- Email: [email protected]
Mortality after thrombolysis
Correspondence
adequately powered trials of omega-3 or other dietary therapies be done to assess their efficacy in reducing seizure frequency. Once another SUDEP risk factor or biomarker is identified, this measure could also be investigated. Scorza and colleagues’ raise important issues in SUDEP biomarker identification and risk modification. If biomarkers for SUDEP risk were found that could help to identify beneficial interventions for further testing and reduce the number of patients or time needed to assess preventive therapies. There are several candidate biomarkers, including interictal heart rate variability and ventricular conduction abnormalities, ictal or postictal heart rate changes or QT changes, and postictal changes in EEG activity (ie, presence and duration of suppression), oxygen saturation, autonomic dysfunction, decreased cerebral blood flow, and blood pressure. There is some evidence in support of these biomarkers, but none have been proven. Because seizures, especially generalised tonic-clonic convulsions, are most strongly associated with SUDEP risk, we believe that efforts to better control seizures are the best opportunity (currently supported by evidence) to reduce SUDEP. Physicians should inform patients about the possibility of SUDEP, why seizure control matters, and provide them with information to help control their seizures (eg, drug adherence, sleep hygiene, limited or no alcohol consumption, etc). In the future, we hope that new preventive approaches focused on SUDEP mechanisms will reduce the risk of this tragic complication of epilepsy. OD receives funding from the National Institute of Neurological Disorders and Stroke (NINDS) Center for SUDEP Research. DCH receives personal fees from Cyberonics, UpsherSmith, and Acorda. DCH is also Associate Editor of Epilepsia and Advisor to the Mount Sinai Injury Prevention Center. DJT receives grant support from UCB Pharma. SL receives funding from the NINDS Center for SUDEP Research, and the Informatics and Data Analytics Core U01-NS09046. SL also receives funding from
1304
the National Institutes of Health (NIH) through NINDS and the National Institute of Biomedical Imaging and Bioengineering. GR reports grant support from the NINDS Center for SUDEP Research.
*Orrin Devinsky, Dale C Hesdorffer, David J Thurman, Samden Lhatoo, George Richerson [email protected] Department of Neurology, Comprehensive Epilepsy Center, NYU Langone Medical Center, New York, NY, USA (OD);Gertrude H Sergievsky Center and Department of Epidemiology, Columbia University, New York, NY, USA (DCH); Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA (DJT); Department of Neurology, University Hospitals, Case Medical Center, Cleveland, OH, USA (SL); and Department of Neurology, University of Iowa, Veteran’s Affairs Medical Center, Iowa City, IA, USA (GR); Department of Molecular Physiology and Biophysics, University of Iowa, Veteran’s Affairs Medical Center, Iowa City, IA, USA (GR) 1
2
3
4
5
Bromfield E, Dworetzky B, Hurwitz S, et al. A randomized trial of polyunsaturated fatty acids for refractory epilepsy. Epilepsy Behav 2008; 12: 187–90. Yuen AW, Sander JW, Fluegel D, et al. Omega-3 fatty acid supplementation in patients with chronic epilepsy: a randomized trial. Epilepsy Behav 2005; 7: 253–58. Yuen AW, Flugel D, Poepel A, Bell GS, Peacock JL, Sander JW. Non-randomized open trial of eicosapentaenoic acid (EPA), an omega-3 fatty acid, in ten people with chronic epilepsy. Epilepsy Behav 2012; 23: 370–72. DeGiorgio CM, Miller P, Meymandi S, Gornbein JA. n-3 fatty acids (fish oil) for epilepsy, cardiac risk factors, and risk of SUDEP: clues from a pilot, double-blind, exploratory study. Epilepsy Behav 2008; 13: 681–84. Devinsky O, Hesdorffer DC, Thurman DJ, Lhatoo S, Richerson G. Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol 2016; 15: 1075–88.
