Appraising the quality of randomized controlled trials: inter-rater reliability for the OTseeker evidence database

Rationale and aims 'OTseeker' is an online database of randomized controlled trials (RCTs) and systematic reviews relevant to occupational therapy. RCTs are critically appraised and rated for quality using the 'PEDro' scale. We aimed to investigate the inter-rater reliability of the PEDro scale before and after revising rating guidelines. Methods In study 1, five raters scored 100 RCTs using the original PEDro scale guidelines. In study 2, two raters scored 40 different RCTs using revised guidelines. All RCTs were randomly selected from the OTseeker database. Reliability was calculated using Kappa and intraclass correlation coefficients [ICC (model 2,1)]. Results Inter-rater reliability was 'good to excellent' in the first study (Kappas >= 0.53; ICCs >= 0.71). After revising the rating guidelines, the reliability levels were equivalent or higher to those previously obtained (Kappas >= 0.53; ICCs >= 0.89), except for the item, 'groups similar at baseline', which still had moderate reliability (Kappa = 0.53). In study 2, two PEDro scale items, which had their definitions revised, 'less than 15% dropout' and 'point measures and variability', showed higher reliability. In both studies, the PEDro items with the lowest reliability were 'groups similar at baseline' (Kappas = 0.53), 'less than 15% dropout' (Kappas

A Comparison of Methodologies from Two Longitudinal Community-Based Randomized Controlled Trials of Similar Interventions in Palliative Care: What Worked and What Did Not

Background: Methodological challenges such as recruitment problems and participant burden make clinical trials in palliative care difficult. In 2001-2004, two community-based randomized controlled trials (RCTs) of case conferences in palliative care settings were independently conducted in Australia-the Queensland Case Conferences trial (QCC) and the Palliative Care Trial (PCT). Design: A structured comparative study of the QCC and PCT was conducted, organized by known practical and organizational barriers to clinical trials in palliative care. Results: Differences in funding dictated study designs and recruitment success; PCT had 6 times the budget of QCC. Sample size attainment. Only PCT achieved the sample size goal. QCC focused on reducing attrition through gatekeeping while PCT maximized participation through detailed recruitment strategies and planned for significant attrition. Testing sustainable interventions. QCC achieved a higher percentage of planned case conferences; the QCC strategy required minimal extra work for clinicians while PCT superimposed conferences on normal work schedules. Minimizing participant burden. Differing strategies of data collection were implemented to reduce participant burden. QCC had short survey instruments. PCT incorporated all data collection into normal clinical nursing encounters. Other. Both studies had acceptable withdrawal rates. Intention-to-treat analyses are planned. Both studies included substudies to validate new outcome measures. Conclusions: Health service interventions in palliative care can be studied using RCTs. Detailed comparative information of strategies, successes and challenges can inform the design of future trials. Key lessons include adequate funding, recruitment focus, sustainable interventions, and mechanisms to minimize participant burden.

CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, for steroid-dependent Crohn's disease: a randomized, double-blind, placebo-controlled trial

Background More than 50% of patients with Crohn's disease become either steroid resistant or dependent. Accordingly, development of new treatments for steroid-dependent Crohn's disease is a research priority. Aim To evaluate CDP571, a humanized antibody to tumour necrosis factor-α, for the treatment of steroid-dependent Crohn's disease. Methods Patients with steroid-dependent Crohn's disease (n = 271) were enrolled in a 36-week, double-blind, placebo-controlled trial. Steroid dependence was defined as use of prednisolone or prednisone (15–40 mg/day) or budesonide (9 mg/day) for ≥8 weeks, a previous failed attempt to decrease or discontinue steroids within 8 weeks of screening, and a Crohn's Disease Activity Index score of ≤150 points. Patients were randomized to receive intravenous CDP571 10 mg/kg or placebo 8-weekly through to week 32. Steroids were then tapered using a defined schedule. The primary efficacy endpoint was the percentage of patients with steroid sparing, defined as discontinuation of steroid therapy without a disease flare (Crohn's Disease Activity Index score ≥220 points) at week 36. Results Steroid sparing occurred in 53 of 181 (29.3%) CDP571 patients and 33 of 90 (36.7%) placebo patients (P = 0.24). Adverse events occurred at similar frequencies in both treatment groups. Conclusions CDP571 was ineffective for sparing steroids in patients with steroid-dependent Crohn's disease. CDP571 was well tolerated.

Small-scale randomized controlled trials need more powerful methods of mediational analysis than the Baron-Kenny method

Objective: To devise more-effective physical activity interventions, the mediating mechanisms yielding behavioral change need to be identified. The Baron-Kenny method is most commonly used. but has low statistical power and May not identify mechanisms of behavioral change in small-to-medium size Studies. More powerful statistical tests are available, Study Design and Setting: Inactive adults (N = 52) were randomized to either a print or a print-plus-telephone intervention. Walking and exercise-related social support Were assessed at baseline, after file intervention, and 4 weeks later. The Baron-Kenny and three alternative methods of mediational analysis (Freedman-Schatzkin; MacKinnon et al.: bootstrap method) were used to examine the effects of social support on initial behavior change and maintenance. Results: A significant mediational effect of social support on initial behavior change was indicated by the MacKinnon et al., bootstrap. and. marginally. Freedman-Schatzkin methods, but not by the Baron-Kenny method. No significant mediational effecl of social support on maintenance of walking was found. Conclusions: Methodologically rigorous intervention studies to identify mediators of change in physical activity are costly and labor intensive, and may not be feasible with large samples. The Use of statistically powerful tests of mediational effects in small-scale studies can inform the development of more effective interventions. (C) 2006 Elsevier Inc. All rights reserved.

