Randomized controlled trial of sirolimus conversion in cardiac transplant recipients with renal insufficiency.

This randomized, comparative, multinational phase 3b/4 study of patients 1-8 years postcardiac transplantation (mean 3.9 years) evaluated the effect of conversion from a calcineurin inhibitor (CNI) to sirolimus on renal function in patients with renal insufficiency. In total, 116 patients on CNI therapy with GFR 40-90 mL/min/1.73 m(2) were randomized (1:1) to sirolimus (n = 57) or CNI (n = 59). Intent-to-treat analysis showed the 1-year adjusted mean change from baseline in creatinine clearance (Cockcroft-Gault) was significantly higher with sirolimus versus CNI treatment (+3.0 vs. -1.4 mL/min/1.73 m(2) , respectively; p = 0.004). By on-therapy analysis, values were +4.7 and -2.1, respectively (p < 0.001). Acute rejection (AR) rates were numerically higher in the sirolimus group; 1 AR with hemodynamic compromise occurred in each group. A significantly higher treatment discontinuation rate due to adverse events (AEs; 33.3% vs. 0%; p < 0.001) occurred in the sirolimus group. Most common treatment-emergent AEs significantly higher in the sirolimus group were diarrhea (28.1%), rash (28.1%) and infection (47.4%). Conversion to sirolimus from CNI therapy improved renal function in cardiac transplant recipients with renal impairment, but was associated with an attendant AR risk and higher discontinuation rate attributable to AEs.

Randomized controlled trial of sirolimus for renal transplant recipients at high risk for nonmelanoma skin cancer.

Sirolimus has antineoplastic effects and may reduce skin cancer rates in kidney transplant patients. This prospective, multicenter, randomized, open-label, controlled trial randomized 86 kidney transplant recipients (≥1 year posttransplant) with history of nonmelanoma skin cancer (NMSC) to continue calcineurin inhibitor (CNI) or convert to sirolimus. Patients were stratified by number of NMSC lesions (0-5, 6-20) in previous year. Primary end point was number of biopsy-confirmed new NMSC lesions per patient-year. Yearly NMSC rate was significantly lower with sirolimus (1.31 vs. 2.48 lesions/patient-year; p = 0.022). Squamous cell carcinoma occurred at a lower rate in the sirolimus versus CNI group (p = 0.038); basal cell carcinoma rate was similar in both. A lower proportion of patients receiving sirolimus developed new or recurrent NMSC (56.4% vs. 80.9%; p = 0.015) or new squamous cell carcinoma (41.0% vs. 70.2%; p = 0.006). No sirolimus patients and one CNI continuation patient experienced acute rejection. Incidence of treatment-emergent adverse events was similar between groups; however, discontinuation rates related to adverse events were significantly higher with sirolimus (46.2% vs. 0%; p < 0.001). In kidney transplant recipients with history of NMSC, conversion from CNI to sirolimus reduced rates of NMSC, without increasing acute rejection risk.

Promoting older peoples' participation in activity, whose responsibility? A case study of the response of health, local government and voluntary organizations.

The benefits for older people of participating in regular activity are well documented. This paper focuses on how publicly funded community-based organizations enable older people to engage in physical activity. The research questions were: (i) What activity promotion schemes/initiatives exist for older people? (ii) Who has responsibility for them, how are they funded and organized and what evidence exists of interagency working? (iii) Who are the older people that participate? (iv) What are the perceived and measurable outcomes of the initiatives identified? To establish the type and range of provision for older people in a sector of London, the strategies and information about existing activity promoting schemes of inner city health, local government and voluntary organizations were reviewed. Key informants were then interviewed to establish the rationale, achievements and different schemes. One hundred and nine activity-promoting initiatives for older people were identified. Most were provided within an environment of short-term funding and organizational upheaval and reflected eclectic theoretical and ideological approaches. The findings demonstrate: (i) the need for organizations to apply evidence about what attracts and sustains older people's participation in physical activity, and (ii) the need to develop funded programmes that build on past achievements, have explicit outcomes and exploit opportunities for cross agency working.

Exercise Evaluation Randomised Trial (EXERT): a randomised trial comparing GP referral for leisure centre-based exercise, community-based walking and advice only.

OBJECTIVES: To evaluate and compare the effectiveness and cost-effectiveness of a leisure centre-based exercise programme, an instructor-led walking programme and advice-only in patients referred for exercise by their GPs. DESIGN: A single-centre, parallel-group, randomised controlled trial, consisting of three arms, with the primary comparison at 6 months. SETTING: Assessments were carried out at Copthall Leisure Centre in Barnet, an outer London borough, and exercise programmes conducted there and at three other leisure centres and a variety of locations suitable for supervised walking throughout the borough. PARTICIPANTS: Participants were aged between 40 and 74 years, not currently physically active and with at least one cardiovascular risk factor. INTERVENTIONS: The 943 patients who agreed to participate in the trial were assessed in cohorts and randomised to one of the following three arms: a 10-week programme of supervised exercise classes, two to three times a week in a local leisure centre; a 10-week instructor-led walking programme, two to three times a week; an advice-only control group who received tailored advice and information on physical activity including information on local exercise facilities. After 6 months the control group were rerandomised to one of the other trial arms. Assessments took place before randomisation, at 10 weeks (in a random 50% subsample of participants), 6 months and 1 year in the leisure centre and walking arms. The control participants were similarly assessed up to 6 months and then reassessed at the same intervals as those initially randomised to the leisure centre and walking groups. MAIN OUTCOME MEASURES: The primary outcome measures were changes in self-reported exercise behaviour, blood pressure, total cholesterol and lipid subfractions. Secondary outcomes included changes in anthropometry, cardiorespiratory fitness, flexibility, strength and power, self-reported lifestyle behaviour, general and psychological health status, quality of life and health service usage. The costs of providing and making use of the service were quantified for economic evaluation. RESULTS: There was a net increase in the proportion of participants achieving at least 150 minutes per week of at least moderate activity in the sport/leisure and walking categories in all three study groups: at 6 months, the net increases were 13.8% in the leisure centre group, 11.1% in the walking group and 7.5% in the advice-only group. There were significant reductions in systolic and diastolic blood pressure in all groups at each assessment point compared with baseline. There were also significant and sustained improvements in cardiorespiratory fitness and leg extensor power, and small reductions in total and low-density lipoprotein cholesterol in all groups, but there were no consistent differences between the groups for any parameter over time. All three groups showed improvement in anxiety and mental well-being scores 6 months after the beginning of the trial. Leisure centre and walking groups maintained this improvement at 1 year. There were no differences between groups. Costs to the participants amounted to pound 100 for the leisure centre scheme and pound 84 for the walking scheme, while provider costs were pound 186 and pound 92, respectively. Changes in overall Short Form 36 scores were small and advice only appeared the most cost-effective intervention. CONCLUSIONS: The results of this trial suggest that referral for tailored advice, supported by written materials, including details of locally available facilities, supplemented by detailed assessments may be effective in increasing physical activity. The inclusion of supervised exercise classes or walks as a formal component of the scheme may not be more effective than the provision of information about their availability. On cost-effectiveness grounds, assessment and advice alone from an exercise specialist may be appropriate to initiate action in the first instance. Subsidised schemes may be best concentrated on patients at higher absolute risk, or with specific conditions for which particular programmes may be beneficial. Walking appears to be as effective as leisure centre classes and is cheaper. Efforts should be directed towards maintenance of increased activity, with proven measures such as telephone support. Further research should include an updated meta-analysis of published exercise interventions using the standardised mean difference approach.