Have you had bleeding from your gums? Self-report to identify giNGival inflammation (The SING diagnostic accuracy and diagnostic model development study).

AIM: To assess the diagnostic performance of self-reported oral health questions and develop a diagnostic model with additional risk factors to predict clinical gingival inflammation in systemically healthy adults in the United Kingdom. METHODS: Gingival inflammation was measured by trained staff and defined as bleeding on probing (present if bleeding sites ≥ 30%). Sensitivity and specificity of self-reported questions were calculated; a diagnostic model to predict gingival inflammation was developed and its performance (calibration and discrimination) assessed. RESULTS: We included 2853 participants. Self-reported questions about bleeding gums had the best performance: the highest sensitivity was 0.73 (95% CI 0.70, 0.75) for a Likert item and the highest specificity 0.89 (95% CI 0.87, 0.90) for a binary question. The final diagnostic model included self-reported bleeding, oral health behaviour, smoking status, previous scale and polish received. Its area under the curve was 0.65 (95% CI 0.63-0.67). CONCLUSION: This is the largest assessment of diagnostic performance of self-reported oral health questions and the first diagnostic model developed to diagnose gingival inflammation. A self-reported bleeding question or our model could be used to rule in gingival inflammation since they showed good sensitivity, but are limited in identifying healthy individuals and should be externally validated.

Partial factorial trials: comparing methods for statistical analysis and economic evaluation.

BACKGROUND: Partial factorial trials compare two or more pairs of treatments on overlapping patient groups, randomising some (but not all) patients to more than one comparison. The aims of this research were to compare different methods for conducting and analysing economic evaluations on partial factorial trials and assess the implications of considering factors simultaneously rather than drawing independent conclusions about each comparison. METHODS: We estimated total costs and quality-adjusted life years (QALYs) within 10 years of surgery for 2252 patients in the Knee Arthroplasty Trial who were randomised to one or more comparisons of different surgical types. We compared three analytical methods: an "at-the-margins" analysis including all patients randomised to each comparison (assuming no interaction); an "inside-the-table" analysis that included interactions but focused on those patients randomised to two comparisons; and a Bayesian vetted bootstrap, which used results from patients randomised to one comparison as priors when estimating outcomes for patients randomised to two comparisons. Outcomes comprised incremental costs, QALYs and net benefits. RESULTS: Qualitative interactions were observed for costs, QALYs and net benefits. Bayesian bootstrapping generally produced smaller standard errors than inside-the-table analysis and gave conclusions that were consistent with at-the-margins analysis, while allowing for these interactions. By contrast, inside-the-table gave different conclusions about which intervention had the highest net benefits compared with other analyses. CONCLUSIONS: All analyses of partial factorial trials should explore interactions and assess whether results are sensitive to assumptions about interactions, either as a primary analysis or as a sensitivity analysis. For partial factorial trials closely mirroring routine clinical practice, at-the-margins analysis may provide a reasonable estimate of average costs and benefits for the whole trial population, even in the presence of interactions. However, such conclusions will be misleading if there are large interactions or if the proportion of patients allocated to different treatments differs markedly from what occurs in clinical practice. The Bayesian bootstrap provides an alternative to at-the-margins analysis for analysing clinical or economic endpoints from partial factorial trials, which allows for interactions while making use of the whole sample. The same techniques could be applied to analyses of clinical endpoints. TRIAL REGISTRATION: ISRCTN, ISRCTN45837371 . Registered on 25 April 2003.

Instrumental variable methods for a binary outcome were used to informatively address noncompliance in a randomized trial in surgery.