Mortality after thrombolysis The group behind the 3rd International Stroke Trial (IST-3)1 has tried to reassure colleagues who are concerned about the increased mortality in thrombolysistreated patients. The investigators argue that the higher mortality seen within the first week after treatment levels out in the long run.2 Almost all trials have shown that treatment with alteplase results in a higher risk of death within 7–10 days after treatment than standard medical care. According to a 2014 Cochrane review 3 (in which IST-3 data are
included), this difference in mortality also seems to last over time. At the end of the follow-up, 1043 (19·4%) deaths occurred in the thrombolysis group versus 865 (18·0%) in the control group. If only alteplase-treated patients were considered, there was still a difference, although not significant (679 [19·1%] deaths in the thrombolysis group vs 640 [18·5%] in the control group).3 So why would a mortality difference disappear over time? In IST-3, there was a non-significant absolute risk reduction for death and dependency of 14/1000 (95% CI –20 to 48),4 corresponding to a number-neededto-treat of 71. It seems very unlikely that such a limited treatment effect could have caused a marked shift in long-term mortality. Stroke patients are, owing to their age, other risk factors, and comorbidity, at high risk for concurrent illnesses. Concurrent health events (that are unrelated to the initial treatment) in both groups over time tend to obscure the mortality excess caused by thrombolysis. Should such confounding effect allow us to look more favourably on thrombolysis? I would say that the answer is no. Thrombolysis is, to my knowledge, the only medical treatment that leads to a higher risk of death in treated patients than in non-treated ones. Changing the focus to long-term mortality only leads to hide this fact, not to reassure. The question remains as to whether an increased mortality can be justified because some survivors achieve a better functional outcome. To me, the answer is again no. I declare no competing interests.
Peter Appelros [email protected] Department of Neurology, Faculty of Medicine and Health, Örebro University, SE-70182 Örebro, Sweden 1
Sandercock P, Wardlaw JM, Lindley, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the Third International Stroke Trial [IST-3]): a randomised controlled trial Lancet 2012; 379: 2352–63.
www.thelancet.com/neurology Vol 15 December 2016
Correspondence
2
3
4
Berge E, Cohen G, Roaldsen MB, et al. Effects of alteplase on survival after ischaemic stroke (IST-3): 3 year follow-up of a randomised, controlled, open-label trial. Lancet Neurol 2016; 15: 1028–34. Wardlaw JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2014; 7: 109–110. Sandercock P, Wardlaw JM, Lindley RI, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the Third International Stroke Trial [IST-3]): a randomised controlled trial. Lancet 2012; 379: 2352–63.
so different patients and their families will come to different decisions when presented with the same information. PAGS and JMW have received support from the Medical Research Council, the Stroke Association, the Health Foundation, and Boehringer Ingelheim. All other authors declare no competing interests.
*Eivind Berge, Geoffrey Cohen, Joanna M Wardlaw, Peter A G Sandercock, William N Whiteley [email protected]
Authors’ reply We thank Peter Appelros for his comments on our Article.1 We agree that alteplase treatment increases case fatality by 1 week after treatment (principally by increasing the risk of intracranial haemorrhage). However, it is also clear that by 6 months, 18 months, and 3 years there is no excess of deaths in patients treated with alteplase, and survivors have a better functional outcome. An early hazard with a later benefit is a feature of many effective treatments, such as carotid endarterectomy and some chemotherapy regimens. The issue to debate is whether the attenuation of the difference in fatality with time is because alteplase leads to improved functional outcome and therefore better survival, or because the high level of fatality in elderly patients with severe strokes in both groups eventually obscures any detectable difference. Observational studies2,3 suggest that stroke patients with a better functional outcome survive for longer, and we find it plausible that even a small positive effect of alteplase on functional outcome could translate into a better long-term survival. We think that it is correct to say that alteplase treatment for ischaemic stroke leads to a higher risk of death in the acute phase, but leads to a better functional outcome in the longer term without a higher risk of death. We believe that most patients with acute stroke and their families will prefer alteplase treatment over no such treatment. However, the decision depends on individual preferences, and
Department of Internal Medicine, Oslo University Hospital, NO-0407 Oslo, Norway (EB); Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK (GC, JMW, PAGS, WNW) 1
2
3
Berge E, Cohen G, Roaldsen MB, et al. Effects of alteplase on survival after ischaemic stroke (IST-3): 3year follow-up of a randomised, controlled, open-label trial. Lancet Neurol 2016; 15: 1028–34. Slot KB, Berge E, Dorman P, et al. Impact of functional status at six months on long term survival in patients with ischaemic stroke: prospective cohort studies. BMJ 2008; 336: 376–79. Magalhaes R, Abreu P, Correia M, et al. Functional status three months after the first ischemic stroke is associated with long-term outcome: data from a community-based cohort. Cerebrovasc Dis 2014; 38: 46–54.
