Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis

Wardlaw, Joanna M.; Murray, Veronica; Berge, Eivind; Zoppo, Gregory J. del; Sandercock, Peter; Lindley, Richard I.; Cohen, Geoff

doi:10.1016/s0140-6736(12)60738-7

Cited by 889 publications

(673 citation statements)

References 24 publications

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“…Although systemic thrombolysis remains the most effective medical treatment for acute ischemic stroke,1 many postthrombolytic patients develop intracranial hemorrhage (ICH), a dreaded complication that frequently leads to early deterioration, and have unfavorable long‐term outcomes 2, 3, 4. Numerous efforts have been made by researchers to identify factors that could cause alterations in the efficacy and safety of systemic thrombolysis,5 among which prestroke medications have always been a major area of interest 6.…”

Section: Introductionmentioning

confidence: 99%

Intravenous Thrombolysis for Acute Ischemic Stroke in Patients Receiving Antiplatelet Therapy: A Systematic Review and Meta‐analysis of 19 Studies

Luo

Zhuang

Zeng

et al. 2016

JAHA

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BackgroundThe safety and long‐term outcome of systemic thrombolysis in patients receiving antiplatelet medications remain subjects of great clinical significance. The objective of this meta‐analysis was to determine how prestroke antiplatelet therapy affects the risks and benefits of intravenous thrombolysis in patients with acute ischemic stroke.Methods and ResultsA dual‐reviewer search was conducted in PubMed and EMBASE databases through November 2015, from which 19 studies involving a total of 108 588 patients with acute ischemic stroke were identified based on preset inclusion criteria. Information on study designs, patient characteristics, exposures, outcomes, and adjusting confounders was extracted, and estimates were combined by using random‐effects models. The pooled crude estimates suggested that taking long‐term antiplatelet medications was associated with higher odds of symptomatic intracranial hemorrhage (odds ratio [OR] 1.70, 95% CI 1.47–1.97) and death (OR 1.46, 95% CI 1.22–1.75) and lower odds of favorable functional outcomes (OR 0.86, 95% CI 0.80–0.93). However, the combined confounder‐adjusted results only confirmed a relatively weak positive association between prior antiplatelet therapy and symptomatic intracranial hemorrhage (OR 1.21, 95% CI 1.02–1.44) and demonstrated no significant relationship between antiplatelet therapy and the other 2 outcomes (favorable outcome OR 1.09, 95% CI 0.96–1.24; death OR 1.02, 95% CI 0.98–1.07). Subgroup analyses revealed that the associations between prestroke antiplatelet therapy and outcomes were dependent on time and antiplatelet agents.ConclusionsPatients with acute ischemic stroke receiving long‐term antiplatelet medications were associated with greater risks of developing symptomatic intracranial hemorrhage after systemic thrombolysis. However, the overall independent association between prestroke antiplatelet therapy and unfavorable outcomes or mortality was insignificant.

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Section: Introductionmentioning

confidence: 99%

Intravenous Thrombolysis for Acute Ischemic Stroke in Patients Receiving Antiplatelet Therapy: A Systematic Review and Meta‐analysis of 19 Studies

Luo

Zhuang

Zeng

et al. 2016

JAHA

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“…The updated Cochrane systematic review [7], which appeared in the same issue of Lancet, confirmed the results, reinforcing the concept that patients older than 80 years achieved similar benefit to those aged 80 years or younger, particularly when treated early.…”

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confidence: 56%

Ischaemic stroke and thrombolysis: ask the onset time, not the age!