OBJECTIVES: Randomization can be used as an instrumental variable (IV) to account for unmeasured confounding when seeking to assess the impact of noncompliance with treatment allocation in a randomized trial. We present and compare different methods to calculate the treatment effect on a binary outcome as a rate ratio in a randomized surgical trial. STUDY DESIGN AND SETTING: The effectiveness of peeling versus not peeling the internal limiting membrane of the retina as part of the surgery for a full thickness macular hole. We compared the IV-based estimates (nonparametric causal bound and two-stage residual inclusion approach [2SRI]) with standard treatment effect measures (intention to treat, per protocol and treatment received [TR]). Compliance was defined in two ways (initial and up to the time point of interest). Poisson regression was used for the model-based approaches with robust standard errors to calculate the risk ratio (RR) with 95% confidence intervals. RESULTS: Results were similar for 1-month macular hole status across methods. For 3- and 6-month macular hole status, nonparametric causal bounds provided a narrower range of uncertainty than other methods, though still had substantial imprecision. For 3-month macular hole status, the TR estimate was substantially different from the other point estimates. CONCLUSION: Nonparametric causal bound approaches are a useful addition to an IV estimation approach, which tend to have large levels of uncertainty. Methods which allow RRs to be calculated when addressing noncompliance in randomized trials exist and may be superior to standard estimates. Further research is needed to explore the properties of different IV methods in a broad range of randomized controlled trial scenarios.

Long-Term Randomized Trial of Intensive Versus Symptomatic Management in Paget's Disease of Bone: The PRISM-EZ Study.

It has been suggested that normalization of bone turnover may improve clinical outcome in Paget's disease of bone (PDB) by preventing complications such as fractures and the development of osteoarthritis. Here we investigated the long-term effects of a treatment strategy that aimed to normalize bone turnover in PDB with that of symptomatic treatment. The study group comprised 502 subjects who were enrolled into a 3-year extension of the Paget's Disease: Randomized Trial of Intensive versus Symptomatic Management (PRISM) study. Intensive bisphosphonate therapy was continued in 270 of these subjects with the aim of normalizing bone turnover using zoledronic acid as the treatment of first choice. Symptomatic treatment continued in 232 subjects in whom bisphosphonates were only given for the treatment of bone pain. The primary outcome was fracture and secondary outcomes were orthopedic procedures, quality of life, and bone pain, adjusted for baseline characteristics. Serum total alkaline phosphatase (ALP) concentrations were significantly lower in the intensive group on entry to the study and the differences between groups increased as the study progressed. There were no clinically important differences in quality of life measures or bone pain between the treatment groups. Intensive treatment was associated with a nonsignificant increase in fracture risk (hazard ratio = 1.90; 95% CI, 0.91 to 3.98; p = 0.087), orthopedic procedures (1.81; 95% CI, 0.71 to 4.61; p = 0.214), and serious adverse events (relative risk 1.28; 95% CI, 0.96 to 1.42). We conclude that long-term intensive bisphosphonate therapy confers no clinical benefit over symptomatic therapy and is associated with a nonsignificant increase in the risk of fractures, orthopedic events, and serious adverse events. The results of this study suggest that in patients with established PDB, bisphosphonate therapy should focus on control of symptoms rather than suppression of bone turnover. © 2016 American Society for Bone and Mineral Research.

A systematic review of the use of an expertise-based randomised controlled trial design.

BACKGROUND: Under a conventional two-arm randomised trial design, participants are allocated to an intervention and participating health professionals are expected to deliver both interventions. However, health professionals often have differing levels of expertise in a skill-based interventions such as surgery or psychotherapy. An expertise-based approach to trial design, where health professionals only deliver an intervention in which they have expertise, has been proposed as an alternative. The aim of this project was to systematically review the use of an expertise-based trial design in the medical literature. METHODS: We carried out a comprehensive search of nine databases--AMED, BIOSIS, CENTRAL, CINAHL, Cochrane Methodology Register, EMBASE, MEDLINE, Science Citation Index, and PsycINFO--from 1966 to 2012 and performed citation searches using the ISI Citation Indexes and Scopus. Studies that used an expertise-based trial design were included. Two review authors independently screened the titles and abstracts and assessed full-text reports. Data were extracted and summarised on the study characteristics, general and expertise-specific study methodology, and conduct. RESULTS: In total, 7476 titles and abstracts were identified, leading to 43 included studies (54 articles). The vast majority (88%) used a pure expertise-based design; three (7%) adopted a hybrid design, and two (5%) used a design that was unclear. Most studies compared substantially different interventions (79%). In many cases, key information relating to the expertise-based design was absent; only 12 (28%) reported criteria for delivering both interventions. Most studies recruited the target sample size or very close to it (median of 101, interquartile range of 94 to 118), although the target was reported for only 40% of studies. The proportion of participants who received the allocated intervention was high (92%, interquartile range of 82 to 99%). CONCLUSIONS: While use of an expertise-based trial design is growing, it remains uncommon. Reporting of study methodology and, particularly, expertise-related methodology was poor. Empirical evidence provided some support for purported benefits such as high levels of recruitment and compliance with allocation. An expertise-based trial design should be considered but its value seems context-specific, particularly when interventions differ substantially or interventions are typically delivered by different health professionals.