Simulation modelling to assess prehospital thrombolysis For patients with acute ischaemic stroke, treatment is more effective when given early after symptom onset (ie, the sooner, the better). Therefore, shortening time to treatment by starting it before hospital admission, as done by the Stroke Emergency Mobile (STEMO) project, might be a promising development in acute stroke treatment delivery. In The Lancet Neurology, Alexander Kunz and colleagues report that shortening the time to intravenous thrombolysis by deploying a STEMO vehicle might translate into better functional outcome at 90 days. 1 However, how such innovative treatment can be implemented into existing organisational models of acute stroke care? And what are the effects on other relevant outcomes, such as
www.thelancet.com/neurology Vol 15 December 2016
travelling time and health-care costs, associated with setting up and staffing a STEMO vehicle besides functional outcome? To convince both clinical and policy stakeholders, all these aspects have to be studied simultaneously, which might be difficult with present methodological approaches. Typically, interventions aimed at improving treatment are studied randomised controlled trials. However, previous attempts at improving service delivery with this approach have resulted in rather disappointing results, considering the time and money invested, for instance, the investigators of the INSTINCT trial reported there were non-significant increases in thrombolysis rates in the intervention group compared with the control group.2 Recent studies have used discrete event simulation modelling as an efficient alternative to clinical trials in identifying and assessing setups of regional stroke pathways in the Netherlands, the UK, and Australia.3–5 Whereas clinical trials are by design restricted to testing a set of interventions at specific time points along the stroke care pathway, use of computer simulation models allows for a large set of interventions— encompassing the overall pathway—to be put to test in silico with minimum effort, time, and cost. Some questions about the implementation of STEMO services in other settings remain. For instance, the effects of an alternative system set-up, in which the ambulance could be used more intensively, covering a larger geographical area, a greater range of patients, or delivered with fewer staff remain to be investigated. Furthermore, regional characteristics like population density (ie, urban or rural) and the availability and condition of road networks could matter in determining the success of the STEMO vehicle. A validated simulation model relying on routinely collected data on stroke pathway set-up and operation might be ideally suited to address 1305
adequately powered trials of omega-3 or other dietary therapies be done to assess their efficacy in reducing seizure frequency. Once another SUDEP risk factor or biomarker is identified, this measure could also be investigated. Scorza and colleagues’ raise important issues in SUDEP biomarker identification and risk modification. If biomarkers for SUDEP risk were found that could help to identify beneficial interventions for further testing and reduce the number of patients or time needed to assess preventive therapies. There are several candidate biomarkers, including interictal heart rate variability and ventricular conduction abnormalities, ictal or postictal heart rate changes or QT changes, and postictal changes in EEG activity (ie, presence and duration of suppression), oxygen saturation, autonomic dysfunction, decreased cerebral blood flow, and blood pressure. There is some evidence in support of these biomarkers, but none have been proven. Because seizures, especially generalised tonic-clonic convulsions, are most strongly associated with SUDEP risk, we believe that efforts to better control seizures are the best opportunity (currently supported by evidence) to reduce SUDEP. Physicians should inform patients about the possibility of SUDEP, why seizure control matters, and provide them with information to help control their seizures (eg, drug adherence, sleep hygiene, limited or no alcohol consumption, etc). In the future, we hope that new preventive approaches focused on SUDEP mechanisms will reduce the risk of this tragic complication of epilepsy. OD receives funding from the National Institute of Neurological Disorders and Stroke (NINDS) Center for SUDEP Research. DCH receives personal fees from Cyberonics, UpsherSmith, and Acorda. DCH is also Associate Editor of Epilepsia and Advisor to the Mount Sinai Injury Prevention Center. DJT receives grant support from UCB Pharma. SL receives funding from the NINDS Center for SUDEP Research, and the Informatics and Data Analytics Core U01-NS09046. SL also receives funding from
1304
the National Institutes of Health (NIH) through NINDS and the National Institute of Biomedical Imaging and Bioengineering. GR reports grant support from the NINDS Center for SUDEP Research.
