Factors affecting the apparent efficacy and safety of tissue plasminogen activator in thrombotic occlusion models of stroke: systematic review and meta-analysis.

Thrombolysis with recombinant tissue plasminogen activator (rtPA) improves outcome in animal models of stroke and in clinical trial, but is associated with increased intracranial hemorrhage. Here, we explore the impact of biologic and experimental design factors on efficacy and bleeding. We conducted a systematic review of studies describing the effect of tPA in thrombotic occlusion models of ischemic stroke followed by random effects meta-analysis, meta-regression, and trim and fill. We identified 202, 66, 128, and 54 comparisons reporting infarct volume, neurobehavioral score, hemorrhage, and mortality, respectively. The rtPA reduced infarct volume by 25.2% (95% confidence interval=21.8 to 28.6, 3388 animals), improved neurobehavioral score by 18.0% (12.6% to 23.3%, n=1243), increased the risk of hemorrhage (odds ratio=1.71, 1.42 to 2.07, n=2833) and had no significant effect on mortality (odds ratio=0.82, 0.62 to 1.08, n=1274). There was an absolute reduction in efficacy of 1.1% (0.7% to 1.4%) for every 10 minutes delay to treatment. Cumulative meta-analysis showed that the estimate of efficacy fell as more data became available. Publication bias inflated efficacy by 5.1% (infarct volume) and 8.1% (neurobehavioral score). This data set was large enough to be adequately powered to estimate with precision the impact of biologic and experimental factors on the efficacy and safety of rtPA.

Comparison of treatment effects between animal experiments and clinical trials: systematic review.

OBJECTIVE: To examine concordance between treatment effects in animal experiments and clinical trials. Study design Systematic review. DATA SOURCES: Medline, Embase, SIGLE, NTIS, Science Citation Index, CAB, BIOSIS. STUDY SELECTION: Animal studies for interventions with unambiguous evidence of a treatment effect (benefit or harm) in clinical trials: head injury, antifibrinolytics in haemorrhage, thrombolysis in acute ischaemic stroke, tirilazad in acute ischaemic stroke, antenatal corticosteroids to prevent neonatal respiratory distress syndrome, and bisphosphonates to treat osteoporosis. Review methods Data were extracted on study design, allocation concealment, number of randomised animals, type of model, intervention, and outcome. RESULTS: Corticosteroids did not show any benefit in clinical trials of treatment for head injury but did show a benefit in animal models (pooled odds ratio for adverse functional outcome 0.58, 95% confidence interval 0.41 to 0.83). Antifibrinolytics reduced bleeding in clinical trials but the data were inconclusive in animal models. Thrombolysis improved outcome in patients with ischaemic stroke. In animal models, tissue plasminogen activator reduced infarct volume by 24% (95% confidence interval 20% to 28%) and improved neurobehavioural scores by 23% (17% to 29%). Tirilazad was associated with a worse outcome in patients with ischaemic stroke. In animal models, tirilazad reduced infarct volume by 29% (21% to 37%) and improved neurobehavioural scores by 48% (29% to 67%). Antenatal corticosteroids reduced respiratory distress and mortality in neonates whereas in animal models respiratory distress was reduced but the effect on mortality was inconclusive (odds ratio 4.2, 95% confidence interval 0.85 to 20.9). Bisphosphonates increased bone mineral density in patients with osteoporosis. In animal models the bisphosphonate alendronate increased bone mineral density compared with placebo by 11.0% (95% confidence interval 9.2% to 12.9%) in the combined results for the hip region. The corresponding treatment effect in the lumbar spine was 8.5% (5.8% to 11.2%) and in the combined results for the forearms (baboons only) was 1.7% (-1.4% to 4.7%). CONCLUSIONS: Discordance between animal and human studies may be due to bias or to the failure of animal models to mimic clinical disease adequately.

National policy approaches to social care for elderly people in the United Kingdom and Singapore 1945-2002.

The authors compare policy approaches in the United Kingdom and Singapore on social care for older persons. The context of these approaches is discussed showing the development of policies, in each country from the aftermath of the Second World War to the present. Given that Singapore is a former British colony, it is of interest to scholars of social policy to examine its welfare approach as compared to the welfare state approach espoused by the United Kingdom. Both nations are faced with the challenges of an aging population, which necessitates handling similar problems with strategies that are in harmony with their respective economic, social, and cultural contexts. This paper considers their divergence of philosophies and policies, concluding with the recognition that the major difference lies in national and governmental expectations regarding the extent of the financial and regulatory responsibility for care for older people carried by the individual, the family, and the state.