Although the increase in the number of patients treated with rt-PA who were alive and independent at 6 months was smaller than originally anticipated and was not significant, the secondary analysis provides supportive evidence of benefit. The ordinal analysis provided evidence that on average, patients treated with intravenous thrombolysis up to 6 h after stroke survived with less disability. At 6 months, vital status was known for most patients and there was no evidence of any difference in the number of deaths, despite the excess of deaths within 7 days of stroke (mainly due to intracranial haemorrhage). Since mortality at 6 months was equal in the two groups, and in view of the evidence that the lower the patients' degree of disability at 6 months, the greater their subsequent survival,31
long-term follow-up beyond 6 months is important. Follow-up for survival, therefore, continues in the UK, Norway, and Sweden to assess whether an overall survival advantage from rt-PA after 6 months emerges.
Since we sought to recruit older patients and patients who did not strictly meet prevailing licence criteria for thrombolytic therapy with rt-PA, we anticipated a higher risk of adverse events, chiefly symptomatic intracranial haemorrhage. The patient information leaflet stated that rt-PA treatment might be associated with an increased risk of fatal intracranial haemorrhage of 4%, which indeed was the rate reported in the trial. Furthermore, applying a similar definition of symptomatic intra-cerebral haemorrhage as in the Cochrane systematic review, the frequency of this disorder within 7 days in IST-3 patients treated with rt-PA (6·8%) was comparable with the 7·3% reported in the Safe Implementation of Thrombolysis in Stroke (SITS) registry of 6483 patients treated within licence in routine clinical practice.32
We also expected a higher risk of death in the control group, and a smaller proportion alive and independent than in previous trials. Reassuringly, despite the different event rates in the control group, for most of the outcomes, there was no clear evidence that the effects of treatment were qualitatively different in IST-3 to those seen in earlier randomised trials, with two exceptions. We identified significant trends towards larger effects of treatment in patients with more severe strokes. We also anticipated a reduction in fatal and non-fatal neurological deterioration due to swelling of the initial infarct,6
so the clear 17 per 1000 excess was unexpected, and inconsistent with data from previous trials.6
As proposed by Kent and colleagues,33
we reported the effect of treatment on the primary outcome in several prespecified subgroups and included the effects sub-divided by the result of a prognostic score. Benefit with treatment was greatest within 3 h, but the analyses did not have sufficient power to define the shape of the relation between benefit and time beyond 3 h. The effect of treatment in patients older than 80 years of age was at least as large as in patients younger than 80 years of age. A formal test for trend showed a significant difference for greater benefit of rt-PA in patients with increasingly severe strokes. However, in view of the overall non-significant benefit for the primary outcome, the significant interactions across subgroups in these analyses should be interpreted with caution. As specified in the statistical analysis plan, we planned additional secondary analyses to explore these apparent effects on the primary outcome (and on other outcomes, such as symptomatic intracranial haemorrhage) and to decide if these effects were due to chance.
has identified limitations in these data, chiefly that IST-3 recruited only half the number of patients originally intended and so was underpowered for the primary outcome (and more so for the subgroup analyses). The many changes in the regulatory environment over the course of the trial delayed the approval of the trial in many centres and precluded the participation of several countries and hence was a significant factor in our failing to achieve our original target.11
Nonetheless, the trial was the largest-ever trial of thrombolysis therapy for stroke34
(over three times larger than any previous trial) and included more patients treated within 3 h of stroke (n=849) than were included in the National Institute of Neurological Disorders and Stroke (NINDS) trial (n=624), the only previous trial examining specifically treatment within 3 h (panel
). The fact that most of the IST-3 patients treated within 3 h were older than 80 years of age (n=726), yet achieved similar benefit to younger patients in NINDS trial, adds to the NINDS trial.
Panel. Research in context
To update the published systematic review of randomised-controlled trials of recombinant tissue plasminogen activator (rt-PA) in patients with acute ischaemic stroke and incorporate the third International Stroke Trial (IST-3) results,6
we searched for additional randomised trials of intravenous rt-PA versus control within 6 h of onset of acute ischaemic stroke up to March 30, 2012, in the Cochrane Stroke Trials Registry (November, 2011), Internet Stroke Trials Centre (March, 2011), Medline and Embase (search strategy available on request), and references lists in review articles and conference abstracts. The primary analysis was for all patients treated up to 6 h after stroke. Data were available for 7012 patients in 12 trials. We tested for heterogeneity between the estimates of effect for key outcomes from two strata: all trials before IST-3 and IST-3. The tests for heterogeneity in the proportional effects of treatment across these two strata were not significant for symptomatic intracranial haemorrhage (χ2
2·13, p=0·1), deaths within 7 days (χ2
1·44, p=0·2), deaths by the end of follow-up (χ2
1·0, p=0·3) and, the proportion alive and independent (modified Rankin score 0–2: χ2
3·08, p=0·08). Similarly, no heterogeneity occurred across the two strata for patients of all ages treated within 3 h (χ2
0·25, p=0·6). The review established that the effects of treatment reported in IST-3—in this wider range of patients (generally outside the current approvals)—were consistent with those seen in previous trials.
