A J Furlan1, G Kanoti. 1. Department of Neurology, Cleveland Clinic Foundation, Ohio, USA. furlana@ccsmmmtp.ccf.org
Abstract
BACKGROUND: Thrombolytic therapy for acute ischemic stroke raises several unsettled bioethical issues related to risk versus benefit. Excluding the National Institutes of Neurological Disorders and Stroke (NINDS) rt-PA trial, the risk of intracerebral hemorrhage averages 10.3%, and there is a 44% increase in the odds of death among fibrinolysis-treated patients. Some investigators have suggested that as yet unidentified subgroups may benefit despite an increased early risk of hemorrhage and death, while others have warned that the widespread use of thrombolysis cannot currently be recommended despite recent Food and Drug Administration approval. The NINDS rt-PA trial showed a net benefit, but the relative risk to benefit ratio in individual patients is uncertain because of incomplete subgroup analysis. We explore these and related issues by applying the bioethical principle of justification to the selection of stroke patients for thrombolysis. SUMMARY OF COMMENT: Justification of a therapy rests on the criteria of safety, efficacy (net benefit under ideal conditions), effectiveness (net benefit under routine conditions), efficiency (cost-effectiveness or cost benefit), and outcome (proportionality and informed consent). The ethical principal of proportionality states that positive outcomes must be proportional to negative outcomes; only the NINDS trial sets equipoise between risk and benefit. The relative risk to benefit ratio and cost-effectiveness of thrombolysis will likely vary among treating physicians and patient subgroups. Although some potential selection factors such as early CT changes, National Institutes of Health Stroke Scale score > 22, and age > 77 years have been identified, it is not yet possible to predict response to treatment in individual patients. The effectiveness of thrombolysis outside of a clinical trial has not yet been demonstrated, and it is not clear that thrombolysis is cost-effective for all potential patient subgroups. CONCLUSIONS: No stroke thrombolysis regimen has met all five justification criteria. Proportional outcome standards that take into account patient preferences must be established. The risk to benefit ratio of thrombolysis in patient subgroups requires clarification and should incorporate cost-efficiency analyses. These issues should be kept in mind when considering thrombolysis therapy in patients with acute ischemic stroke and when designing clinical trials.
BACKGROUND: Thrombolytic therapy for acute ischemic stroke raises several unsettled bioethical issues related to risk versus benefit. Excluding the National Institutes of Neurological Disorders and Stroke (NINDS) rt-PA trial, the risk of intracerebral hemorrhage averages 10.3%, and there is a 44% increase in the odds of death among fibrinolysis-treated patients. Some investigators have suggested that as yet unidentified subgroups may benefit despite an increased early risk of hemorrhage and death, while others have warned that the widespread use of thrombolysis cannot currently be recommended despite recent Food and Drug Administration approval. The NINDS rt-PA trial showed a net benefit, but the relative risk to benefit ratio in individual patients is uncertain because of incomplete subgroup analysis. We explore these and related issues by applying the bioethical principle of justification to the selection of strokepatients for thrombolysis. SUMMARY OF COMMENT: Justification of a therapy rests on the criteria of safety, efficacy (net benefit under ideal conditions), effectiveness (net benefit under routine conditions), efficiency (cost-effectiveness or cost benefit), and outcome (proportionality and informed consent). The ethical principal of proportionality states that positive outcomes must be proportional to negative outcomes; only the NINDS trial sets equipoise between risk and benefit. The relative risk to benefit ratio and cost-effectiveness of thrombolysis will likely vary among treating physicians and patient subgroups. Although some potential selection factors such as early CT changes, National Institutes of Health Stroke Scale score > 22, and age > 77 years have been identified, it is not yet possible to predict response to treatment in individual patients. The effectiveness of thrombolysis outside of a clinical trial has not yet been demonstrated, and it is not clear that thrombolysis is cost-effective for all potential patient subgroups. CONCLUSIONS: No stroke thrombolysis regimen has met all five justification criteria. Proportional outcome standards that take into account patient preferences must be established. The risk to benefit ratio of thrombolysis in patient subgroups requires clarification and should incorporate cost-efficiency analyses. These issues should be kept in mind when considering thrombolysis therapy in patients with acute ischemic stroke and when designing clinical trials.