*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.
I was an IST-3 trial participant.
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
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