Veronica Murray

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

Summary Background Recombinant tissue plasminogen activator (rt-PA, alteplase) improved functional outcome in patients treated soon after acute ischaemic stroke in randomised trials, but licensing is restrictive and use varies widely. The IST-3 trial adds substantial new data. We therefore assessed all the evidence from randomised trials for rt-PA in acute ischaemic stroke in an updated systematic review and meta-analysis. Methods We searched for randomised trials of intravenous rt-PA versus control given within 6 h of onset of acute ischaemic stroke up to March 30, 2012. We estimated summary odds ratios (ORs) and 95% CI in the primary analysis for prespecified outcomes within 7 days and at the final follow-up of all patients treated up to 6 h after stroke. Findings In up to 12 trials (7012 patients), rt-PA given within 6 h of stroke significantly increased the odds of being alive and independent (modified Rankin Scale, mRS 0–2) at final follow-up (1611/3483 [46·3%] vs 1434/3404 [42·1%], OR 1·17, 95% CI 1·06–1·29; p=0·001), absolute increase of 42 (19–66) per 1000 people treated, and favourable outcome (mRS 0–1) absolute increase of 55 (95% CI 33–77) per 1000. The benefit of rt-PA was greatest in patients treated within 3 h (mRS 0–2, 365/896 [40·7%] vs 280/883 [31·7%], 1·53, 1·26–1·86, p<0·0001), absolute benefit of 90 (46–135) per 1000 people treated, and mRS 0–1 (283/896 [31·6%] vs 202/883 [22·9%], 1·61, 1·30–1·90; p<0·0001), absolute benefit 87 (46–128) per 1000 treated. Numbers of deaths within 7 days were increased (250/2807 [8·9%] vs 174/2728 [6·4%], 1·44, 1·18–1·76; p=0·0003), but by final follow-up the excess was no longer significant (679/3548 [19·1%] vs 640/3464 [18·5%], 1·06, 0·94–1·20; p=0·33). Symptomatic intracranial haemorrhage (272/3548 [7·7%] vs 63/3463 [1·8%], 3·72, 2·98–4·64; p<0·0001) accounted for most of the early excess deaths. Patients older than 80 years achieved similar benefit to those aged 80 years or younger, particularly when treated early. Interpretation The evidence indicates that intravenous rt-PA increased the proportion of patients who were alive with favourable outcome and alive and independent at final follow-up. The data strengthen previous evidence to treat patients as early as possible after acute ischaemic stroke, although some patients might benefit up to 6 h after stroke. Funding UK Medical Research Council, Stroke Association, University of Edinburgh, National Health Service Health Technology Assessment Programme, Swedish Heart-Lung Fund, AFA Insurances Stockholm (Arbetsmarknadens Partners Forsakringsbolag), Karolinska Institute, Marianne and Marcus Wallenberg Foundation, Research Council of Norway, Oslo University Hospital.

Aphasia in acute stroke and relation to outcome

Abstract. Laska AC, Hellblom A, Murray V, Kahan T, von Arbin M (Danderyd Hospital, Danderyd, Sweden). Aphasia in acute stroke and relation to outcome. J Intern Med 2001; 249: 413–422.

Thrombolysis for Acute Ischemic Stroke

Graeme J. Hankey MD, FRACP, FRCP Section Editor: Recombinant tissue plasminogen activator (rtPA) is licensed for thrombolytic therapy in ischemic stroke if administered within 3 hours of stroke onset in selected patients (to be extended to 4.5 hours in some countries). However, many patients who could benefit from rtPA are not offered it and there is evidence that rtPA could benefit many patients who do not meet current license criteria. Furthermore, the patient characteristics that might assist in stratifying risk and benefit and the latest time at which thrombolysis may be effective remain unknown. The objectives of this study were to assess the safety and efficacy of thrombolytic agents used in acute treatment of ischemic stroke, factors that might influence risk or benefit, and estimate if current data can identify the latest time window for treatment. We used the Cochrane Stroke Group Trials Register, MEDLINE, and EMBASE; contact with trialists, and hand-searching of pertinent journals (all to October 2008). Selection criteria were randomized trials of any thrombolytic agent compared with a control in patients with definite ischemic stroke. Two reviewers applied the inclusion criteria, extracted the data (published and unpublished), and assessed trial quality. We calculated ORs and 95% CIs for all main outcomes using fixed effects methods (additionally by random effects methods where significant between-trial heterogeneity was present), calculated the effect per 1000 patients …

The molecular basis of thrombolysis and its clinical application in stroke

Murray V, Norrving B, Sandercock PAG, Terént A, Wardlaw JM, Wester P (Karolinska Institutet Danderyd Hospital, Stockholm; Department of Neurology, Lund, Sweden; Division of Clinical Neurosciences, Edinburgh, UK; Acute and Internal Medicine, Uppsala; Umeå Stroke Centre, Umeå; Sweden). The molecular basis of thrombolysis and its clinical application in stroke (Review). J Intern Med 2010; 267: 191–208.

