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
Background
Thrombolysis is of net benefit in patients with acute ischaemic stroke, who are younger than 80 years of age and are treated within 4·5 h of onset. The third International Stroke Trial (IST-3) sought to determine whether a wider range of patients might benefit up to 6 h from stroke onset.
Methods
In this international, multicentre, randomised, open-treatment trial, patients were allocated to 0·9 mg/kg intravenous recombinant tissue plasminogen activator (rt-PA) or to control. The primary analysis was of the proportion of patients alive and independent, as defined by an Oxford Handicap Score (OHS) of 0—2 at 6 months. The study is registered, ISRCTN25765518.
Findings
3035 patients were enrolled by 156 hospitals in 12 countries. All of these patients were included in the analyses (1515 in the rt-PA group vs 1520 in the control group), of whom 1617 (53%) were older than 80 years of age. At 6 months, 554 (37%) patients in the rt-PA group versus 534 (35%) in the control group were alive and independent (OHS 0—2; adjusted odds ratio [OR] 1·13, 95% CI 0·95—1·35, p=0·181; a non-significant absolute increase of 14/1000, 95% CI −20 to 48). An ordinal analysis showed a significant shift in OHS scores; common OR 1·27 (95% CI 1·10—1·47, p=0·001). Fatal or non-fatal symptomatic intracranial haemorrhage within 7 days occurred in 104 (7%) patients in the rt-PA group versus 16 (1%) in the control group (adjusted OR 6·94, 95% CI 4·07—11·8; absolute excess 58/1000, 95% CI 44—72). More deaths occurred within 7 days in the rt-PA group (163 [11%]) than in the control group (107 [7%], adjusted OR 1·60, 95% CI 1·22—2·08, p=0·001; absolute increase 37/1000, 95% CI 17—57), but between 7 days and 6 months there were fewer deaths in the rt-PA group than in the control group, so that by 6 months, similar numbers, in total, had died (408 [27%] in the rt-PA group vs 407 [27%] in the control group).
Interpretation
For the types of patient recruited in IST-3, despite the early hazards, thrombolysis within 6 h improved functional outcome. Benefit did not seem to be diminished in elderly patients.
So what did we think? Well, a lot of colleagues had already raised questions about it (@DrGDH has an excellent article on his blog here). It was very interesting to chew the fat over this paper for an hour.
Statistical gimmickry, ordinal analyses, logistic regression and a triple reducing power calculation aside, let’s look at the headline stats.
An 4% Absolute risk increase of death in the T’lysis group within the first 7 days.
An overall ARR of 2% for the primary outcome of alive with Oxford Handicap Score <3 at 6/12 with T’lysis
An overall mortality rate of 27% in both control and T’lysis groups at 6/12.
Thus, we can take things back to basics……let’s think through an example of how this might work in practice.
What if 100 people aged 50-80 with varying severities of stroke present to my emergency department with a time onset of anywhere between 0 and 5 hours.
I thrombolyse 50 of them. The others get standard care.
In the Thrombolysed group, 2 of the 50 will be dead within a week. 1 more than the control arm will be alive and relatively independent at 6 months.
In both groups, about 13-14 will be dead in 6/12 regardless.
Not the kind of figures that make me want to redirect ambulances and develop a regional stroke network. And not the kind of pharmacotherapy I would want for my 90 year old nan. Goes with the previously maligned views published on the best bets website
Any dissenters??? Who is up for it based on face validity and the possibility of type 2 error in this trial? Who has a golden anecdotal story? Who thinks the benefits outweigh the risks of being a wheelchair bound dysphagic dependent?
Time for a serious contemplation of why we invest so heavily in therapies that have such potential to harm.
I have a slightly meandering epic on every single tPA RCT here if you have a month spare to read it… http://emergencymedicineireland.com/lytics-in-stroke/ David Newman has one at smartem.org and theNNT.com and @dreapadoirtas and @emlitofnote do a little line on it too. Yet to hear an EM doc speak positively about IST3
I have a slightly meandering epic on every single tPA RCT here if you have a month spare to read it… http://emergencymedicineireland.com/lytics-in-stroke/ David Newman has one at smartem.org and theNNT.com and @dreapadoirtas and @emlitofnote do a little line on it too. Yet to hear an EM doc speak positively about IST3
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