*Orrin Devinsky, Dale C Hesdorffer, David J Thurman, Samden Lhatoo, George Richerson [email protected] Department of Neurology, Comprehensive Epilepsy Center, NYU Langone Medical Center, New York, NY, USA (OD);Gertrude H Sergievsky Center and Department of Epidemiology, Columbia University, New York, NY, USA (DCH); Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA (DJT); Department of Neurology, University Hospitals, Case Medical Center, Cleveland, OH, USA (SL); and Department of Neurology, University of Iowa, Veteran’s Affairs Medical Center, Iowa City, IA, USA (GR); Department of Molecular Physiology and Biophysics, University of Iowa, Veteran’s Affairs Medical Center, Iowa City, IA, USA (GR) 1
2
3
4
5
Bromfield E, Dworetzky B, Hurwitz S, et al. A randomized trial of polyunsaturated fatty acids for refractory epilepsy. Epilepsy Behav 2008; 12: 187–90. Yuen AW, Sander JW, Fluegel D, et al. Omega-3 fatty acid supplementation in patients with chronic epilepsy: a randomized trial. Epilepsy Behav 2005; 7: 253–58. Yuen AW, Flugel D, Poepel A, Bell GS, Peacock JL, Sander JW. Non-randomized open trial of eicosapentaenoic acid (EPA), an omega-3 fatty acid, in ten people with chronic epilepsy. Epilepsy Behav 2012; 23: 370–72. DeGiorgio CM, Miller P, Meymandi S, Gornbein JA. n-3 fatty acids (fish oil) for epilepsy, cardiac risk factors, and risk of SUDEP: clues from a pilot, double-blind, exploratory study. Epilepsy Behav 2008; 13: 681–84. Devinsky O, Hesdorffer DC, Thurman DJ, Lhatoo S, Richerson G. Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol 2016; 15: 1075–88.
Mortality after thrombolysis The group behind the 3rd International Stroke Trial (IST-3)1 has tried to reassure colleagues who are concerned about the increased mortality in thrombolysistreated patients. The investigators argue that the higher mortality seen within the first week after treatment levels out in the long run.2 Almost all trials have shown that treatment with alteplase results in a higher risk of death within 7–10 days after treatment than standard medical care. According to a 2014 Cochrane review 3 (in which IST-3 data are
included), this difference in mortality also seems to last over time. At the end of the follow-up, 1043 (19·4%) deaths occurred in the thrombolysis group versus 865 (18·0%) in the control group. If only alteplase-treated patients were considered, there was still a difference, although not significant (679 [19·1%] deaths in the thrombolysis group vs 640 [18·5%] in the control group).3 So why would a mortality difference disappear over time? In IST-3, there was a non-significant absolute risk reduction for death and dependency of 14/1000 (95% CI –20 to 48),4 corresponding to a number-neededto-treat of 71. It seems very unlikely that such a limited treatment effect could have caused a marked shift in long-term mortality. Stroke patients are, owing to their age, other risk factors, and comorbidity, at high risk for concurrent illnesses. Concurrent health events (that are unrelated to the initial treatment) in both groups over time tend to obscure the mortality excess caused by thrombolysis. Should such confounding effect allow us to look more favourably on thrombolysis? I would say that the answer is no. Thrombolysis is, to my knowledge, the only medical treatment that leads to a higher risk of death in treated patients than in non-treated ones. Changing the focus to long-term mortality only leads to hide this fact, not to reassure. The question remains as to whether an increased mortality can be justified because some survivors achieve a better functional outcome. To me, the answer is again no. I declare no competing interests.
Peter Appelros [email protected] Department of Neurology, Faculty of Medicine and Health, Örebro University, SE-70182 Örebro, Sweden 1
Sandercock P, Wardlaw JM, Lindley, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the Third International Stroke Trial [IST-3]): a randomised controlled trial Lancet 2012; 379: 2352–63.
www.thelancet.com/neurology Vol 15 December 2016
Correspondence
2
3
4
Berge E, Cohen G, Roaldsen MB, et al. Effects of alteplase on survival after ischaemic stroke (IST-3): 3 year follow-up of a randomised, controlled, open-label trial. Lancet Neurol 2016; 15: 1028–34. Wardlaw JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2014; 7: 109–110. Sandercock P, Wardlaw JM, Lindley RI, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the Third International Stroke Trial [IST-3]): a randomised controlled trial. Lancet 2012; 379: 2352–63.
so different patients and their families will come to different decisions when presented with the same information. PAGS and JMW have received support from the Medical Research Council, the Stroke Association, the Health Foundation, and Boehringer Ingelheim. All other authors declare no competing interests.
