Monday, August 4, 2014

The tPA Cochrane Review Takes Us For Fools

It’s been 5 years since the last Cochrane Review synthesizing the evidence regarding tPA in acute ischemic stroke.  Clearly, given such a time span, in an area of active clinical controversy, a great deal of new, important, randomized evidence has been generated!

Or, sadly, the only new evidence available to inform practice is IST-3 – a study failing to demonstrate benefit, despite its pro-tPA flaws and biases.  So, it ought not be a very exciting update, considering the 2009 version included 26 trials, and the 2014 update now includes only 27 trials.  Their summary conclusion, with only additional evidence of regression to the mean, ought remain essentially the same, or even less optimistic, right?

Of course not:
Overall, thrombolytic therapy appears to result in a significant net reduction in the proportion of patients dead or dependent in activities of daily living. This overall benefit was apparent despite an increase both in deaths (evident at seven to 10 days and at final follow up) and in symptomatic intracranial haemorrhages. Further trials are needed to identify which patients are most likely to benefit from treatment and the environment in which thrombolysis may best be given in routine practice.
Thrombolytic therapy given up to six hours after stroke reduces the proportion of dead or dependent people. Those treated within the first three hours derive substantially more benefit than with later treatment. This overall benefit was apparent despite an increase in symptomatic intracranial haemorrhage, deaths at seven to 10 days, and deaths at final follow-up (except for trials testing rt-PA, which had no effect on death at final follow-up). Further trials are needed to identify the latest time window, whether people with mild stroke benefit from thrombolysis, to find ways of reducing symptomatic intracranial haemorrhage and deaths, and to identify the environment in which thrombolysis may best be given in routine practice. 
They added a neutral trial comprising 43% of the tPA subjects to the existing analysis, and now it can be decisively promoted “up to six hours”?  How is this conceivable?

So, in the most literal sense, technically, the authors' statement is not untrue.  Analyses 1.12 and 1.13 aggregate all patients treated in trials between 0-6 hours, looking at mRS 0-2 and 0-1 at the end of follow up.  Indeed, for mRS 0-2, the OR favors thrombolysis at 1.17 (1.06 to 1.29), and for mRS 0-1, the OR favors thrombolysis at 1.29 (1.16 to 1.43).  Therefore, the authors are not falsely advertising tPA as beneficial for reducing death and dependency out to six hours – as long as you wear your pro-tPA blinders.

These authors, with multiple professional and financial conflicts-of-interest, simply choose to focus on inappropriate chunking of data for a theoretically time-dependent condition, rather than acknowledge their own analyses performed providing evidence to the contrary.  Analysis 1.21, in which they split out the patients treated into 0-3 and 3-6 hour cohorts, clearly demonstrates there is no basis upon which to claim benefit beyond 3 hours.  The OR for favorable outcome with thrombolysis in the 0-3 hour window is 1.53 (1.26 to 1.86), but the OR for 3-6 hours is 1.07 (0.96 to 1.20).  Then, the authors also neglect to mention Analysis 1.26, showing deaths are neutral between 0-3 hours, with an OR of 0.91 (0.73 to 1.13), but increased by thrombolysis in the 3-6 window, with an OR of 1.16 (1.00 to 1.35).

So, tPA after 3 hours: no functional outcome benefit and increased deaths – yet the authors are extolling the benefits of tPA to 6 hours?  There is no reasonable justification for such distorted reporting of their own analyses.  Simply unacceptable – and grossly misleading for the vast population of clinicians who do not or cannot access the full text, and only read the abstract.

Let's be perfectly clear – I am not anti-tPA.  I am, however, opposed to the unfettered expansion of tPA as guideline-mandatory treatment to a larger eligible cohort – as is increasingly prevalent across contemporary literature, and fueled by manufactured-sponsored COI.  Acute ischemic stroke is a heterogenous disease, with varying underlying etiology and diverse cerebrovascular substrate.  It is clear there are subsets of patients for whom the likelihood of harm from tPA exceeds the benefit, and we ought to be using precision medicine to narrow the treatment population, not expand it.

Thanks to Rory Speigel (@EMNerd_) for alerting me to this publication.

“Thrombolysis for acute ischaemic stroke (Review)”


  1. See the Stroke Thrombolysis Trialists' Collaboration publication this week in the Lancet of the individual patient data meta-analysis of all rt-PA trials. Published Online
    August 6, 2014, It confirms the results of the tabular data analysis in the Cochrane systematic review and may help to overcome your worries about the latest time window.

    1. Thanks for the feedback, Joanna. I still disagree regarding the most reasonable conclusion available based on the tabular data presented in the Cochrane Systematic Review.

      The updated meta-analysis, unfortunately, suffers from the same data quality issues as prior – if not worse, considering the inclusion of patients from an open-label, unblinded trial. The pervasive involvement of employees of Boehringer Ingelheim and Genentech in the majority of trials and publications limits the trustworthiness of the data and conclusions. This is, after all, the same company that just settled for USD$650M with regard to deliberately misleading data as relates to dabigatran.

      My post regarding the meta-analysis is here:

  2. Dear Dr Radecki: this updated systematic review is published in The Cochrane Library. There is a mechanism within the published review for submitting comments and feedback. The Cochrane Stroke Group Editorial Board invites you to submit your comments on this review by following the link to the review at the end of your article and clicking on 'Submit comments' under the heading 'Article Tools'. Your comments will then go through a formal process and will be published, along with the authors' response, as part of the review. Thank you.

    1. Does the formal process result in a response published open access? Otherwise, this blog is far more visible a public medium for post-publication peer review.

    2. Yes, all comments and author responses are published open access as part of the full review. Cochrane reviews are made freely available in the Cochrane Database of Systematic Reviews on The Cochrane Library 12 months after publication, and the comments and responses, once published, remain as part of the review in perpetuity. It also has the added benefit that all comments and responses, and any resulting changes to the review are published together in one place and fully documented.

    3. Ah, excellent. Thank you for the informative follow-up.

  3. Hi Ryan,
    Have you posted your comment on the "The Cochrane Library" website? Have tried finding it without success. It would be interesting to read their comment / answer regarding the above discussed issue. I am writing a paper on the field of stroke treatment by thrombolytics (med.student from Copenhagen)
    /Martin - Cheers from Europe

    1. I have not posted or formally responded on the Cochrane site. I imagine any response would simply deflect the issue, as above, to the more recent individual-patient meta-analysis. Then, as I mention on this site as well, it just returns to concerns regarding the reliability of data and the involvement of the sponsor.

  4. Hi Dr Radecki,

    Thank you for your comments. In conversation with Dr. Wardlaw, I believe she would be happy to directly discuss your concerns re: the integrity of the data involved in the IPD, as she was an author on this paper as well - including issues related to statistical and clinical heterogeneity. (Whether she would have any comments re: bias introduced by the sponsor I do not know.) At any rate I think it would actually be a good idea to post on Cochrane as mentioned above in order to foster a productive dialogue.


    1. Thank you for your follow-up.

      I will try to find the time to respond formally via the Cochrane Collaboration.

      I might note, however, my concerns are not unique. The methodology-oriented revision to the ACEP Clinical Policy on tPA is also concerned regarding the heterogeneity of trials, methods, and problems with bias. The only Class I evidence in their analysis of trials is NINDS, while ECASS III was Class II. The remaining evidence was downgraded to Class III. The issue of this Cochrane Review being full of junk data – with misleading conclusions re: 0-6 vs. the 0-3/3-6 chunking – stands.


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