2012

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As of May 2012, indications for thrombolysis in acute ischaemic stroke were particularly limited [1]: patients had to be treated within 4.5 h from the onset, should be younger than 80 years old, should present with a moderate neurological deficit, and should not present important early ischaemic changes on admission head CT scan, and should not have any of the traditional contraindications for rt-PA therapy. As a consequence, it is not surprising that, despite the commendable efforts of many stroke clinicians, the number of treated patients was very small, with figures around 2-3 % of all strokes [2].On 23 May 2012, during the European Stroke Conference in Lisbon, results of international stroke trial 3 (IST 3) were presented. The IST 3 is the largest randomised study on thrombolysis in acute ischaemic stroke ever done. The trial, whose complete results were subsequently published in Lancet on the 23 June 2012 [3], included 3,035 patients, without age or severity limits, randomised and treated within 6 h from symptoms onset. IST 3 is a non-profit trial, driven by researchers, with financial support from public agencies, randomized, with open treatment but blind assessment (PROBE design); it lasted 12 years (from 2000 to 2012). It is obvious that during this time many aspects changed in analysing and interpreting stroke trials results, and therefore some adjustments had been necessary during the trial conduct, to adequately study new information, particularly in the field of outcome evaluation. In fact, at the trial start a traditional cut off in Rankin scale (0-2 vs. 3-6) was chosen to evaluate the outcome, and from this cut off a sample size of 3,100 patients was calculated, to show an absolute benefit of 4 %. In the following years, however, two facts prompted the steering committee to add further prognostic evaluations: the first one was ECASS 3 results publication [4], which were not conventionally significant for 2/3 Rankin cut-off, but were statistically significant when using a different cut off (0-1 vs. 2-6); these results caused a wide variation in clinical practice, moving the time limit of treatment from 3 to 4.5 h. The second one was the re-evaluation of trials results by means of ordinal shift analysis [5], a statistical tool which uses all the information from the data, considering all the shifts from one to another grade in Rankin scale, and therefore is more powerful and sensitive for outcome evaluation in acute stroke. Therefore, the steering committee decided, much in advance of the database opening, to introduce these two new endpoints (Rankin cut-off 1/2 and OSA), and to publish the whole statistical analysis plan [6], a procedure not very frequent in stroke trials; in this way, anyone could know the plans for data analysis and interpretation, with the researchers still blind to the actual results.Further to the whole analysis of data, with the three aforementioned endpoints, a few hypotheses, based on clinical impressions and beliefs, had to be verified by IST 3 results: the earlier the trea...

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“…rt‐PA has been shown to improve outcomes of survival and independence 7, 8, 12, 13, 14, 15. However, its use is limited by the very short window of opportunity for treatment and risk of bleeding, making less than 6% of stroke patients eligible for such treatment 16, 17.…”

Section: Discussionmentioning

confidence: 99%

The value of patient selection in demonstrating treatment effect in stroke recovery trials: lessons from the CHIMES study of MLC601 (NeuroAiD)

Venketasubramanian

Lee

Wong

et al. 2015

Journal of Evidence-Based Medicine

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ObjectiveThe CHIMES Study compared MLC601 to placebo in patients with ischemic stroke of intermediate severity in the preceding 72 hours. We aimed to verify if patient selection based on two prognostic factors (ie, stroke severity and time to treatment) improves detection of a treatment effect with MLC601.MethodsAnalyses were performed using data from the CHIMES Study, an international, randomized, placebo‐controlled, double‐blind trial comparing MLC601 to placebo in patients with ischemic stroke of intermediate severity in the preceding 72 hours. Three subgroups, that is, onset to treatment time (OTT) ≥48 hours; baseline National Institute of Health Stroke Scale (NIHSS) ≥10; both OTT ≥48 hours and baseline NIHSS ≥10, were analyzed using modified Rankin Scale (mRS) ≤1 and a composite endpoint of mRS ≤1, Barthel Index ≥95, and NIHSS ≤1 at month 3.ResultsPlacebo response rates were lower (ie, worse natural outcome) among subgroups with prognostic factors. Conversely, MLC601 treatment effects were significantly higher in the subgroups with prognostic factors than for the entire cohort, being highest among patients with both OTT ≥48 hours and baseline NIHSS of 10 to 14: odds ratios of 2.18 (95% CI 1.02 to 4.65) for month 3 mRS ≤1 and 3.88 (95% CI 1.03 to 14.71) for the composite endpoint.Conclusions: Patients who have moderately severe strokes and longer OTT demonstrate better treatment effects with MLC601. These factors can guide patient selection in future trials.

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Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis

Cited by 889 publications

References 24 publications

Intravenous Thrombolysis for Acute Ischemic Stroke in Patients Receiving Antiplatelet Therapy: A Systematic Review and Meta‐analysis of 19 Studies

Intravenous Thrombolysis for Acute Ischemic Stroke in Patients Receiving Antiplatelet Therapy: A Systematic Review and Meta‐analysis of 19 Studies

Ischaemic stroke and thrombolysis: ask the onset time, not the age!

The value of patient selection in demonstrating treatment effect in stroke recovery trials: lessons from the CHIMES study of MLC601 (NeuroAiD)

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