Update on the third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke and baseline features of the 3035 patients recruited

BackgroundIntravenous recombinant tissue plasminogen activator (rtPA) is approved in Europe for use in patients with acute ischaemic stroke who meet strictly defined criteria. IST-3 sought to improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of rtPA in acute ischaemic stroke, and to determine whether a wider range of patients might benefit.DesignInternational, multi-centre, prospective, randomized, open, blinded endpoint (PROBE) trial of intravenous rtPA in acute ischaemic stroke. Suitable patients had to be assessed and able to start treatment within 6 hours of developing symptoms, and brain imaging must have excluded intracranial haemorrhage and stroke mimics.ResultsThe initial pilot phase was double blind and then, on 01/08/2003, changed to an open design. Recruitment began on 05/05/2000 and closed on 31/07/2011, by which time 3035 patients had been included, only 61 (2%) of whom met the criteria for the 2003 European approval for thrombolysis. 1617 patients were aged over 80 years at trial entry. The analysis plan will be finalised, without reference to the unblinded data, and published before the trial data are unblinded in early 2012. The main trial results will be presented at the European Stroke Conference in Lisbon in May 2012 with the aim to publish simultaneously in a peer-reviewed journal. The trial result will be presented in the context of an updated Cochrane systematic review. We also intend to include the trial data in an individual patient data meta-analysis of all the relevant randomised trials.ConclusionThe data from the trial will: improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of iv rtPA in acute ischaemic stroke; provide: new evidence on the balance of risk and benefit of intravenous rtPA among types of patients who do not clearly meet the terms of the current EU approval; and, provide the first large-scale randomised evidence on effects in patients over 80, an age group which had largely been excluded from previous acute stroke trials.Trial registrationISRCTN25765518

A randomized controlled trial on very early speech and language therapy in acute stroke patients with aphasia.

Background: Aphasia affects one third of acute stroke patients. There is a considerable spontaneous recovery in aphasia, but impaired communication ability remains a great problem. Communication difficulties are an impediment to rehabilitation. Early treatment of the language deficits leading to increased communication ability would improve rehabilitation. The aim of this study is to elucidate the efficacy of very early speech and language therapy (SLT) in acute stroke patients with aphasia. Methods: A prospective, open, randomized, controlled trial was carried out with blinded endpoint evaluation of SLT, starting within 2 days of stroke onset and lasting for 21 days. 123 consecutive patients with acute, first-ever ischemic stroke and aphasia were randomized. The SLT treatment was Language Enrichment Therapy, and the aphasia tests used were the Norsk grunntest for afasi (NGA) and the Amsterdam-Nijmegen everyday language test (ANELT), both performed by speech pathologists, blinded for randomization. Results: The primary outcome, as measured by ANELT at day 21, was 1.3 in the actively treated patient group and 1.2 among controls. NGA led to similar results in both groups. Patients with a higher level of education (>12 years) improved more on ANELT by day 21 than those with <12 years of education (3.4 vs. 1.0, respectively). In 34 patients in the treatment group and 19 in the control group improvement was ≧1 on ANELT (p < 0.05). There was no difference in the degree of aphasia at baseline except for fluency, which was higher in the group responding to treatment. Conclusions: Very early intensive SLT with the Language Enrichment Therapy program over 21 days had no effect on the degree of aphasia in unselected acute aphasic stroke patients. In aphasic patients with more fluency, SLT resulted in a significant improvement as compared to controls. A higher educational level of >12 years was beneficial.