Cardiovascular disease and vitamin D supplementation: trial analysis, systematic review, and meta-analysis.

BACKGROUND: Low 25-hydroxyvitamin D status has been associated with increased cardiovascular events in epidemiologic studies. OBJECTIVE: We assessed whether vitamin D supplementation reduces cardiac failure, myocardial infarction (MI), and stroke through an analysis of the Randomised Evaluation of Calcium Or vitamin D (RECORD) randomized controlled trial (RCT), a systematic review, and a meta-analysis. DESIGN: Two analyses were undertaken. The first analysis was a trial analysis. The RECORD was a factorial RCT that compared vitamin D3 (800 IU/d), calcium (1000 mg/d), vitamin D plus calcium, and a placebo. Cardiovascular events were collected throughout the trial and 3-y posttrial follow-up. Data were analyzed by using Cox regression. The second analysis was a systematic review. MEDLINE, EMBASE, CENTRAL, conference abstracts, and ongoing trials were searched for RCTs that evaluated vitamin D from 1980 to 2013. RCTs with ≥1 y of follow-up and participants mean or median age ≥60 y were included. Meta-analyses were based on a Bayesian fixed-effects model by using a complementary log-log link function to account for varying lengths of follow-up. RESULTS: In the trial analysis, we showed that, for the 5292 participants in the RECORD trial, HRs (95% CIs) for vitamin D compared with no vitamin D for cardiac failure, MI, and stroke were 0.75 (0.58, 0.97), 0.97 (0.75,1.26), and 1.06 (0.8, 1.32), respectively. Twenty-one studies met the inclusion criteria for the systematic review (n = 13,033). Estimated HRs (credible intervals) for vitamin D compared with the placebo or control for on-study events for cardiac failure, MI, and stroke were 0.82 (0.58, 1.15), 0.96 ( 0.83, 1.10), and 1.07 (0.91, 1.29), respectively. CONCLUSION: Vitamin D supplementation might protect against cardiac failure in older people but does not appear to protect against MI or stroke.

Selective decontamination of the digestive tract in critically ill patients treated in intensive care units: a mixed-methods feasibility study (the SuDDICU study).

