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

Oleh:

Perel, Pablo ; Roberts, Ian ; Sena, Emily ; Wheble, Philipa ; Sandercock, Peter ; Macleod, Malcolm ; E Mignin, Luciano ; Jayaram, Pradeep ; Khalid, S. Khan

Jenis: Article from Journal - ilmiah internasional
Dalam koleksi: British Medical Journal (keterangan: ada di Proquest) vol. 334 no. 7586 (Jan. 2007), page 197.

Ketersediaan

Perpustakaan FK Nomor Panggil: B16.K.2007.04 Non-tandon: 1 (dapat dipinjam: 0) Tandon: tidak ada

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Isi artikel

ABSTRACT 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 in the prevention and treatment of 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 infarctvolume 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 forthe hip region. The corresponding treatment effect in the lumbar spine was 8.5% (5.8% to 11.2%) and in the combined results forthe 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. animal experiments are not applicable to humans because of biological differences between the species and the type of animal model used.2 In this paper we compared treatment effects from systematic reviews of clinical trials with a systematic review of corresponding animal experiments.3'S METHODS We identified six interventions with evidence of a treatment effect (benefit or harm) in systematic reviews of clinical trials: corticosteroids in head injury,68 antifibrinolytics in haemorrhage,9 thrombo¬lysis in stroke, 10 II tirilazad in stroke,12 antenatal corticosteroids to prevent neonatal respiratory distress syndrome,13 and bisphosphonates to treat osteoporosis.14 We then systematically searched for randomised and non-randomised controlled studies of the interventions in animal models (see bmj.com). For dichotomous measures we estimated odds ratios and confidence intervals and for continuous mea¬sures we estimated the effect size (see bmj.com). We calculated pooled odds ratios, effect sizes, and 95% confidence intervals using a random effects model. Heterogeneity was examined using the 12 statistic. IS We investigated the possibility of publication bias using a funnel plot and statistical methods.16 RESULTS The quality of the experiments for each intervention was poor (see bmj.com). Corticosteroids for traumatic head injury Clinical trials of corticosteroids for head injury did not show any benefit and showed an increased risk of mor¬tality.6 Seventeen reports were found in animal models of head injury.wl.wl? Three reported adequate allocation concealment. Two reported the effect of corticosteroids on mortality but an effect estimate could not be calcu¬lated owing to missing numbers in one experiment and death of all the animals in the other. Seven experiments reported neurological outcomes. Neurological status was assessed by the grip test (see bmj.com) and neurological severity score. Four experi¬ments reported the grip test: pooled odds ratio 0.58 (95% confidence interval 0.41 to 0.83; see bmj.com). No heterogeneity was found (12=0%). Three experiments reported neurological severity scores but none reported the scores in each group.

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