VALUE OF STROKE CLOTBUSTERS QUESTIONED

Thrombolysis review controversy

Sarah Colyer  in the Australian Jnl of Medicine MJA  Monday, 13 October, 2014 reviews the raging argument:   “LEADING neurologists have condemned an Australasian College for Emergency Medicine decision to fund its own analysis of thrombolysis for acute stroke, which the college claims would be free of the conflicts of interest that plague existing guidance on the treatment.The Australasian College for Emergency Medicine (ACEM) is inviting proposals for consultants to analyse the published literature on thrombolysis in acute ischaemic stroke, which it has refused to endorse as a standard of care. (1)

Professor Yusuf Nagree, chair of the ACEM Scientific Committee, said unlike reviews published to date, its analysis would be “uniquely independent”.

“We are trying to find researchers who have no preconceived views or biases”, he told MJA InSight. An expert advisory panel would also be established to support the project, including an emergency physician, neurologist, GP, public health expert and lay person.

A Cochrane review published earlier this year found thrombolytic therapy significantly reduced death and dependency rates at 3‒6 months after stroke, and that this overall benefit was apparent despite an increase in symptomatic intracranial haemorrhage and deaths at 7‒10 days.(2)

While we await sight of the full Cochrane  paper, it is noteworthy that the abstract fails to give the absolute numbers.

Cochrane Database Syst Rev. 2014 Jul 29;7:CD000213. doi: 10.1002/14651858.CD000213.pub3.

Thrombolysis for acute ischaemic stroke.  Wardlaw JM1, Murray V, Berge E, del Zoppo GJ.:

“Most strokes are due to blockage of an artery in the brain by a blood clot. Prompt treatment with thrombolytic drugs can restore blood flow before major brain damage has occurred and improve recovery after stroke in some people. Thrombolytic drugs, however, can also cause serious bleeding in the brain, which can be fatal. One drug, recombinant tissue plasminogen activator (rt-PA), is licensed for use in selected patients within 4.5 hours of stroke in Europe and within three hours in the USA. There is an upper age limit of 80 years in some countries, and a limitation to mainly non-severe stroke in others. Forty per cent more data are available since this review was last updated in 2009.

OBJECTIVES:

To determine whether, and in what circumstances, thrombolytic therapy might be an effective and safe treatment for acute ischaemicstroke.

SEARCH METHODS:

We searched the Cochrane Stroke Group Trials Register (last searched November 2013), MEDLINE (1966 to November 2013) and EMBASE (1980 to November 2013). We also handsearched conference proceedings and journals, searched reference lists and contacted pharmaceutical companies and trialists.

SELECTION CRITERIA:

Randomised trials of any thrombolytic agent compared with control in people with definite ischaemic stroke.

DATA COLLECTION AND ANALYSIS:

Two review authors applied the inclusion criteria, extracted data and assessed trial quality. We verified the extracted data with investigators of all major trials, obtaining additional unpublished data if available.

MAIN RESULTS:

We included 27 trials, involving 10,187 participants, testing urokinase, streptokinase, rt-PA, recombinant pro-urokinase or desmoteplase. Four trials used intra-arterial administration, while the rest used the intravenous route. Most data come from trials that started treatment up to six hours after stroke. About 44% of the trials (about 70% of the participants) were testing intravenous rt-PA. In earlier studies very few of the participants (0.5%) were aged over 80 years; in this update, 16% of participants are over 80 years of age due to the inclusion of IST-3 (53% of participants in this trial were aged over 80 years). Trials published more recently utilised computerised randomisation, so there are less likely to be baseline imbalances than in previous versions of the review. More than 50% of trials fulfilled criteria for high-grade concealment; there were few losses to follow-up for the main outcomes.Thrombolytic therapy, mostly administered up to six hours after ischaemic stroke, significantly reduced the proportion of participants who were dead or dependent (modified Rankin 3 to 6) at three to six months after stroke (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.78 to 0.93). Thrombolytic therapy increased the risk of symptomatic intracranial haemorrhage (OR 3.75, 95% CI 3.11 to 4.51), early death (OR 1.69, 95% CI 1.44 to 1.98; 13 trials, 7458 participants) and death by three to six months after stroke (OR 1.18, 95% CI 1.06 to 1.30). Early death after thrombolysis was mostly attributable to intracranial haemorrhage. Treatment within three hours of stroke was more effective in reducing death or dependency (OR 0.66, 95% CI 0.56 to 0.79) without any increase in death (OR 0.99, 95% CI 0.82 to 1.21; 11 trials, 2187 participants). There was heterogeneity between the trials. Contemporaneous antithrombotic drugs increased the risk of death. Trials testing rt-PA showed a significant reduction in death or dependency with treatment up to six hours (OR 0.84, 95% CI 0.77 to 0.93, P = 0.0006; 8 trials, 6729 participants) with significant heterogeneity; treatment within three hours was more beneficial (OR 0.65, 95% CI 0.54 to 0.80, P < 0.0001; 6 trials, 1779 participants) without heterogeneity. Participants aged over 80 years benefited equally to those aged under 80 years, particularly if treated within three hours of stroke.

AUTHORS’ CONCLUSIONS:

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.”

Post-publication commentary:   Ryan Radecki2014 Aug 04 09:38 a.m.    “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?

Interv Neurol. 2014 May;2(3):97-104. doi: 10.1159/000356087.

Future directions for intra-arterial therapy for acute ischaemic stroke: is there life after three negative randomized controlled studies?

Maingard J1, Yan B2.   Royal Melbourne Hospital, Melbourne, Vic., Australia.

The three randomised controlled trials, Interventional Management of Stroke III (IMS3), Mechanical Retrieval and Revascularization of Stroke Clots Using Embolectomy (MR RESCUE) and Synthesis Expanasion: A Randomized Controlled Trial on Intra-Arterial Versus Intravenous Thrombolysis in Acute Ischaemic Stroke (SYNTHESIS EXP) showed no significant difference in clinical outcomes comparing intra-arterial (IA) therapy with intravenous thrombolysis. This article will explore the reasons for failure to show superiority of IA therapy.:

There are many reasons for the disappointing results of the three randomised controlled trials. Opposing views on IA therapy exist. Critics argue that only a small percentage of patients will be eligible for IA therapy and that it will never be cost-effective. Additionally, current trials have failed to address superior recanalization rates of new generation devices and lack of patient selection by advanced imaging. Time-to-treatment is longer in these randomised controlled trials and stroke outcomes were worse than anticipated. The current randomised controlled trials also took long periods to complete. There is emerging evidence that general anesthetic negatively influences outcome. Next generation trials will attempt to address these issues. Key Messages: There are disparate explanations for the disappointing results from the three IA therapy randomized controlled studies. Poor recanalisation rates with first generation endovascular devices, lack of advanced neuroimaging to aid in patient selection, lack of data surrounding the use of general anaesthesia, and prolonged time-to-treatment are potential contributors to negative results. The new generation of trials has the potential of addressing these pressing issues.

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