High dose steroid treatment in cerebral infarction. A comparison of the scientific quality of publicly and privately funded randomized controlled drug trials. An analysis of the effect of funding source in randomized clinical trials of second generation antipsychotics for the treatment of schizophrenia. Trends in acute ischemic stroke trials through the 20th century. Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Twelve-year results of the Coronary Risk Factor Study (CORIS). A cluster-randomized trial to improve stroke care in hospitals. Association of industry sponsorship to published outcomes in gastrointestinal clinical research. A double blind placebo controlled trial of ginkgo biloba extract in acute cerebral ischaemia. Improving the quality of care for patients with pneumonia in very small hospitals.
Steroid treatment is widely used in acute cerebral infarction yet its value is controversial. High dose dexamethasone (480 mg over 12 days) was given in a double blind, randomised controlled trial to 113 consecutive eligible patients with acute cerebral infarction admitted to an acute stroke unit. Those with stroke for more than 48 hours, known embolic sources, diabetes, and infection were excluded. Death and quality of survival were recorded over 21 days. The active drug group (54 patients) matched the placebo group (59 patients) for age, initial stroke score, delay in beginning treatment, and other relevant variables. The two groups did not differ significantly in death rate or quality of survivorship. The small difference in mortality between the two groups may have represented a marginal therapeutic effect, which might reach significance in a larger sample. The widespread use of steroids in response to such a marginal therapeutic gain would expose large numbers of patients with stroke to more serious hazards of steroid treatment and convert patients who would otherwise have died into neurovegetative survivors. High dose steroid treatment was ineffective in ischaemic stroke, and the data suggest that further evaluation by a larger multicentre trial is not justified. There is disagreement but few objective data on the relative quality of publicly or privately funded research. Cochrane reviews of randomized trials provide a good comparison opportunity because there is widespread agreement on how trial quality should be assessed and the Cochrane reviewers routinely do this.
                To compare the quality of publicly or privately funded randomized controlled trials.
                A total of 105 trials included in two Cochrane reviews were studied. Their quality assessments were abstracted from the relevant review and information about their funding source was collected from the original trial publications.
                Funding information was obtained for 87 trials. Of these, trials funded by pharmaceutical companies were larger (median sample size 126 vs. 45, P<0.001), more likely to have avoided ascertainment bias 11/14 vs. 15/41 (P=0.05). Non-significant trends in avoiding entry bias 19/19 vs. 35/37 and performance bias 13/22 vs. 14/48 also favoured the commercial trials. Commercial trials also had higher recorded attrition rates (median 6% vs. 1%, P=0.007), but this difference was entirely caused by more non-commercial trials reporting a zero attrition rate.
                The apparently lower attrition rate in the non-commercial trials should be interpreted with caution. Zero attrition in clinical trials with follow-up of many months is somewhat implausible.
                Commercially funded randomized trials tend to be of higher methodological quality than government-funded ones.
                © 2010 Blackwell Publishing Ltd. The effect of funding source on the outcome of randomized controlled trials has been investigated in several medical disciplines; however, psychiatry has been largely excluded from such analyses. In this article, randomized controlled trials of second generation antipsychotics in schizophrenia are reviewed and analyzed with respect to funding source (industry vs. non-industry funding).
                A literature search was conducted for randomized, double-blind trials in which at least one of the tested treatments was a second generation antipsychotic. In each study, design quality and study outcome were assessed quantitatively according to rating scales. Mean quality and outcome scores were compared in the industry-funded studies and non-industry-funded studies. An analysis of the primary author's affiliation with industry was similarly performed.
                Results of industry-funded studies significantly favored second generation over first generation antipsychotics when compared to non-industry-funded studies. Non-industry-funded studies showed a trend toward higher quality than industry-funded studies; however, the difference between the two was not significant. Also, within the industry-funded studies, outcomes of trials involving first authors employed by industry sponsors demonstrated a trend toward second generation over first generation antipsychotics to a greater degree than did trials involving first authors employed outside the industry (p=0.05).
                While the retrospective design of the study limits the strength of the findings, the data suggest that industry bias may occur in randomized controlled trials in schizophrenia. There appears to be several sources by which bias may enter clinical research, including trial design, control of data analysis and multiplicity/redundancy of trials. The advent of controlled clinical trials revolutionized clinical medicine over the course of the 20th century. The objective of this study was to quantitatively characterize developments in clinical trial methodology over time in the field of acute ischemic stroke.