A double-blind, randomized, placebo-controlled trial of macrolide in the treatment of chronic rhinosinusitis

Objectives: The antiinflammatory effect of macrolide antibiotics has been well-established, as has their role in the treatment of certain disorders of chronic airway inflammation. Several studies have suggested that long-term, low-dose macrolides may be efficacious in the treatment of chronic rhinosinusitis; however, these studies have lacked a control group. To date, this effect has not been tested in a randomized, placebo-controlled study. Method: The authors conducted a double-blind, randomized, placebo-controlled clinical trial on 64 patients with chronic rhinosinusitis. Subjects received either 150 mg roxithromycin daily for 3 months or placebo. Outcome measures included the Sinonasal Outcome Test-20 (SNOT-20), measurements of peak nasal inspiratory flow, saccharine transit time, olfactory function, nasal endoscopic scoring, and nasal lavage assays for interleukin-8, fucose, and a2-macroglobulin. Results. There were statistically significant improvements in SNOT-20 score, nasal endoscopy, saccharine transit time, and IL-8 levels in lavage fluid (P < .05) in the macrolide group. A correlation was noted between improved outcome measures and low IgE levels. No significant improvements were noted for olfactory function, peak nasal inspiratory flow, or lavage levels for fucose and a2-macroglobulin. No improvement in any outcome was noted in the placebo-treated patients. Conclusion: These findings suggest that macrolides may have a beneficial role in the treatment of chronic rhinosinusitis, particularly in patients with low levels of IgE, and supports the in vitro evidence of their antiinflammatory activity. Additional studies are required to assess their place in clinical practice.

Homocysteine and cardiovascular disease in renal disease

Elevated homocysteine (hyperhomocysteinaemia) in renal patients is a major concern for physicians. Although cause and effect between homocysteine and cardiovascular disease (CVD) has not been established in either the general population or renal patients, there is much evidence that this relationship does exist. Purported mechanisms that may explain this effect include increases in endothelial injury, smooth muscle cell proliferation, low-density lipoprotein oxidation and changes in haemostatic balance. Renal patients have a much greater incidence of hyperhomocysteinaemia and this may be explained by decreases in either the renal or extrarenal metabolism of the compound. We conclude that data from long-term placebo-controlled trials are urgently required to determine whether hyperhomocysteinaemia in renal patients is a cause of CVD events and requires therapeutic targeting.

Preliminary experiences with a single-patient trials service in general practice

Objective: To pilot a single-patient trials (SPTs) service in general practice, designed to improve decision-making about long-term medications for chronic conditions. Design: 12-week within-patient, randomised, double-blind, placebo-controlled, crossover comparison of ibuprofen with paracetamol for osteoarthritis, involving three pairs of two-week treatment periods for each participating patient. Setting and patients: Patients attending an academic general practice with a clinical diagnosis of osteoarthritis, with pain of at least a month's duration severe enough to warrant consideration of long-term non-steroidal anti-inflammatory drug (NSAID) use. Main outcome measures: Pain and stiffness; measures of overall arthritis compared with previous fortnight; preference for NSAID at the end of each two-week treatment period; use of escape analgesia; side effects; and management changes as a result of the SPTs. Results: Eight of 14 patients completed SPTs. One was a clear responder to NSAIDs, five were non-responders, and two were indefinite. Of the five who were using NSAIDs before the SPT, two continued and three ceased using them. Clinically useful information assisted decision-making for all eight participants. Medication management changed for six. Conclusions: Single-patient trials can be successfully implemented in general practice and might be a valuable method for GPs to identify patients who respond to medication for chronic stable conditions such as osteoarthritis, in which individual response to medication is variable.

Clinical trials with glycoprotein IIB/IIIA antagonists - No benefit without bleeding?

As the glycoprotein GPIIb/IIIa receptor is the final common pathway in platelet aggregation, antagonists of this receptor cause a profound inhibition of aggregation induced by any agonist. The short-term efficacy and safety of GPIIb/IIIa antagonists in patients undergoing coronary angioplasty was demonstrated with murine 7E3 Fab, but this antibody was immunogenic. Abciximab is a chimeric human-mouse monoclonal antibody that is less immunogenic. The first major trial with a GPIIb/IIIa antagonist was the EPIC trial with abciximab, which showed that abciximab reduced the ischemic complications of coronary balloon angioplasty and atherectomy in high-risk patients, but increased the risk of bleeding. Subsequent studies showed that using less concurrent heparin reduced bleeding. Abciximab also reduced the rate of revascularization. Further studies have shown that the benefits of abciximab extended to all patients undergoing angioplasty (EPILOG), including patients with unstable angina (CAPTURE) and acute myocardial infarction (RAPPORT). Clinical trials with eptifibatide and tirofiban have failed to demonstrate benefit, at the doses used, in angioplasty. Abciximab and eptifibatide, but not oral xemilofiban, improve the safety of the coronary stenting procedure. Shortterm intravenous treatment with lamifiban, eptifibatide or tirofiban is beneficial in acute coronary syndromes (unstable angina, non-Q wave myocardial infarction). Orally active GPIIb/IIIa antagonists are being developed for use in acute coronary syndromes and myocardial infarction. However, no benefit has been shown with lefradafiban in acute coronary syndromes and sibrafiban and orbofiban are harmful. Eptifibatide, lamifiban and abciximab improve coronary patency in myocardial infarction, and long-term trials of GPIIb/IIIa antagonists are being conducted in acute myocardial infarction. Abciximab can cause thrombocytopenia, and all the GPIIb/IIIa antagonists increase the incidence of bleeding, but there is no excess of intracranial hemorrhage. (C) 2001 Prous Science. All rights reserved.