- Email: [email protected]
Thrombolysis in acute ischaemic stroke – Authors' reply
Correspondence
*David H Newman, Ashley E Shreves Department of Emergency Medicine, Mount Sinai School of Medicine, New York City, NY 10029, USA
should be generally agreed before IST-3 data are included in a definitive individual patient meta-analysis of rt-PA in acute ischaemic stroke.
1
I was an IST-3 trial participant.
[email protected]
2
3
The IST-3 collaborative group. 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. Hróbjartsson A, Boutron I. Blinding in randomized clinical trials: imposed impartiality. Clin Pharmacol Ther 2011; 90: 732–36. Sandercock P, Lindley R, Wardlaw J, et al, for the IST-3 collaborative group. Update on the third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke and baseline features of the 3035 patients recruited. Trials 2011; 12: 252–60.
The IST-3 trial results1 suggest that the benefits of treatment with recombinant tissue plasminogen activator (rt-PA) increase with stroke severity, so it is disappointing that treatment response is described only in terms of the proportion alive and independent at 6 months. Not only is this statistically inefficient, but it does little to help clinicians, patients, and families faced with challenging decisions. For someone with a severe stroke it is surely less important to know whether treatment might increase the remote chance of making a full recovery than whether it might reduce the real risk of surviving with severe disability. Conversely, a patient with a mild stroke, who has a 75% chance of making a good spontaneous recovery, might be less interested in a small change in this probability with treatment than in the risk of severe cerebral haemorrhage. A better solution would be to adjust the threshold for “good outcome” to reflect the patient’s initial prognosis,2 as is done naturally in clinical practice. Since trial data collection is already complete, however, it would be more helpful to publish all outcome indicators for patients in each stratum of stroke severity so that the benefits and harms of treatment for each category of patients can be explicitly estimated. More importantly, the template for such subgroup analysis 1054
David Barer [email protected] Cherry Tree House, Cherry Tree Lane, Wylam NE41 8AF, UK 1
2
The IST-3 collaborative group. 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. Berge E, Barer D. Could stroke trials be missing important treatment effects? Cerebrovasc Dis 2002; 13: 73–75.
The IST-3 report on the use of thrombolysis after stroke1 raises important ethical and statistical issues. The statistical issues are fairly obvious, with a non-significant difference in the primary outcome of living independently at 6 months, yet a secondary ordinal analysis showing a significant effect in favour of treatment. This situation raises familiar questions about how we should interpret a significant effect apparent only in a secondary analysis, especially when it relates to an outcome whose clinical and financial relevance is unclear. The ethical questions relate to how we should regard an intervention that does serious harm to some patients while providing substantial benefit to about an equal number of others. How should we regard a treatment intervention that has a roughly equal chance of killing or curing a patient, if overall clinical benefits are marginal? Taking primum non nocere as a principle, is it not the case that in such a situation many doctors and patients would prefer to let nature take its course? Additionally, how should we balance the increased risk of death within 7 days against the consequent reduction in risk thereafter? On the one hand, a quick death after stroke might spare the patient a period of distress,
disability, and indignity. On the other, it might deprive the patient and relatives of an opportunity for adjustment in a variety of emotional and practical ways. Thus, many people might regard the outcome of death within 7 days as substantially worse than a delayed death occurring within 6 months. For many, a summary interpretation claiming that, despite the early hazards, thrombolysis improved functional outcome might not seem to do justice to the complex issues involved. I declare that I have no conflicts of interest.
David Curtis [email protected] Centre for Psychiatry, Barts and the London School of Medicine and Dentistry, London E1 1BB, UK 1
The IST-3 collaborative group. 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.
Authors’ reply Daniel Fatovich and colleagues, Brendon Smith, and David Newman and Ashley Shreves interpret the third International Stroke Trial (IST-3) too rigidly in stating that the nonsignificant result of the statistically inefficient dichotomous analysis of the primary outcome measure implies that thrombolysis up to 6 h is ineffective. Since the trial sought to provide information on the risks and benefits in people who did not meet the licence criteria for thrombolysis, it posed a more subtle question than “does thrombolysis work?” We expected that, given previous data, and the fact that 95% of the patients in IST-3 did not meet the approval criteria for recombinant tissue plasminogen activator (rt-PA), the overall effect of allocation to rt-PA would be modest,1 as was the case. The included patients were also very different from those in ECASS-III, so the comparison by Smith of the proportion with a modified Rankin score of 0–2 in the rt-PA groups of the two trials is unduly simplistic. The appropriate interpretation of evidence from any www.thelancet.com Vol 380 September 22, 2012
Correspondence
We declare that we have no conflicts of interest other than those stated in the original paper.
