding and sample size calculation, was revealed. Number of patients, funding source, type of intervention and country were also retrieved from each trial. The methodological reporting quality was descriptively reported. Ninety trials were involved and 57.8% (52/90) reported adequate allocation sequence generation, 46.7% (42/90) reported adequate allocation concealment, 34.4% (31/90) reported adequate blinding and 37.8% (34/90) reported adequate sample size calculation. This study shows that the methodological reporting quality of RCTs in the spine field needs further improvement.

Methodological Reporting of Randomized Clinical Trials in Respiratory Research in 2010

Although randomized controlled trials (RCTs) are considered the highest level of evidence, they are also subject to bias, due to a lack of adequately reported randomization, and therefore the reporting should be as explicit as possible for readers to determine the significance of the contents. We evaluated the methodological quality of RCTs in respiratory research in high ranking clinical journals, published in 2010. We assessed the methodological quality, including generation of the allocation sequence, allocation concealment, double-blinding, sample-size calculation, intention-to-treat analysis, flow diagrams, number of medical centers involved, diseases, funding sources, types of interventions, trial registration, number of times the papers have been cited, journal impact factor, journal type, and journal endorsement of the CONSORT (Consolidated Standards of Reporting Trials) rules, in RCTs published in 12 top ranking clinical respiratory journals and 5 top ranking general medical journals. We included 176 trials, of which 93 (53%) reported adequate generation of the allocation sequence, 66 (38%) reported adequate allocation concealment, 79 (45%) were double-blind, 123 (70%) reported adequate sample-size calculation, 88 (50%) reported intention-to-treat analysis, and 122 (69%) included a flow diagram. Multivariate logistic regression analysis revealed that journal impact factor ≥ 5 was the only variable that significantly influenced adequate allocation sequence generation. Trial registration and journal impact factor ≥ 5 significantly influenced adequate allocation concealment. Medical interventions, trial registration, and journal endorsement of the CONSORT statement influenced adequate double-blinding. Publication in one of the general medical journal influenced adequate sample-size calculation. The methodological quality of RCTs in respiratory research needs improvement. Stricter enforcement of the CONSORT statement should enhance the quality of RCTs.

Chemoembolization for intermediate HCC: Is there proof of survival benefit?

Hepatocellular carcinoma (HCC) results in more than 600,000 deaths per year. Transarterial embolisation(TAE) and transarterial chemoembolisation (TACE) have become standard loco-regional treatments for unresectable HCC. To assess the beneficial and harmful effects of TACE or TAE. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Cancer Network register,The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and The Latin American Caribbean Health Sciences Literature(LILACS) from dates of inceptions up to September 2010. We considered for inclusion all randomised trials that compared TACE or TAE versus placebo, sham, or no intervention.Co-interventions were allowed if comparable between intervention groups. Trials with inadequate randomisation were excluded. For all-cause mortality, we calculated the log hazard ratio (HR) with standard error as point estimate and pooled them for meta-analysis using the inverse variance method. Sub-group analyses were performed regarding intervention regimen, trial truncation, or co-interventions. We validated the results with trial sequential analyses. We used random-effects model in all meta-analyses in anticipation of statistical heterogeneity among the trials. We included nine trials with 645 participants. Six trials assessed TACE versus control and three trials assessed TAE versus control. Seven trials had low risk of selection bias based on adequate generation of allocation sequence and concealment – but all these trials had other risks of bias. Three trials were stopped early due to interim inspections and one due to slow accrual. For all-cause mortality,statistical heterogeneity between trials was low to moderate(I2) = 30%). Meta-analysis of trials with low risk of selection bias showed that TACE or TAE versus control does not significantly increase survival (HR 0.88; 95% CI 0.71–1.10). Two trials with low risk of selection bias, no early stopping, and no co-intervention did not establish any significant effect of TACE or TAE on overall survival(hazard ratio 1.22, 95% confidence interval 0.82–1.83; P = 0.33). Trials equential analysis confirmed the absence of evidence for a beneficial effect of TACE or TAE on survival indicating the need for future randomisation of up to 383 additional participants. Substantial differences in criteria for assessing tumor response did not allow quantitative analyses. One trial investigated quality of life but did not detect any significant differences between the intervention groups. A range of adverse events including post-embolisation syndrome and serious complications were reported. AUTHORS’ There is no firm evidence to support or refute TACE or TAE for patients with unresectable HCC. More adequately powered and bias-protected trials are needed.

Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma

Hepatocellular carcinoma (HCC) results in more than 600,000 deaths per year. Transarterial embolisation (TAE) and transarterial chemoembolisation (TACE) have become standard loco-regional treatments for unresectable HCC. To assess the beneficial and harmful effects of TACE or TAE. We searchedThe Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Cancer Network register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and The Latin American Caribbean Health Sciences Literature (LILACS) from dates of inceptions up to September 2010. We considered for inclusion all randomised trials that compared TACE or TAE versus placebo, sham, or no intervention. Co-interventions were allowed if comparable between intervention groups. Trials with inadequate randomisation were excluded. For all-cause mortality, we calculated the log hazard ratio (HR) with standard error as point estimate and pooled them for meta-analysis using the inverse variance method. Sub-group analyses were performed regarding intervention regimen, trial truncation, or co-interventions. We validated the results with trial sequential analyses. We used random-effects model in all meta-analyses in anticipation of statistical heterogeneity among the trials. We included nine trials with 645 participants. Six trials assessed TACE versus control and three trials assessed TAE versus control. Seven trials had low risk of selection bias based on adequate generation of allocation sequence and concealment - but all these trials had other risks of bias. Three trials were stopped early due to interim inspections and one due to slow accrual. For all-cause mortality, statistical heterogeneity between trials was low to moderate (I(2)= 30%). Meta-analysis of trials with low risk of selection bias showed that TACE or TAE versus control does not significantly increase survival (HR 0.88; 95% CI 0.71 to 1.10). Two trials with low risk of selection bias, no early stopping, and no co-intervention did not establish any significant effect of TACE or TAE on overall survival (hazard ratio 1.22, 95% confidence interval 0.82 to 1.83; P = 0.33). Trial sequential analysis confirmed the absence of evidence for a beneficial effect of TACE or TAE on survival indicating the need for future randomisation of up to 383 additional participants. Substantial differences in criteria for assessing tumour response did not allow quantitative analyses. One trial investigated quality of life but did not detect any significant differences between the intervention groups. A range of adverse events including post-embolisation syndrome and serious complications were reported. There is no firm evidence to support or refute TACE or TAE for patients with unresectable HCC. More adequately powered and bias-protected trials are needed.

Placebo-controlled trials of Chinese herbal medicine and conventional medicine comparative study

Chinese herbal medicine (CHM) is increasingly used in the West, but the evidence on its effectiveness is a matter of debate. We compared the characteristics, study quality and results of clinical trials of CHM and conventional medicine. Comparative study of placebo-controlled trials of CHM and conventional medicine. Eleven bibliographic databases and searches by hand of 48 Chinese-language journals. Conventional medicine trials matched for condition and type of outcome were randomly selected from the Cochrane Controlled Trials Register (issue 1, 2003). Trials described as double-blind, with adequate generation of allocation sequence and adequate concealment of allocation, were assumed to be of high quality. Data were analysed using funnel plots and multivariable meta-regression models. 136 CHM trials (119 published in Chinese, 17 published in English) and 136 matched conventional medicine trials (125 published in English) were analysed. The quality of Chinese-language CHM trials tended to be lower than that of English-language CHM trials and conventional medicine trials. Three (2%) CHM trials and 10 (7%) conventional medicine trials were of high quality. In all groups, smaller trials showed more beneficial treatment effects than larger trials. CHM trials published in Chinese showed considerably larger effects than CHM trials published in English (adjusted ratio of ORs 0.29, 95% confidence intervals 0.17-0.52). Biases are present both in placebo-controlled trials of CHM and conventional medicine, but may be most pronounced in CHM trials published in Chinese-language journals. Only few CHM trials of adequate methodology exist and the effectiveness of CHM therefore remains poorly documented.

Matched-pair study showed higher quality of placebo-controlled trials in Western phytotherapy than conventional medicine

Objectives Herbal medicine (phytotherapy) is widely used, but the evidence for its effectiveness is a matter of ongoing debate. We compared the quality and results of trials of Western phytotherapy and conventional medicine. Study Design and Setting A random sample of placebo-controlled trials of Western phytotherapy was identified in a comprehensive literature search (19 electronic databases). Conventional medicine trials matched for condition and type of outcome were selected from the Cochrane Central Controlled Trials Register (issue 1, 2003). Data were extracted in duplicate. Trials described as double-blind, with adequate generation of allocation sequence and adequate concealment of allocation were assumed to be of higher methodological quality. Results Eighty-nine herbal medicine and 89 matched conventional medicine trials were analyzed. Studies of Western herbalism were smaller, less likely to be published in English, and less likely to be indexed in MEDLINE than their counterparts from conventional medicine. Nineteen (21%) herbal and four (5%) conventional medicine trials were of higher quality. In both groups, smaller trials showed more beneficial treatment effects than larger trials. Conclusions Our findings challenge the widely held belief that the quality of the evidence on the effectiveness of herbal medicine is generally inferior to the evidence available for conventional medicine.