Long-Term Antidepressant Treatment with Moclobemide for Aphasia in Acute Stroke Patients: A Randomised, Double-Blind, Placebo-Controlled Study

Background and Purpose: Pharmacotherapy aimed at stroke rehabilitation through direct central nervous effects may be assumed to work in a similar way for language recovery and sensory-motor recovery. Some data suggest that antidepressant drugs could be beneficial also for functional improvement. This prompted us to investigate whether regression from aphasia after acute stroke could be enhanced by antidepressive drug therapy. Methods: We randomised 90 acute stroke patients with aphasia to either 600 mg moclobemide or placebo daily for 6 months, within 3 weeks of the onset of stroke. Aphasia was assessed prior to treatment and at 6 months, using Reinvang’s ‘Grunntest for afasi’ and the Amsterdam-Nijmegen-Everyday-Language-Test (ANELT). Result: The degree of aphasia decreased significantly at 6 months, with no difference between the moclobemide- and the placebo-treated groups. Multivariate regression analysis including treatment group, activities of daily living, aetiology of stroke, ANELT, and Reinvang’s coefficient at baseline, and neurological deficit confirmed these results. In all, 13 in the moclobemide and 10 in the placebo group stopped taking the study medication. No further change was found in the 56 aphasic patients followed up for another 6 months with no medication. Conclusions: Compared to placebo, treatment with moclobemide for 6 months did not enhance the regression of aphasia following an acute stroke.

Recognition of Depression in Aphasic Stroke Patients

Background: Data on post-stroke depression in aphasia are scarce. Methods: Eighty-nine acute stroke patients with aphasia of all types were followed for 6 months to investigate if depression can be reliably diagnosed (DSM-IV criteria) and validly assessed by the verbal Montgomery-Åsberg Depression Rating Scale (MADRS) and a global technique (Clinical Global Impressions Rating Scale for Severity). A standard aphasia test was performed. Results: In 60 patients (67%) at baseline and in 100% at 6 months, comprehension allowed a reliable DSM-IV diagnosis. Among these patients MADRS was feasible in 95% at baseline and in 100% at 6 months. The assistance of relatives and staff increases the feasibility and decreases the validity. Depression was identified in 24% during the 6 months. Conclusion: Depression diagnosis and severity rating can reliably be made in the acute phase in at least two thirds of aphasic patients, and feasibility increases over time.

Should more patients with acute ischaemic stroke receive thrombolytic treatment

In developed countries, stroke is the third most common cause of death and the most common cause of dependency in adults. Thrombolysis with recombinant tissue plasminogen activator (rt-PA) was licensed for use in highly selected patients within three hours of acute ischaemic stroke in the United States in 1996 on the basis of the National Institutes of Neurological Disorders and Stroke (NINDS) randomised controlled trial (n=624),1 which showed substantially lower combined rates of death or dependency with this treatment (140/1000 fewer) despite an excess of symptomatic intracranial haemorrhage (60/1000 more). The Cochrane review of all data from randomised trials of rt-PA and a meta-analysis of individual patient data agreed with these findings.2 3 In Europe, a conditional licence for use within three hours in highly selected patients was granted in 2002 on the basis of the NINDS trial plus data from two European randomised controlled trials (n=930).4 5 However, six years after European and 10 years after US licensing, fewer than 10% of eligible patients receive thrombolysis—1-7% in the US,6 7 3% in Canada,8 3% in Germany,9 and 3.3% in Sweden (www.riks-stroke.org)—and use of rt-PA varies greatly between European countries.10 Clinicians and managers are uncertain about how widely to use rt-PA in routine clinical practice.11 The fact that treatment licenses are based on data from fewer than 1000 randomised patients with narrow entry criteria, the substantial excess of symptomatic intracranial haemorrhage, plus the restricted licence conditions may worry many clinicians. In 2009, a systematic review of all randomised trials comparing thrombolysis with control (mostly placebo) in patients with acute ischaemic stroke analysed 26 trials of various thrombolytic drugs, 11 of which tested rt-PA up to six hours after stroke (n=3977) (figure⇓).12 Compared with control, rt-PA given up to six …

Diagnostic errors discovered by CT in patients with suspected stroke

We assessed the frequency of stroke diagnostic errors revealed by CT in 197 patients. In five Patients, CT was an emergency procedure. In the other 192 patients, CT was used to check diagnosis based on routine investigations. All but eight diagnoses (4%) were thereby confirmed. Either hemorrhage was discovered where an ischemic lesion had been suspected (2 cases) or the reverse (3 cases). Disorders other than stroke were found in three Patients—subdural hematoma, hydrocephalus, and suspected tumor. Thus, few but important errors investigations.