                All controlled trials targeting acute ischemic stroke with a final report in English were identified through MEDLINE and international trial registries. Data regarding trial design, implementation, and results were extracted. A formal 100-point scale was used to rate trial quality.
                A total of 178 controlled acute stroke trials were identified, encompassing 73 949 patients. Eighty-eight trials involved neuroprotective agents, 59 rheological/antithrombotic agents, 26 agents with both neuroprotective and rheological/antithrombotic effects, and 5 a nonpharmacological intervention. Only 3 trials met conventional criteria for a positive outcome. Between the 1950s and 1990s, the number of trials per decade increased from 3 to 99, and mean trial sample size increased from 38 (median, 26) to 661 (median, 113). During 1980-1999, median time window allowed for enrollment decreased per half decade from 48 to 12 hours. Reported pharmaceutical sponsorship increased substantially over time, from 38% before 1970 to 68% in the 1990s. Trial quality improved substantially from a median score of 12 in the 1950s to 72 in the 1990s.
                Accelerating trends in acute stroke controlled trials include growth in number, sample size, and quality, and reduction in entry time window. These changes reflect an increased understanding of the pathophysiology of acute stroke, the imperative for treatment initiation within a critical time window, and more sophisticated trial design. Edaravone, a novel free radical scavenger, demonstrates neuroprotective effects by inhibiting vascular endothelial cell injury and ameliorating neuronal damage in ischemic brain models. The present study was undertaken to verify its therapeutic efficacy following acute ischemic stroke. We performed a multicenter, randomized, placebo-controlled, double-blind study on acute ischemic stroke patients commencing within 72 h of onset. Edaravone was infused at a dose of 30 mg, twice a day, for 14 days. At discharge within 3 months or at 3 months after onset, the functional outcome was evaluated using the modified Rankin Scale. Two hundred and fifty-two patients were initially enrolled. Of these, 125 were allocated to the edaravone group and 125 to the placebo group for analysis. Two patients were excluded because of subarachnoid hemorrhage and disseminated intravascular coagulation. A significant improvement in functional outcome was observed in the edaravone group as evaluated by the modified Rankin Scale (p = 0.0382). Edaravone represents a neuroprotective agent which is potentially useful for treating acute ischemic stroke, since it can exert significant effects on functional outcome as compared with placebo. Aspirin is effective in the treatment of acute myocardial infarction and in the long-term prevention of serious vascular events in survivors of stroke and myocardial infarction. There is, however, no reliable evidence on the effectiveness of early aspirin use in acute ischaemic stroke.
                The Chinese Acute Stroke Trial (CAST) was a large randomised, placebo-controlled trial of the effects in hospital of aspirin treatment (160 mg/day) started within 48 h of the onset of suspected acute ischaemic stroke and continued in hospital for up to 4 weeks. The primary endpoints were death from any cause during the 4-week treatment period and death or dependence at discharge, and the analyses were by intention to treat. 21,106 patients with acute ischaemic stroke were enrolled in 413 Chinese hospitals at a mean of 25 h after the onset of symptoms (10,554 aspirin, 10,552 placebo). 87% had a CT scan before randomisation. It was prospectively planned that the results would be analysed in parallel with those of the concurrent. International Stroke Trial (IST) of 20,000 patients with acute stroke from other countries.
                There was a significant 14% (SD 7) proportional reduction in mortality during the scheduled treatment period (343 [3.3%] deaths among aspirin-allocated patients vs 398 [3.9%] deaths among placebo-allocated patients; 2p = 0.04). There were significantly fewer recurrent ischaemic strokes in the aspirin-allocated than in the placebo-allocated group (167 [1.6%] vs 215 [2.1%]; 2p = 0.01) but slightly more haemorrhagic strokes (115 [1.1%] vs 93 [0.9%]; 2p > 0.1). For the combined in-hospital endpoint of death or non-fatal stroke at 4 weeks, there was a 12% (6) proportional risk reduction with aspirin (545 [5.3%] vs 614 [5.9%]; 2p = 0.03), an absolute difference of 6.8 (3.2) fewer cases per 1000. At discharge, 3153 (30.5%) aspirin-allocated patients and 3266 (31.6%) placebo-allocated patients were dead or dependent, corresponding to 11.4 (6.4) fewer per 1000 in favour of aspirin (2p = 0.08).