Response to Letter: "Critical Appraisal of Individual Trials?"

TO THE EDITOR: We appreciate Dr. Barden's concern that ensuring adequate randomization may be difficult. In our study on the association between the journal impact factor and the quality and outcome of randomized clinical trials we extracted randomization methods and blinding as quality measures (1). Unclear reporting of these measures may conceal methodological flaws. Dr. Barden argues that both adequate allocation sequence generation, allocation concealment, and blinding is necessary to ensure adequate randomization. We agree that the use of small blocks of fixed size and lack of blinding (or unblinding) could compromise the allocation concealment (2). However, the block size is rarely stated in trial protocols, e.g., only in 14 of 102 consecutive protocols from Denmark (2). Furthermore, previous empirical studies show that each component may be associated with bias in randomized clinical trials (3,4,5). To address Dr. Bardens concern, we have performed a post hoc analysis to determine the number of trials in which all quality measures were adequate. The analysis showed that only 75 of the 530 randomized trials included in our study (14%) reported both adequate allocation sequence generation, allocation concealment, and blinding. Non-parametric analyses for trend suggested that the impact factor was a significant predictor of the proportion of these trials (p= 0.01). This result supports our findings.

The Journal Impact Factor as a Predictor of Trial Quality and Outcomes: Cohort Study of Hepatobiliary Randomized Clinical Trials

To examine the association between the impact factor and characteristics of hepatobiliary randomized clinical trials. A cohort study of 530 hepatobiliary randomized clinical trials was performed. The journal impact factor was extracted from Science Citation Index. For each trial, we extracted the sample size, the quality of randomization and blinding methods, and the statistical significance of the primary outcome measure. The median sample size was 45 participants (interquartile range 25-88). The allocation sequence generation was adequate in 273 trials (52%). Allocation concealment was adequate in 178 trials (34%). The primary outcome measure was statistically significant in 374 (71%) trials. Nonparametric analyses for trend indicated that the impact factor was significantly associated with the sample size (p < 0.01) and the proportion of trials with adequate allocation sequence generation (p < 0.01) or allocation concealment (p= 0.02). The impact factor was not significantly associated with the study outcome (p= 0.28). The present study supports the use of the impact factor as a rough quality indicator. However, even trials in high impact journals may be small or may have inadequate quality. Critical appraisal of individual trials is always necessary, irrespective of the place of publication.

Quality assessment of reports on clinical trials in the Journal of Hepatology

Background/Aims: Electronic searches on databases for randomised clinical trials and controlled clinical trials do not identify as many trials as handsearches, and trial reporting may be flawed. The aims were to identify all fully reported randomised clinical trials in the Journal of Hepatology and to make a qualitative assessment of the reporting. Methods: The publications were identified by systematically handsearching the full text of the journal and searching MEDLINE. Central dimensions of trial quality were used to assess the reporting quality of the trials. Results: Randomised clinical trials represented 8.4% of the original articles ( 171 2028 ). Ten original articles (0.5%) could not be classified. A search on MEDLINE identified 81.3% of the randomised clinical trials, i.e., 139 out of the 171 identified by the handsearch. A total of 166 randomised clinical trials could be quality assessed. Forty-seven (28.3%) of them reported adequate generation of allocation sequence; 22 (13.3%) adequate allocation concealment; 95 (57.2%) allowed intention-to-treat analysis with only a fewlosses to follow-up; 50 (30.1%) were double-blind; 33 (19.9%) reported sample-size calculations; 13 trials (7.8%) employed the crossover design; and the median number of subjects per intervention arm in parallel group trials was 19 subjects (interquartile range: 11–31; range: 5–519). The quality of reporting was significantly better in regular issue articles than in supplement articles. Conclusions: Many important randomised clinical trials are published in the Journal of Hepatology, but there seems to be ample room for improvement of quality of reporting.