BACKGROUND: Hospital-acquired infections (HAIs) are a major cause of morbidity and mortality. Critically ill patients in intensive care units (ICUs) are particularly susceptible to these infections. One intervention that has gained much attention in reducing HAIs is selective decontamination of the digestive tract (SDD). SDD involves the application of topical non-absorbable antibiotics to the oropharynx and stomach and a short course of intravenous (i.v.) antibiotics. SDD may reduce infections and improve mortality, but has not been widely adopted in the UK or internationally. Hence, there is a need to identify the reasons for low uptake and whether or not further clinical research is needed before wider implementation would be considered appropriate. OBJECTIVES: The project objectives were to (1) identify and describe the SDD intervention, (2) identify views about the evidence base, (3) identify acceptability of further research and (4) identify feasibility of further randomised controlled trials (RCTs). DESIGN: A four-stage approach involving (1) case studies of two ICUs in which SDD is delivered including observations, interviews and documentary analysis, (2) a three-round Delphi study for in-depth investigation of clinicians' views, including semi-structured interviews and two iterations of questionnaires with structured feedback, (3) a nationwide online survey of consultants in intensive care medicine and clinical microbiology and (4) semistructured interviews with international clinical triallists to identify the feasibility of further research. SETTING: Case studies were set in two UK ICUs. Other stages of this research were conducted by telephone and online with NHS staff working in ICUs. PARTICIPANTS: (1) Staff involved in SDD adoption or delivery in two UK ICUs, (2) ICU experts (intensive care consultants, clinical microbiologists, hospital pharmacists and ICU clinical leads), (3) all intensive care consultants and clinical microbiologists in the UK with responsibility for patients in ICUs were invited and (4) international triallists, selected from their research profiles in intensive care, clinical trials and/or implementation trials. INTERVENTIONS: SDD involves the application of topical non-absorbable antibiotics to the oropharynx and stomach and a short course of i.v. antibiotics. MAIN OUTCOME MEASURES: Levels of support for, or opposition to, SDD in UK ICUs; views about the SDD evidence base and about barriers to implementation; and feasibility of further SDD research (e.g. likely participation rates). RESULTS: (1) The two case studies identified complexity in the interplay of clinical and behavioural components of SDD, involving multiple staff. However, from the perspective of individual staff, delivery of SDD was regarded as simple and straightforward. (2) The Delphi study (n = 42) identified (a) specific barriers to SDD implementation, (b) uncertainty about the evidence base and (c) bimodal distributions for key variables, e.g. support for, or opposition to, SDD. (3) The national survey (n = 468) identified uncertainty about the effect of SDD on antimicrobial resistance, infection rates, mortality and cost-effectiveness. Most participants would participate in further SDD research. (4) The triallist interviews (n = 10) focused largely on the substantial challenges of conducting a large, multinational clinical effectiveness trial. CONCLUSIONS: There was considerable uncertainty about possible benefits and harms of SDD. Further large-scale clinical effectiveness trials of SDD in ICUs may be required to address these uncertainties, especially relating to antimicrobial resistance. There was a general willingness to participate in a future effectiveness RCT of SDD. However, support was not unanimous. Future research should address the barriers to acceptance and participation in any trial. There was some, but a low level of, interest in adoption of SDD, or studies to encourage implementation of SDD into practice. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 25. See the NIHR Journals Library website for further project information.

A randomised controlled trial of the clinical effectiveness and cost-effectiveness of different knee prostheses: the Knee Arthroplasty Trial (KAT).

BACKGROUND: In the late 1990s, new developments in knee replacement were identified as a priority for research within the NHS. The newer forms of arthroplasty were more expensive and information was needed on their safety and cost-effectiveness. OBJECTIVES: The Knee Arthroplasty Trial examined the clinical effectiveness and cost-effectiveness of four aspects of knee replacement surgery: patellar resurfacing, mobile bearings, all-polyethylene tibial components and unicompartmental replacement. DESIGN: This study comprised a partial factorial, pragmatic, multicentre randomised controlled trial with a trial-based cost-utility analysis which was conducted from the perspective of the NHS and the patients treated. Allocation was computer generated in a 1 : 1 ratio using a central system, stratified by eligible comparisons and surgeon, minimised by participant age, gender and site of disease. Surgeons were not blinded to allocated procedures. Participants were unblinded if they requested to know the prosthesis they received. SETTING: The setting for the trial was UK secondary care. PARTICIPANTS: Patients were eligible for inclusion if a decision had been made for them to have primary knee replacement surgery. Patients were recruited to comparisons for which the surgeon was in equipoise about which type of operation was most suitable. INTERVENTIONS: Patients were randomised to receive a knee replacement with the following: patellar resurfacing or no patellar resurfacing irrespective of the design of the prosthesis used; a mobile bearing between the tibial and femoral components or a bearing fixed to the tibial component; a tibial component made of either only high-density polyethylene ('all polyethylene') or a polyethylene bearing fixed to a metal backing plate with attached stem; or unicompartmental or total knee replacement. MAIN OUTCOME MEASURES: The primary outcome was the Oxford Knee Score (OKS). Other outcomes were Short Form 12; EuroQol 5D; intraoperative and postoperative complications; additional surgery; cost; and cost-effectiveness. Patients were followed up for a median of 10 years; the economic evaluation took a 10-year time horizon, discounting costs and quality-adjusted life-years (QALYs) at 3.5% per annum. RESULTS: A total of 116 surgeons in 34 centres participated and 2352 participants were randomised: 1715 in patellar resurfacing; 539 in mobile bearing; 409 in all-polyethylene tibial component; and 34 in the unicompartmental comparisons. Of those randomised, 345 were randomised to two comparisons. We can be more than 95% confident that patellar resurfacing is cost-effective, despite there being no significant difference in clinical outcomes, because of increased QALYs [0.187; 95% confidence interval (CI) -0.025 to 0.399] and reduced costs (-£104; 95% CI -£630 to £423). We found no definite advantage or disadvantage of mobile bearings in OKS, quality of life, reoperation and revision rates or cost-effectiveness. We found improved functional results for metal-backed tibias: complication, reoperation and revision rates were similar. The metal-backed tibia was cost-effective (particularly in the elderly), costing £35 per QALY gained. CONCLUSIONS: The results provide evidence to support the routine resurfacing of the patella and the use of metal-backed tibial components even in the elderly. Further follow-up is required to assess the stability of these findings over time and to inform the decision between mobile and fixed bearings. TRIAL REGISTRATION: Current Controlled Trials ISRCTN45837371. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and the orthopaedic industry. It will be published in full in Health Technology Assessment; Vol. 18, No. 19. See the NIHR Journals Library website for further project information.