                There are two major trials of aspirin in acute ischaemic stroke. Taken together, CAST and the similarly large IST show reliably that aspirin started early in hospital produces a small but definite net benefit, with about 9 (SD 3) fewer deaths or non-fatal strokes per 1000 in the first few weeks (2p = 0.001), and with 13 (5) fewer dead or dependent per 1000 after some weeks or months of follow-up (2p < 0.01). After 4 years a coronary heart disease risk factor intervention programme produced equally large and significantly reduced risk profiles in two intervention towns compared with a control town. Intervention effects through community participation were assessed after cessation of the active intervention programme. The impact of secular trends was assessed in the control town and in two previously unstudied towns.
                Cross-sectional surveys were done in a random sample of 1620 participants aged 15-64 years in the three original towns 12 years after the initial quasi-experimental study. Two years later 327 subjects, aged 35-44 years, were studied in the original control town and in two non-intervention towns. Risk factor knowledge, smoking and medical histories were determined by questionnaire. Blood pressure, anthropometry and blood lipids were recorded. Data were compared across towns, and with previous surveys.
                At 12 years the low intensity intervention town maintained a significantly better risk factor profile than the control town, while the high intensity intervention town now matched the control town. No differences in risk factor profiles were found between the control town and the two new towns. Deaths from coronary heart disease and strokes showed a downward trend in the study area.
                Outcome suggests large ongoing secular trends during the study could have overtaken the intervention effects in the high intensity town, but not in the low intensity intervention town, which showed an advantage over the control town. These results support the effectiveness of media-based, long term health promotion strategies to reduce cardiovascular disease risk profiles. We evaluated the effect of performance feedback on acute ischemic stroke care quality in Minnesota hospitals.
                A cluster-randomized controlled trial design with hospital as the unit of randomization was used. Care quality was defined as adherence to 10 performance measures grouped into acute, in-hospital, and discharge care. Following preintervention data collection, all hospitals received a report on baseline care quality. Additionally, in experimental hospitals, clinical opinion leaders delivered customized feedback to care providers and study personnel worked with hospital administrators to implement changes targeting identified barriers to stroke care. Multilevel models examined experimental vs control, preintervention and postintervention performance changes and secular trends in performance.
                Nineteen hospitals were randomized with a total of 1,211 acute ischemic stroke cases preintervention and 1,094 cases postintervention. Secular trends were significant with improvement in both experimental and control hospitals for acute (odds ratio = 2.7, p = 0.007) and in-hospital (odds ratio = 1.5, p < 0.0001) care but not discharge care. There was no significant intervention effect for acute, in-hospital, or discharge care.
                There was no definite intervention effect: both experimental and control hospitals showed significant secular trends with performance improvement. Our results illustrate the potential fallacy of using historical controls for evaluating quality improvement interventions.
                This study provides Class II evidence that informing hospital leaders of compliance with ischemic stroke quality indicators followed by a structured quality improvement intervention did not significantly improve compliance more than informing hospital leaders of compliance with stroke quality indicators without a quality improvement intervention. Recent years have seen an increase in industry sponsorship of clinical trials throughout medicine. We conducted a study to evaluate the association of industry sponsorship to published outcomes in gastrointestinal (GI) clinical research. Our aims were (1) to evaluate the trends in the source of funding for GI clinical research during the period from 1992 to 2002-2003, (2) to determine whether the source of study funding predicted the likelihood that a study would publish results that favor the drug or device being tested, and (3) to determine whether differences exist in the methodologic quality of the investigational study methods used in studies funded by private industry versus other sources.
                We selected all clinical studies evaluating a drug or device from 4 prominent GI journals (Gastroenterology, The American Journal of Gastroenterology, Hepatology, and Gastrointestinal Endoscopy). All studies were abstracted by using a standardized data abstraction form. We evaluated the trends in funding source for studies published during the years 1992, 2002, and 2003. All selected studies were scored for methodologic quality by using a previously validated scoring system. The percentage of studies that reported outcomes that favored the device or drug being tested against the standard therapy or placebo was determined for each funding source. A funnel plot was constructed to assess for the presence of negative publication bias.