*Peter Sandercock, Joanna Wardlaw, Martin Dennis, Gordon Murray, Richard Lindley [email protected] www.thelancet.com Vol 380 September 22, 2012
2
3
4
5
Sandercock P, Lindley R, Wardlaw J, Whiteley W, Murray G, for the IST-3 Collaborative Group. Statistical analysis plan for the third International Stroke Trial (IST-3): part of a ‘thread’ of reports of the trial. Int J Stroke 2012; 7: 186–87. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869. Wardlaw JM, Murray V, Berge E, et al. Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet 2012; 379: 2364–72. McHugh GS, Butcher I, Steyerberg EW, et al. A simulation study evaluating approaches to the analysis of ordinal outcome data in randomized controlled trials in traumatic brain injury: results from the IMPACT Project. Clin Trials 2010; 7: 44–57. Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. A prospective study of acute cerebrovascular disease in the community: the Oxfordshire Community Stroke Project—1981–86. 2. Incidence, case fatality rates and overall outcome at one year of cerebral infarction, primary intracerebral and subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 1990; 53: 16–22.
Antipsychotic drugs for relapse prevention in schizophrenia In their meta-analysis on antipsychotics for relapse prevention in schizophrenia, Stefan Leucht and colleagues (June 2, p 2063)1 found that these treatments reduced relapse rates at around 1 year (7–12 months) from 64% (placebo) to 27% (risk ratio 0·40, 95% CI 0·33–0·49; risk difference –39%, 95% CI –46 to –32); 24 randomised trials, published from 1962 to 2010, were included in this analysis. Since these trials covered nearly 50 years, we used standard metaregression techniques2–5 to examine the temporal trend of the primary result of Leucht and colleagues’ study. We thought our meta-regression to be worthwhile because other metaregression covariates were assessed by these authors, but time was not.
Proportion with relapse at 7–12 months
1
A 1·0 0·8 0·6 0·4 0·2 0
B Proportion with relapse at 7–12 months
University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK (PS, JW, MD, GM); Sydney Medical School, Westmead Hospital, Sydney, NSW, Australia (RL); and George Institute for Global Health, University of Sydney, Sydney, NSW, Australia (RL)
1·0 0·8 0·6 0·4 0·2 0
C 0 Risk difference
trial requires it to be viewed in the context of the totality of evidence;2 the estimates of effect seen in IST-3 were comparable with, and reinforced the results of, previous trials.3 Fatovich and colleagues state that we had decided “ordinal analysis was not appropriate”; this was the view of the steering committee in 2009. However, as stated in the statistical analysis plan,1 that decision was altered in 2011, and the ordinal analysis was added, before the investigators were unmasked to the data, as a secondary outcome, because empirical evidence had emerged to show that the ordinal method was not only statistically more efficient (crucial given that the sample size had been reduced relative to the original target) but also robust against even substantial deviations from the proportional odds assumption.4 Smith believes that we changed the primary measure of outcome from the modified Rankin Scale to the Oxford Handicap Scale (OHS). We did not; we merely clarified that we would use the 1990 modification of the Rankin Scale (now referred to as the OHS) throughout.5 We agree with David Barer, David Curtis, and Newman and Shreves that discussions with patients and their families about the immediate risks of death and long-term benefits of thrombolysis should be informed by good quality data. IST-3 on its own lacks statistical power to provide reliable answers on whether rt-PA is more beneficial in specific categories—eg, severe strokes—or perhaps harmful at 3·0– 4·5 h; such answers could emerge from the individual patient data metaanalysis by the Stroke Thrombolysis Trialists’ Collaboration, which will also provide the independent scrutiny suggested by Smith.
–0·2 –0·4 –0·6 –0·8 1960
1970
1980
1990
2000
2010
Year
Figure: Meta-regression analysis (random effects model) of temporal trends of outcomes in patients with schizophrenia treated with antipsychotics versus controls: data from 24 randomised trials Endpoint (relapse at 7–12 months) is separately shown for patients given antipsychotics (A) and controls (B). C shows timecourse of risk difference. In all panels, y-axis scale is 0–1. Regression equations are: RATE=0·004 × (YEAR–1960) + 0·12 (p=0·058) in A; RATE=0·006 × (YEAR–1960) + 0·478 (p=0·092) in B; RATE= –0·002 × (YEAR–1960) – 0·33 (p=0·386) in C. Each study is represented by a circle, the diameter of which is proportional to its statistical weight.