*Eivind Berge, Geoffrey Cohen, Joanna M Wardlaw, Peter A G Sandercock, William N Whiteley [email protected]
Authors’ reply We thank Peter Appelros for his comments on our Article.1 We agree that alteplase treatment increases case fatality by 1 week after treatment (principally by increasing the risk of intracranial haemorrhage). However, it is also clear that by 6 months, 18 months, and 3 years there is no excess of deaths in patients treated with alteplase, and survivors have a better functional outcome. An early hazard with a later benefit is a feature of many effective treatments, such as carotid endarterectomy and some chemotherapy regimens. The issue to debate is whether the attenuation of the difference in fatality with time is because alteplase leads to improved functional outcome and therefore better survival, or because the high level of fatality in elderly patients with severe strokes in both groups eventually obscures any detectable difference. Observational studies2,3 suggest that stroke patients with a better functional outcome survive for longer, and we find it plausible that even a small positive effect of alteplase on functional outcome could translate into a better long-term survival. We think that it is correct to say that alteplase treatment for ischaemic stroke leads to a higher risk of death in the acute phase, but leads to a better functional outcome in the longer term without a higher risk of death. We believe that most patients with acute stroke and their families will prefer alteplase treatment over no such treatment. However, the decision depends on individual preferences, and
Department of Internal Medicine, Oslo University Hospital, NO-0407 Oslo, Norway (EB); Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK (GC, JMW, PAGS, WNW) 1
2
3
Berge E, Cohen G, Roaldsen MB, et al. Effects of alteplase on survival after ischaemic stroke (IST-3): 3year follow-up of a randomised, controlled, open-label trial. Lancet Neurol 2016; 15: 1028–34. Slot KB, Berge E, Dorman P, et al. Impact of functional status at six months on long term survival in patients with ischaemic stroke: prospective cohort studies. BMJ 2008; 336: 376–79. Magalhaes R, Abreu P, Correia M, et al. Functional status three months after the first ischemic stroke is associated with long-term outcome: data from a community-based cohort. Cerebrovasc Dis 2014; 38: 46–54.
Simulation modelling to assess prehospital thrombolysis For patients with acute ischaemic stroke, treatment is more effective when given early after symptom onset (ie, the sooner, the better). Therefore, shortening time to treatment by starting it before hospital admission, as done by the Stroke Emergency Mobile (STEMO) project, might be a promising development in acute stroke treatment delivery. In The Lancet Neurology, Alexander Kunz and colleagues report that shortening the time to intravenous thrombolysis by deploying a STEMO vehicle might translate into better functional outcome at 90 days. 1 However, how such innovative treatment can be implemented into existing organisational models of acute stroke care? And what are the effects on other relevant outcomes, such as
www.thelancet.com/neurology Vol 15 December 2016
travelling time and health-care costs, associated with setting up and staffing a STEMO vehicle besides functional outcome? To convince both clinical and policy stakeholders, all these aspects have to be studied simultaneously, which might be difficult with present methodological approaches. Typically, interventions aimed at improving treatment are studied randomised controlled trials. However, previous attempts at improving service delivery with this approach have resulted in rather disappointing results, considering the time and money invested, for instance, the investigators of the INSTINCT trial reported there were non-significant increases in thrombolysis rates in the intervention group compared with the control group.2 Recent studies have used discrete event simulation modelling as an efficient alternative to clinical trials in identifying and assessing setups of regional stroke pathways in the Netherlands, the UK, and Australia.3–5 Whereas clinical trials are by design restricted to testing a set of interventions at specific time points along the stroke care pathway, use of computer simulation models allows for a large set of interventions— encompassing the overall pathway—to be put to test in silico with minimum effort, time, and cost. Some questions about the implementation of STEMO services in other settings remain. For instance, the effects of an alternative system set-up, in which the ambulance could be used more intensively, covering a larger geographical area, a greater range of patients, or delivered with fewer staff remain to be investigated. Furthermore, regional characteristics like population density (ie, urban or rural) and the availability and condition of road networks could matter in determining the success of the STEMO vehicle. A validated simulation model relying on routinely collected data on stroke pathway set-up and operation might be ideally suited to address 1305