                A total of 6326 studies were reviewed. For the 1992 trend data, 1860 studies were reviewed, and 135 were selected for inclusion in the study. Ninety-five studies were studies involving the investigation of drugs, and 40 studies involved the testing of a device. For the 2002-2003 data 4466 studies were reviewed, and 315 were selected for inclusion in the study. Two hundred twenty-two studies were clinical trials involving the investigation of drugs, and 93 were clinical trials involving devices. In comparing 1992 to 2002, the percentage of studies funded by industry sources more than doubled from 10% to greater than 28% of the total studies assessed. There was an associated decline in the proportion of studies with funding from non-industry sources during this period (62% to less than 48%). The percentage of studies that did not disclose a funding source fell modestly from 28% to 24%. We found that 86% of studies funded by private industry reported a result favorable to the study drug or device, and 83% of studies funded by academic sources reported a result favorable to the study drug or device (P=.572). On average, studies funded by private industry had a higher methodology score than studies funded by traditional academic sources (75 of 100 vs 65 of 100; P=.005). Analysis of the funnel plot did not reveal evidence of bias against the publication of small studies with insignificant results.
                The proportion of research funded by industry has more than doubled during the last decade and currently comprises almost half of the funding for GI clinical research. Industry-sponsored studies are, on average, of superior methodologic quality to studies funded by other sources. Industry-sponsored studies in leading GI journals were no more likely than other studies to publish results that favored the study sponsor, although an extremely high percentage of all studies in these journals reported positive results. There has been only a modest decline in studies not acknowledging a funding source. A double blind placebo controlled trial was conducted in 55 patients of acute ischaemic stroke. Twenty one and twenty six patients were randomly allotted in group A and group B respectively. In group A, the patients received 40 mg Ginkgo biloba extract at 6 hourly intervals along with routine management. The placebo tablets were dispensed in the tablet form of same size, shape and colour and were given in the same way. After the patients were subjected to computerized tomographic (CT) scan to confirm acute ischaemic infarction, they were assessed on Mathew's scale and reassessed, at 2 weeks and 4 weeks of drug/placebo administration. Both groups showed significant improvement in Mathew's scale score after 2 weeks and 4 weeks. The difference in degree of change was negligible (p > 0.05) in either group. Estimation of relative changes of neurological deficit based on baseline values also showed negligible (p > 0.05) difference. A trial of Ginkgo biloba extract within 6 hours of stroke in a larger dose and in larger sample could be beneficial clinically in patients of cerebral ischaemic infarct, and needs further study. The usefulness of the plant extract has been demonstrated clinically and experimentally in more than 40 trials of chronic cerebral ischaemia, done elsewhere. This was not evident in our study as our study group was different (more than 48 hours after stroke). There appears to be no contraindication or adverse effect of this medication (Ginkgo biloba) in acute ischaemic stroke. Despite the publication of guidelines for the management of pneumonia, significant variation in care continues to exist. While there have been several published reports of quality improvement projects for pneumonia, there are few data on the effectiveness of these efforts in small hospitals. The purpose of this study was to demonstrate that a project implemented by a quality improvement organization in small hospitals would lead to an improvement in care that could not be accounted for by secular trends in the management of pneumonia.
                Medicare-insured hospital admissions for pneumonia were reviewed from 20 small hospitals in Oklahoma (intervention group) at baseline and after feedback. Project intervention included onsite feedback presentations to the medical staff, samples of performance improvement materials, and comparative measures of performance of predefined quality indicators. A second group of 16 demographically similar hospitals (control group) was selected for review during the same 2 periods. These hospitals subsequently underwent an identical intervention with a follow-up assessment.
                Statistically significant improvements in process measures were demonstrated in the intervention hospitals, including performance of a sputum (P<.01) and blood (P<.001) cultures, antibiotic administration within 4 hours of hospital admission (P<.001), and administration of the first dose of antibiotic in the emergency department (P<.001). These measures in the control hospitals did not change significantly (P =.93, .08, .79, and .52, respectively) during the 2 periods.
                Improvements in processes of care achieved by the intervention hospitals resulted from activities initiated because of participation in a quality improvement organization-directed project. This study demonstrated the effectiveness of quality improvement activities in very small hospitals.
The risk of bias in the included trials was moderate and the sample was small. Hence, although the data in this review show an effective treatment trend of edaravone for acute ischaemic stroke, further large, high-quality trials are required to confirm this trend.