Calcium supplements and cancer risk: a meta-analysis of randomised controlled trials.

Some evidence suggests that Ca and vitamin D supplements affect cancer risk; however, it is uncertain whether the effects are due to Ca, vitamin D or the combination. We investigated the effect of Ca supplements without co-administered vitamin D on cancer risk. Medline, Embase and the Cochrane Central Register of Controlled Trials, reference lists of meta-analyses and two clinical trial registries were searched for randomised, placebo-controlled trials of Ca supplements ( ≥ 500 mg/d), with ≥ 100 participants and duration >1 year. The lead authors of eligible trials supplied data on cancer outcomes. Trial-level data were analysed using random-effects meta-analyses and patient-level data using Cox proportional hazards models. A total of sixteen trials were eligible, six had no data available, ten provided trial-level data (n 10,496, mean duration 3·9 years), and of these, four provided patient-level data (n 7221, median duration 3·5 years). In the meta-analysis of trial-level data, allocation to Ca did not alter the risk of total cancer (relative risk 0·95, 95% CI 0·76, 1·18, P= 0·63), colorectal cancer (relative risk 1·38, 95% CI 0·89, 2·15, P= 0·15), breast cancer (relative risk 1·01, 95% CI 0·64, 1·59, P= 0·97) or cancer-related mortality (relative risk 0·96, 95% CI 0·74, 1·24, P= 0·75), but reduced the risk of prostate cancer (relative risk 0·54, 95 % CI 0·30, 0·96, P= 0·03), although there were few events. The meta-analysis of patient-level data showed similar results, with no effect of Ca on the risk of total cancer (hazard ratio 1·07, 95% CI 0·89, 1·28, P= 0·50). Ca supplements without co-administered vitamin D did not alter total cancer risk over 4 years, although the meta-analysis lacked power to detect very small effects, or those with a longer latency.

Clustering in surgical trials--database of intracluster correlations.

BACKGROUND: Randomised trials evaluation of surgical interventions are often designed and analysed as if the outcome of individual patients is independent of the surgeon providing the intervention. There is reason to expect outcomes for patients treated by the same surgeon tend to be more similar than those under the care of another surgeon due to previous experience, individual practice, training, and infrastructure. Such a phenomenon is referred to as the clustering effect and potentially impacts on the design and analysis adopted and thereby the required sample size. The aim of this work was to inform trial design by quantifying clustering effects (at both centre and surgeon level) for various outcomes using a database of surgical trials. METHODS: Intracluster correlation coefficients (ICCs) were calculated for outcomes from a set of 10 multicentre surgical trials for a range of outcomes and different time points for clustering at both the centre and surgeon level. RESULTS: ICCs were calculated for 198 outcomes across the 10 trials at both centre and surgeon cluster levels. The number of cases varied from 138 to 1370 across the trials. The median (range) average cluster size was 32 (9 to 51) and 6 (3 to 30) for centre and surgeon levels respectively. ICC estimates varied substantially between outcome type though uncertainty around individual ICC estimates was substantial, which was reflected in generally wide confidence intervals. CONCLUSIONS: This database of surgical trials provides trialists with valuable information on how to design surgical trials. Our data suggests clustering of outcome is more of an issue than has been previously acknowledged. We anticipate that over time the addition of ICCs from further surgical trial datasets to our database will further inform the design of surgical trials.

Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D(3) and/or calcium (RECORD trial).

CONTEXT: Vitamin D or calcium supplementation may have effects on vascular disease and cancer. OBJECTIVE: Our objective was to investigate whether vitamin D or calcium supplementation affects mortality, vascular disease, and cancer in older people. DESIGN AND SETTING: The study included long-term follow-up of participants in a two by two factorial, randomized controlled trial from 21 orthopedic centers in the United Kingdom. PARTICIPANTS: Participants were 5292 people (85% women) aged at least 70 yr with previous low-trauma fracture. INTERVENTIONS: Participants were randomly allocated to daily vitamin D(3) (800 IU), calcium (1000 mg), both, or placebo for 24-62 months, with a follow-up of 3 yr after intervention. MAIN OUTCOME MEASURES: All-cause mortality, vascular disease mortality, cancer mortality, and cancer incidence were evaluated. RESULTS: In intention-to-treat analyses, mortality [hazard ratio (HR) = 0.93; 95% confidence interval (CI) = 0.85-1.02], vascular disease mortality (HR = 0.91; 95% CI = 0.79-1.05), cancer mortality (HR = 0.85; 95% CI = 0.68-1.06), and cancer incidence (HR = 1.07; 95% CI = 0.92-1.25) did not differ significantly between participants allocated vitamin D and those not. All-cause mortality (HR = 1.03; 95% CI = 0.94-1.13), vascular disease mortality (HR = 1.07; 95% CI = 0.92-1.24), cancer mortality (HR = 1.13; 95% CI = 0.91-1.40), and cancer incidence (HR = 1.06; 95% CI = 0.91-1.23) also did not differ significantly between participants allocated calcium and those not. In a post hoc statistical analysis adjusting for compliance, thus with fewer participants, trends for reduced mortality with vitamin D and increased mortality with calcium were accentuated, although all results remain nonsignificant. CONCLUSIONS: Daily vitamin D or calcium supplementation did not affect mortality, vascular disease, cancer mortality, or cancer incidence.

Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis.

OBJECTIVE: To investigate whether calcium supplements increase the risk of cardiovascular events. DESIGN: Patient level and trial level meta-analyses. DATA SOURCES: Medline, Embase, and Cochrane Central Register of Controlled Trials (1966-March 2010), reference lists of meta-analyses of calcium supplements, and two clinical trial registries. Initial searches were carried out in November 2007, with electronic database searches repeated in March 2010. STUDY SELECTION: Eligible studies were randomised, placebo controlled trials of calcium supplements (>or=500 mg/day), with 100 or more participants of mean age more than 40 years and study duration more than one year. The lead authors of eligible trials supplied data. Cardiovascular outcomes were obtained from self reports, hospital admissions, and death certificates. RESULTS: 15 trials were eligible for inclusion, five with patient level data (8151 participants, median follow-up 3.6 years, interquartile range 2.7-4.3 years) and 11 with trial level data (11 921 participants, mean duration 4.0 years). In the five studies contributing patient level data, 143 people allocated to calcium had a myocardial infarction compared with 111 allocated to placebo (hazard ratio 1.31, 95% confidence interval 1.02 to 1.67, P=0.035). Non-significant increases occurred in the incidence of stroke (1.20, 0.96 to 1.50, P=0.11), the composite end point of myocardial infarction, stroke, or sudden death (1.18, 1.00 to 1.39, P=0.057), and death (1.09, 0.96 to 1.23, P=0.18). The meta-analysis of trial level data showed similar results: 296 people had a myocardial infarction (166 allocated to calcium, 130 to placebo), with an increased incidence of myocardial infarction in those allocated to calcium (pooled relative risk 1.27, 95% confidence interval 1.01 to 1.59, P=0.038). CONCLUSIONS: Calcium supplements (without coadministered vitamin D) are associated with an increased risk of myocardial infarction. As calcium supplements are widely used these modest increases in risk of cardiovascular disease might translate into a large burden of disease in the population. A reassessment of the role of calcium supplements in the management of osteoporosis is warranted.

