Thrombolysis in Stroke - Are We Done Yet?
Amit Maini
Following the publication of the International Stroke Trial (IST-3) in May 2012 in the Lancet, I have had various discussions with my colleagues regarding the utility of thrombolysis for acute stroke. When presented with the unfortunate hypothetical scenario where they have been afflicted with the neurological insult in question, it surprised me somewhat that the general consensus was that they would choose to be thrombolysed (colleagues from radiology, medicine, emergency medicine as well as neurologists). Looking at the abstract of the IST-3 study, it's not hard to see why...
Summary
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.
"For the types of patient recruited in IST-3, despite early hazards, thrombolysis within 6 hours improved functional outcome. Benefit did not seem to be diminished in elderly patients".
Looking at the above statement, you would be forgiven for thinking that this large trial has finally answered the difficult question regarding this controversial therapy in stroke. When you add to this the enthusiastic recommendation in the editorial section of the same edition, it's hard not to come to the conclusion that thrombolysis in acute stroke is a done deal :
"In the meantime, the default situation for the first health-care professional who identifies the stroke patient should be to treat, and the role of stroke and emergency physicians is now not to identify patients who will be given rt-PA, but to identify the few who will not."
Let's take a reality check at this point, and look at the findings from this important study.
- Thrombolysis failed to reduce death or dependence at six months. This was the primary outcome being studied.
- In the tPA group, 36.5% of patients were alive, and independent. In the control group it was 35%. This was found to be statistically insignificant.
- The investigators were unable to establish any correlation between timing of therapy with tPA and clinical effect. Curiously some benefit was seen from 0-3 hours, then harm from 3-4.5 hrs, and then benefit again from 4.5 hrs to the magic 6 hour mark. The only sensible conclusion to be drawn here is that the timing of administration of therapy was not significant, as previous studies had alluded to.
So, the primary outcomes were no different between the control group and the tPA group. Add to this the unblinded nature of the trial, and you can see the invisible cracks have already started to form. However, due to some creative jiggery pokery in the statistical analysis, a secondary outcome measure showed some potential benefit - some patients may have been less dependent than they would otherwise have been.
Indeed, the only consistent finding across the board when considering thrombolysis in stroke is the increased incidence of harm by way of intracranial haemorrhage.
In the 12 major trials so far, 10 have shown no primary outcome benefit, 5 of which were ceased early due to harm, with only 2 studies (NINDS 2 & ECASS 3) demonstrating any significant benefit (and these were tenuous at best).
Lysis as a therapy for stroke is a treatment that I desperately wanted to believe in. I wish that it had consistently shown benefit in the same way that it did as a therapy in acute STEMI patients. But the fact of the matter is that it hasn't. Is it perhaps time to call it a day on this controversial therapy for the treatment of acute ischaemic stroke?
Additional Resources
Thrombolyitics for Acute Ischaemic Stroke - the NNT.com analysis
Reader Comments (1)
The reader comments on Emergency Medicine Journal Watch following the IST-3 summary say it all. I just love those words "In a secondary analysis"... (which means - since we found no significant benefit, this is how we manipulated the data to make it appear so).
The below comments by people much smarter people than myself (see the second comment by Rob Dunn), are well worth reading.
http://emergency-medicine.jwatch.org/cgi/content/full/2012/615/1
UNFORTUNATELY, NO BENEFIT HERE
David H Newman, MSSM, 16 Jun 2012 2:26 PM EST
Competing interests: None declared
Specialty: Emergency Medicine
Despite the authors' conclusions, this study demonstrated no benefit to thrombolytics, rather definitively. The p-value for the primary outcome comparison was 0.4 (not 0.04) — no difference, and not close. A "secondary exploratory" analysis, the only way the authors could claim a hint of benefit, is exactly that: exploratory and secondary. Let's keep our eye on the ball, rather than fall prey to a conventional wisdom, or to rose- colored author conclusions. In this day and age we are educated enough to know better.
ANOTHER STROKE TRIAL THAT IS NOT ALL THAT IT SEEMS
A/Prof R J Dunn, Royal Adelaide Hospital, 18 Jun 2012 8:01 AM EST
Competing interests: None declared
Specialty: Emergency Medicine
The difference in primary outcome variable (alive and OHS score 0-2 was not statistically significant and was only 2% different in any case (i.e.NNT = 50). The authors have managed to find a post hoc analysis (alive and OHS score 0-1) that is statistically, but not really clinically, significant to make the trial sound positive. The secondary variables (quality of life and place of residence) that were part of the initial data plan were not reported, but no reason for this is given. Despite what the authors say (all of whom are supported in some way by the company that makes tPA), this is a negative trial, and even if it were positive, the potential benefits of tPA in this population are minimal, and unlikely to be worth the effort of increased complications and resource useage.
EVIDENCE APPEARS TO SUGGEST THE OPPOSITE CONCLUSION
Amit Shah, 18 Jun 2012 9:25 AM EST
Competing interests: None declared
Specialty: Emergency Medicine
I continue to find the gap between evidence for stroke thrombolysis and the enthusiasm for its use to be striking. This study shows that we need to treat 25 people to kill one extra person at the 1 week mark, but only 16 people need to be treated to cause one extra intracranial bleed. All of this for the benefit of having no difference in the primary outcome, and at the cost of a very expensive drug and a very expensive thrombolysis program. Our health care system can't afford this kind of thinking.
CONFIRMING THE EFFECTIVENESS OF THROMBOLYSIS IN STROKE - AH, NO!
Matthew MacPartlin, 30 Jun 2012 2:41 AM EST
Competing interests: None declared
Specialty: Critical Care Med (Int Med)
All the primary outcomes appear to indicate exactly the converse; i.e. there is no benefit for thrombolysis, especially in the first week. The tantalizing shift of the bar towards better functional outcome at 6 months (kind of the opposite to DECRA in TBI) is interesting, but it's a secondary analysis with all of the traps. Suggestive, hypothesis generating, but not practice determining.