By providing estimates on the benefits and harms of treating patients with acute ischaemic stroke outside the current approvals, IST-3 enables clinicians to consider thrombolytic treatment for a wider range of patients, especially those older than 80 years of age. The data reinforce the need for further efforts to increase the proportion of all ischaemic strokes treated within 3 h. The additional data from IST-3 give greater confidence that mortality is not increased by treatment. The implications for ongoing research are that the data strengthen the rationale for the ongoing trials of thrombolysis in patients presenting more than 4·5 h after onset of stroke, and suggest that the imposition of upper age limits on future trials in acute stroke will become harder to justify.
The absence of masking is most relevant for the assessment of the events within 7 days. However, every possible precaution was taken to ensure masking of the expert panel assessing the scans, and the adjudication committee, who also assessed clinical data on all potential cerebral events. The proportional effect of treatment on fatal and non-fatal events within 7 days was very similar, which perhaps suggest that masking of the assessors was successful. The self-assessment at 6 months by patients or their carer by postal questionnaire or masked telephone interview was unmasked and so could be subject to reporting bias.34
However, self-reported outcome by patients is necessarily subjective and affected by many things besides knowledge of treatment allocation. The subgroup analysis subdivided by trial phase provides some reassurance in that no significant difference was seen in the effect of treatment on the primary outcome in the double-blind phase and the open phase (). The measurement of outcome with OHS at 6 months is different from previous trials that measured the modified Rankin score at 3 months. When we planned IST-3 in 1998, the modified Rankin score and OHS were judged to be equivalent. Both are derivatives of the original Rankin scale, developed by members of our group. While the proportion of patients recorded as dependent might be slightly different with each scale, the choice of outcome scale would not bias the assessment of treatment effect between treatment and control groups.
The outcome was recorded at 6 months and 18 months, to assess the effects on survival free of disability after a few months and also in the long term (the longer the benefit persists, the greater the cost-effectiveness). The longer time to follow-up allowed any differential effect of rt-PA on early and late death to become clearer. Outcome (other than survival) was not recorded at 3 months, although the proportional effects on death and disability seen at 6 months in IST-3 are comparable with those seen at 3 months in previous trials.
Lyden also comments that the sampling approach to monitoring in IST-3 was less intense than in many commercial studies, and is a potential concern, but also states: “many clinical trialists believe that source verification of some clinical trial data assures safety, accuracy, and validity of the trial data. Authorities do not agree on the minimum quantity of verified data to assure validity (100%, half, 10% sample)…but there is no evidence to suggest any problems with the [IST-3] data set due to limited monitoring.”34
When the results of IST-3 are incorporated into an updated systematic review,35
the estimates of relative treatment effect are broadly compatible with the previous rt-PA trials for each of the main outcomes: alive and independent; death at final follow-up; and fatal intracranial haemorrhage.
Our trial was underpowered to reliably detect important subgroup effects, and so a collaborative individual patient data meta-analysis (the Stroke Thrombolysis Trialists Collaboration [STTC]) has been established, which will include data from all the completed intravenous rt-PA trials and will update the previous pooled analysis.7
The meta-analysis will explore which baseline factors, other than time, might modify the effects of treatment on major outcomes (such as death, functional outcome, and intracerebral haemorrhage), and so provide better guidance for clinicians and patients to apply this treatment as effectively as possible in routine practice.
For the types of patient recruited in IST-3 (about three quarters of whom were randomised after 3 h, and half of all patients were older than 80 years of age), by 6 months there was evidence that rt-PA improved functional outcome. The data add weight to the policy of treating patients as soon as possible, and also justify extending treatment to patients older than 80 years of age. The data do not support any restriction of treatment on the basis of stroke severity or the presence of early ischaemic change on the baseline brain scan. The data support the need for randomised trials of thrombolysis in selected patients more than 4·5 h after stroke.
Correspondence to: Prof Peter Sandercock, Division of Clinical Neurosciences, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK