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Do risks outweigh benefits in thrombolysis for stroke?

BMJ 2013; 347 doi: (Published 29 August 2013) Cite this as: BMJ 2013;347:f5215

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Re: Do risks outweigh benefits in thrombolysis for stroke?

Graeme Hankey promotes the concept that time-to-drug is important for stroke thrombolysis.(1) For acute myocardial infarction it took 60000 subjects to satisfactorily demonstrate that thrombolysis benefit was present, confined to STEMI (and no other MI subgroup), and time-dependent. In this case all trials and analyses showed statistical benefit and there was an uncontested and consistent relationship between time-to-drug and outcome. Stroke data on this matter, which include one sixth as many subjects, are far less uniform.

Among the twelve commonly cited trials of thrombolysis for stroke, two suggest a statistical benefit on favorable outcomes with tPA.(2) Moreover, there is just one analysis that finds time-to-drug to be associated with benefit(3), and a number that do not. The Cochrane authors, to their apparent surprise, find no such association despite a much more comprehensive examination(4). This absence of relationship between time-to-drug and effect was confirmed not only in re-analysis of the NINDS trial(5), but also in the largest ever trial of thrombolysis for stroke, IST-3, which reports comparisons of 0-3 hrs, 3-4.5 hrs and >4.5 hrs to be nonsignificant (p = 0.613).(6)

Graeme Hankey also promotes meta-analysis as the best method of evaluating the data. However, the BMJ has highlighted problems with meta-analysis. Based on methodologic flaws(7), missing patient data from studies stopped early for harm(8), heterogeneity calculations strongly suggesting pooling of data to be inappropriate(2, 8), imbalances in baseline stroke severity (NINDS, ECASS-3), the use of a subjective outcome measure with weak inter-rater reliability(9), and the influence of manufacturer involvement in the only two studies suggesting benefit, it is no wonder that the BMJ has called for urgent action to restore the integrity of the medical evidence base.(10)

Discussions on controversies contribute to our understanding of deficiencies in existing data. Perhaps the most glaring deficiency in data on thrombolysis for stroke is the absence of replication for trials suggesting benefit. It is unethical not to attempt to replicate these data. The medical literature is replete with initially positive studies followed by multiple larger, more reliable, conclusively negative studies.(11) Indeed, most existing evidence suggests thrombolysis to be either unsafe or non-beneficial.(8) In the face of a dangerous and unscientific rush to judgment, and a conspicuous intervention bias (to do something rather than nothing)(12), the BMJ should be commended for its encouragement of critical thinking. Critical evaluation by thoughtful minds is essential to maintaining the integrity of medicine, an attribute that, in the current debate over thrombolysis for stroke, is endangered.


1. Brown SG, Macdonald SP, Hankey GJ. Do risks outweigh benefits in thrombolysis for stroke? BMJ. 2013;347:f5215.
2. Wardlaw JM, Murray V, Berge E, del Zoppo G, Sandercock P, Lindley RL, et al. Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet. 2012 Jun 23;379(9834):2364-72.
3. Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010 May 15;375(9727):1695-703.
4. Wardlaw JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for acute ischaemic stroke (Review). Cochrane Database of Systematic Reviews [serial on the Internet]. 2009; (4. Art. No.: CD000213. ): Available from:
5. Hoffman JR, Schriger DL. A graphic reanalysis of the NINDS Trial. Ann Emerg Med. 2009 Sep;54(3):329-36, 36 e1-35.
6. Sandercock P, Wardlaw JM, Lindley RI, Dennis M, Cohen G, Murray G, et al. 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 Jun 23;379(9834):2352-63.
7. DeMaria AN. Meta-analysis. J Am Coll Cardiol. 2008 Jul 15;52(3):237-8.
8. Newman DH. Thrombolytics for acute ischemic stroke. The NNT Group; 2010 (accessed September 2013); Available from:
9. Quinn TJ, Dawson J, Walters MR, Lees KR. Reliability of the modified Rankin Scale: a systematic review. Stroke. 2009 Oct;40(10):3393-5.
10. Godlee F, Loder E. Missing clinical trial data: setting the record straight. BMJ. 2010;341:c5641.
11. Fatovich DM. Medical reversal: What are you doing wrong for your patient today? Emerg Med Australas. 2013 Feb;25(1):1-3.
12. Foy AJ, Filippone EJ. The case for intervention bias in the practice of medicine. Yale J Biol Med. 2013 Jun;86(2):271-80.

Competing interests: No competing interests

05 September 2013
Daniel M Fatovich
Emergency Physician, Professor of Emergency Medicine
Royal Perth Hospital, University of Western Australia
Box X2213 GPO, Perth, WA, 6847, Australia