In our meta-regression, the proportion of relapsed patients at 1 year showed a quite surprising tendency to increase over time. In the experimental (figure A) and control (figure B) groups, the tendency towards these worsened outcomes with time did not reach the conventional threshold of significance, but was close to it (p=0·058). Anyhow, these findings clearly suggest that there has been no therapeutic improvement over 1055
*David H Newman, Ashley E Shreves Department of Emergency Medicine, Mount Sinai School of Medicine, New York City, NY 10029, USA
should be generally agreed before IST-3 data are included in a definitive individual patient meta-analysis of rt-PA in acute ischaemic stroke.
1
I was an IST-3 trial participant.
[email protected]
2
3
The IST-3 collaborative group. 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. Hróbjartsson A, Boutron I. Blinding in randomized clinical trials: imposed impartiality. Clin Pharmacol Ther 2011; 90: 732–36. Sandercock P, Lindley R, Wardlaw J, et al, for the IST-3 collaborative group. Update on the third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke and baseline features of the 3035 patients recruited. Trials 2011; 12: 252–60.
The IST-3 trial results1 suggest that the benefits of treatment with recombinant tissue plasminogen activator (rt-PA) increase with stroke severity, so it is disappointing that treatment response is described only in terms of the proportion alive and independent at 6 months. Not only is this statistically inefficient, but it does little to help clinicians, patients, and families faced with challenging decisions. For someone with a severe stroke it is surely less important to know whether treatment might increase the remote chance of making a full recovery than whether it might reduce the real risk of surviving with severe disability. Conversely, a patient with a mild stroke, who has a 75% chance of making a good spontaneous recovery, might be less interested in a small change in this probability with treatment than in the risk of severe cerebral haemorrhage. A better solution would be to adjust the threshold for “good outcome” to reflect the patient’s initial prognosis,2 as is done naturally in clinical practice. Since trial data collection is already complete, however, it would be more helpful to publish all outcome indicators for patients in each stratum of stroke severity so that the benefits and harms of treatment for each category of patients can be explicitly estimated. More importantly, the template for such subgroup analysis 1054
David Barer [email protected] Cherry Tree House, Cherry Tree Lane, Wylam NE41 8AF, UK 1
2
The IST-3 collaborative group. 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. Berge E, Barer D. Could stroke trials be missing important treatment effects? Cerebrovasc Dis 2002; 13: 73–75.
The IST-3 report on the use of thrombolysis after stroke1 raises important ethical and statistical issues. The statistical issues are fairly obvious, with a non-significant difference in the primary outcome of living independently at 6 months, yet a secondary ordinal analysis showing a significant effect in favour of treatment. This situation raises familiar questions about how we should interpret a significant effect apparent only in a secondary analysis, especially when it relates to an outcome whose clinical and financial relevance is unclear. The ethical questions relate to how we should regard an intervention that does serious harm to some patients while providing substantial benefit to about an equal number of others. How should we regard a treatment intervention that has a roughly equal chance of killing or curing a patient, if overall clinical benefits are marginal? Taking primum non nocere as a principle, is it not the case that in such a situation many doctors and patients would prefer to let nature take its course? Additionally, how should we balance the increased risk of death within 7 days against the consequent reduction in risk thereafter? On the one hand, a quick death after stroke might spare the patient a period of distress,
disability, and indignity. On the other, it might deprive the patient and relatives of an opportunity for adjustment in a variety of emotional and practical ways. Thus, many people might regard the outcome of death within 7 days as substantially worse than a delayed death occurring within 6 months. For many, a summary interpretation claiming that, despite the early hazards, thrombolysis improved functional outcome might not seem to do justice to the complex issues involved. I declare that I have no conflicts of interest.
David Curtis [email protected] Centre for Psychiatry, Barts and the London School of Medicine and Dentistry, London E1 1BB, UK 1
The IST-3 collaborative group. 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.
Authors’ reply Daniel Fatovich and colleagues, Brendon Smith, and David Newman and Ashley Shreves interpret the third International Stroke Trial (IST-3) too rigidly in stating that the nonsignificant result of the statistically inefficient dichotomous analysis of the primary outcome measure implies that thrombolysis up to 6 h is ineffective. Since the trial sought to provide information on the risks and benefits in people who did not meet the licence criteria for thrombolysis, it posed a more subtle question than “does thrombolysis work?” We expected that, given previous data, and the fact that 95% of the patients in IST-3 did not meet the approval criteria for recombinant tissue plasminogen activator (rt-PA), the overall effect of allocation to rt-PA would be modest,1 as was the case. The included patients were also very different from those in ECASS-III, so the comparison by Smith of the proportion with a modified Rankin score of 0–2 in the rt-PA groups of the two trials is unduly simplistic. The appropriate interpretation of evidence from any www.thelancet.com Vol 380 September 22, 2012
Correspondence
We declare that we have no conflicts of interest other than those stated in the original paper.
*Peter Sandercock, Joanna Wardlaw, Martin Dennis, Gordon Murray, Richard Lindley [email protected] www.thelancet.com Vol 380 September 22, 2012
2
3
4
5
Sandercock P, Lindley R, Wardlaw J, Whiteley W, Murray G, for the IST-3 Collaborative Group. Statistical analysis plan for the third International Stroke Trial (IST-3): part of a ‘thread’ of reports of the trial. Int J Stroke 2012; 7: 186–87. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869. Wardlaw JM, Murray V, Berge E, et al. Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet 2012; 379: 2364–72. McHugh GS, Butcher I, Steyerberg EW, et al. A simulation study evaluating approaches to the analysis of ordinal outcome data in randomized controlled trials in traumatic brain injury: results from the IMPACT Project. Clin Trials 2010; 7: 44–57. Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. A prospective study of acute cerebrovascular disease in the community: the Oxfordshire Community Stroke Project—1981–86. 2. Incidence, case fatality rates and overall outcome at one year of cerebral infarction, primary intracerebral and subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 1990; 53: 16–22.
Antipsychotic drugs for relapse prevention in schizophrenia In their meta-analysis on antipsychotics for relapse prevention in schizophrenia, Stefan Leucht and colleagues (June 2, p 2063)1 found that these treatments reduced relapse rates at around 1 year (7–12 months) from 64% (placebo) to 27% (risk ratio 0·40, 95% CI 0·33–0·49; risk difference –39%, 95% CI –46 to –32); 24 randomised trials, published from 1962 to 2010, were included in this analysis. Since these trials covered nearly 50 years, we used standard metaregression techniques2–5 to examine the temporal trend of the primary result of Leucht and colleagues’ study. We thought our meta-regression to be worthwhile because other metaregression covariates were assessed by these authors, but time was not.
Proportion with relapse at 7–12 months
1
A 1·0 0·8 0·6 0·4 0·2 0
B Proportion with relapse at 7–12 months
University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK (PS, JW, MD, GM); Sydney Medical School, Westmead Hospital, Sydney, NSW, Australia (RL); and George Institute for Global Health, University of Sydney, Sydney, NSW, Australia (RL)
1·0 0·8 0·6 0·4 0·2 0
C 0 Risk difference
trial requires it to be viewed in the context of the totality of evidence;2 the estimates of effect seen in IST-3 were comparable with, and reinforced the results of, previous trials.3 Fatovich and colleagues state that we had decided “ordinal analysis was not appropriate”; this was the view of the steering committee in 2009. However, as stated in the statistical analysis plan,1 that decision was altered in 2011, and the ordinal analysis was added, before the investigators were unmasked to the data, as a secondary outcome, because empirical evidence had emerged to show that the ordinal method was not only statistically more efficient (crucial given that the sample size had been reduced relative to the original target) but also robust against even substantial deviations from the proportional odds assumption.4 Smith believes that we changed the primary measure of outcome from the modified Rankin Scale to the Oxford Handicap Scale (OHS). We did not; we merely clarified that we would use the 1990 modification of the Rankin Scale (now referred to as the OHS) throughout.5 We agree with David Barer, David Curtis, and Newman and Shreves that discussions with patients and their families about the immediate risks of death and long-term benefits of thrombolysis should be informed by good quality data. IST-3 on its own lacks statistical power to provide reliable answers on whether rt-PA is more beneficial in specific categories—eg, severe strokes—or perhaps harmful at 3·0– 4·5 h; such answers could emerge from the individual patient data metaanalysis by the Stroke Thrombolysis Trialists’ Collaboration, which will also provide the independent scrutiny suggested by Smith.
–0·2 –0·4 –0·6 –0·8 1960
1970
1980
1990
2000
2010
Year
Figure: Meta-regression analysis (random effects model) of temporal trends of outcomes in patients with schizophrenia treated with antipsychotics versus controls: data from 24 randomised trials Endpoint (relapse at 7–12 months) is separately shown for patients given antipsychotics (A) and controls (B). C shows timecourse of risk difference. In all panels, y-axis scale is 0–1. Regression equations are: RATE=0·004 × (YEAR–1960) + 0·12 (p=0·058) in A; RATE=0·006 × (YEAR–1960) + 0·478 (p=0·092) in B; RATE= –0·002 × (YEAR–1960) – 0·33 (p=0·386) in C. Each study is represented by a circle, the diameter of which is proportional to its statistical weight.
In our meta-regression, the proportion of relapsed patients at 1 year showed a quite surprising tendency to increase over time. In the experimental (figure A) and control (figure B) groups, the tendency towards these worsened outcomes with time did not reach the conventional threshold of significance, but was close to it (p=0·058). Anyhow, these findings clearly suggest that there has been no therapeutic improvement over 1055