Randomized trial of intensive bisphosphonate treatment versus symptomatic management in Paget's disease of bone.

Bisphosphonates are widely regarded as the treatment of choice for Paget's disease of bone (PDB) because of their potent inhibitory effects on bone turnover, but the effects of bisphosphonate therapy on symptoms and complications of PDB have been little studied. Here we report the results of a randomized trial that compared the effects of symptomatic treatment with intensive bisphosphonate therapy in a cohort of 1324 patients with PDB who were followed up for a median of 3 years (range 2 to 5 years). The symptomatic treatment group was treated only if they had pagetic bone pain, for which they were first given analgesics or anti-inflammatory drugs, followed by bisphosphonates if they did not respond. The intensive group received repeat courses of bisphosphonates irrespective of symptoms with the aim of reducing and maintaining serum alkaline phosphatase (ALP) levels within the normal range. The endpoints were fracture, orthopedic surgery, quality of life, bone pain, and hearing thresholds. Serum ALP levels were significantly lower in the intensive treatment group than in with the symptomatic treatment group within 4 months of commencing treatment and remained lower throughout the study (p < .001). There was no difference between the groups in quality of life (as assessed by the SF36 questionnaire), in overall bodily pain, or in pagetic bone pain. Hearing thresholds, as assessed by audiometry did not change significantly and did not differ between the treatment groups. Clinical fractures occurred in 46 of 661 patients (7.0%) in the intensive treatment group compared with 49 of 663 patients (7.4%) in the symptomatic treatment group, and orthopedic surgery was required in 50 of 661 patients (7.3%) in the intensive treatment group and in 55 of 663 patients (8.3%) in the symptomatic treatment group. These differences were not significant. Subgroup analyses of patients with elevated ALP levels at baseline and those who did or did not receive bisphosphonates during the study yielded similar results to those in the study group as a whole. We conclude that striving to maintain normal ALP levels with intensive bisphosphonate therapy confers no clinical advantage over symptom-driven management in patients with established PDB. Neither management strategy had a significant beneficial impact on pain or quality of life (Clinical trial registration number ISRCTN12989577).

Uric acid levels and outcome from coronary artery bypass grafting.

OBJECTIVE: Elevated uric acid levels have been associated with an adverse cardiovascular outcome in several settings. Their utility in patients undergoing surgical revascularization has not, however, been assessed. We hypothesized that serum uric acid levels would predict the outcome of patients undergoing coronary artery bypass grafting. METHODS: The study cohort consisted of 1140 consecutive patients undergoing nonemergency coronary artery bypass grafting. Clinical details were obtained prospectively, and serum uric acid was measured a median of 1 day before surgery. The primary end point was all-cause mortality. RESULTS: During a median of 4.5 years, 126 patients (11%) died. Mean (+/- standard deviation) uric acid levels were 390 +/- 131 micromol/L in patients who died versus 353 +/- 86 micromol/L among survivors (hazard ratio 1.48 per 100 micromol/L; 95% confidence interval, 1.25-1.74; P < .001). The excess risk associated with an elevated uric acid was particularly evident among patients in the upper quartile (>or=410 micromol/L; hazard ratio vs all other quartiles combined 2.18; 95% confidence interval, 1.53-3.11; P < .001). After adjusting for other potential prognostic variables, including the European System for Cardiac Operative Risk Evaluation, uric acid remained predictive of outcome. CONCLUSION: Increasing levels of uric acid are associated with poorer survival after coronary artery bypass grafting. Their prognostic utility is independent of other recognized risk factors, including the European System for Cardiac Operative Risk Evaluation.

Sample size calculator for cluster randomized trials.

Cluster randomized trials, where individuals are randomized in groups are increasingly being used in healthcare evaluation. The adoption of a clustered design has implications for design, conduct and analysis of studies. In particular, standard sample sizes have to be inflated for cluster designs, as outcomes for individuals within clusters may be correlated; inflation can be achieved either by increasing the cluster size or by increasing the number of clusters in the study. A sample size calculator is presented for calculating appropriate sample sizes for cluster trials, whilst allowing the implications of both methods of inflation to be considered.