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.
2014: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?
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.
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)”