On-line version ISSN 2078-5135
SAMJ, S. Afr. med. j. vol.101 n.1 Cape Town Jan. 2011
South African ischaemic stroke guideline, 2010
To the Editor: We believe the guideline by Bryer et al.1 to be overdue and well constructed, and generally to contain excellent recommendations. However, the authors note that intravenous tissue plasminogen activator (tPA) 'is an accepted therapy' and 'significantly improves outcome'; particular reference is made to the ECASS III trial2 to justify its use within 4.5 hours of stroke onset. We believe that this is a dangerous and unsupported recommendation.
Most of the initial thrombolysis trials in stroke were negative; some were stopped early due to harm. The ethics that would allow more trials to continue in the light of such existing studies are hard to conceive, but permission was granted and the NINDS trial finally reported a positive outcome.3 However, NINDS was a relatively small study (312 patients received thrombolytic therapy with tPA), and significantly higher scores for stroke severity in the placebo group could explain the improved outcome attributed to thrombolysis. Others have re-analysed the NINDS data and shown no improvement in outcome.4 This takes no consideration of the massively increased intra-cerebral bleed rate in the treatment arm (6.4% v. 0.6%). Furthermore, conflicts of interest were not well disclosed; for instance Genentech, the manufacturer of tPA, contributed US$11 million to the American Heart Association, and paid for its national headquarters in Dallas.5
There are many flaws in the ECASS III trial.2 Patients in the treatment group were younger, and had lower stroke severity scores and fewer prior strokes. Although the Modified Rankin Scale was 7% better in the treated group, the rate of symptomatic intracranial haemorrhage was 2.5% v. 0.2%; the 90-day mortality was the same in both groups. Like NINDS, ECASS III was massively funded by the pharmaceutical industry. Previous studies with similar design, such as the ATLANTIS trial, were stopped early due to harm.6
There have been over 940 trials of pharmacological treatment for acute ischaemic stroke; 20% (with over 16 000 patients), of which the majority were funded by pharmaceutical companies,7 have never been reported in full.
The emphasis of the guideline1 on treating stroke as an emergency, establishing stroke centres, and providing high-quality supportive treatment (to prevent secondary brain injury) is highly commended. There is no compelling evidence to support the use of tPA in stroke; its use beyond 3 hours is dangerous, and it should not form part of national guidelines.
The authors have no conflicts of interest to declare.
Division of Emergency Medicine
University of Cape Town and Stellenbosch University
1. Bryer A, Connor MD, Haug P, et al. South African guideline for management of ischaemic stroke and transient ischaemic attack 2010: A guideline from the South African Stroke Society (SASS) and the SASS Writing Committee. S Afr Med J 2010;100(11):747-778. [ Links ]
2. Hacke W, Kaste M, Bluhmki E, et al. ECASS thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke.N Engl J Med 2008;359(13):1317-1329. [ Links ]
3. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581-1587. [ Links ]
4. Hoffman JR, Schriger DL. A graphic reanalysis of the NINDS trial. Ann Emerg Med 2009;54:329-365. [ Links ]
5. Lenzer J. Alteplase for stroke: money and optimistic claims buttress the 'brain attack' campaign. BMJ 2002;324:723-729. [ Links ]
6. Clark WM, Wissman S, Albers GW, et al. Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. JAMA 1999;282:2019-2026. [ Links ]
7. Gibson LM, Brazzelli M, Thomas BM, Sandercock PAG. A systematic review of clinical trials of pharmacologic interventions for acute ischaemic stroke (1955-2008) that were completed, but not published in full. Trials 2010;11:43. http://www.biomedcentral.com/content/pdf/1745-6215-11-43.pdf (accessed 7 December 2010). [ Links ]
Dr Alan Bryer replies: I thank Wallis and Lahri for their comments on the stroke guideline. A new treatment always requires a balance between potential benefits and harm. However, it was felt that the potential benefits of treatment have been shown to reasonably outweigh the potential harm. Wallis and Lahri alluded to possible collusion between Genentech, which manufactures tissue plasminogen activator (tPA) in the USA, and the American Heart/ Stroke Association concerning their recommendation for use of IVI tPA in their stroke guideline and by implication the Food and Drug Administration (FDA) approval of the use of tPA for acute ischaemic stroke. This seems unlikely and would not apply to the other countries and their respective professional bodies or stroke organisations and independent regulatory authorities. Nevertheless I acknowledge and share their concerns about drug company sponsorship in the stroke trials, which is also commonplace in other large clinical trials. Although the ideal would be for all studies to be investigator led without pharmaceutical company involvement, the large trials needed to confirm or refute drug efficacy are difficult to perform without their backing.
Initial thrombolysis studies using streptokinase were stopped because it appeared to cause harm in the doses used. However, evidence for the benefit of tPa within 3 hours of onset of ischaemic stroke is robust. A Cochrane review on thrombolysis for acute ischaemic stroke included 26 trials with data on 7 152 patients testing urokinase, streptokinase, tPA, recombinant prourokinase or desmoteplase with 56% of all data that came from trials testing tPA - 11 trials, 3 977 patients.1 Overall, tPA significantly reduced the proportion of patients with poor outcomes after stroke and increased the proportion with good outcomes. This benefit at 3 months was apparent despite a non-significant increase in deaths, mostly attributable to intracranial haemorrhage. The authors concluded that the available evidence supported the clinical use of tPA within the existing licence. However, current data are insufficient to determine risks and benefits in certain subgroups of patients, especially those aged 80 years and older.
The European Medicines Evaluation Agency granted licence in 2002 for the use of tPA for treating ischaemic stroke patients within 3 hours of symptom onset on condition of completing: (i) a prospective registry of patient treatment experience with tPA given within the 3-hour window from symptom onset (Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST));2 and (ii) a prospective, randomised, placebo-controlled trial of tPA administered between 3 and 4.5 hours after stroke onset, ECASS-III. Under European Union regulations, SITS-MOST was required to assess the safety profile of tPA in clinical practice by comparison with results in randomised controlled trials. A total of 6 483 patients were recruited from 285 centres (50% with little previous experience in stroke thrombolysis) in 14 countries for this prospective, open, monitored, observational study. Primary outcomes were symptomatic (a deterioration in National Institutes of Health stroke scale score of >4) intracerebral haemorrhage within 24 hours, and mortality at 3 months. Mortality, the proportion of patients with symptomatic intracerebral haemorrhage as per the Cochrane definition, and functional outcome at 3 months were compared with pooled results from randomised controlled trials. Results from the SITS-MOST study found that intravenous tPA is safe and effective in routine clinical use within 3 hours of stroke onset, even by centres with little previous experience of thrombolytic therapy for acute stroke. They encouraged wider use of thrombolytic therapy for suitable patients treated in stroke centres.
The UK National Institute for Health Care and Clinical Excellence reviewed the Cochrane review and the results of the meta-analysis (including the undue weight of the NINDS trial in the meta-analysis) and the results of large observational studies such as SITS-MOST and concluded that tPA was effective in the treatment of acute ischaemic stroke.3 Another pooled analysis of individual data of six tPA trials showed that, even within a 3-hour window, earlier treatment results in a better outcome (0 -90 minutes: odds ratio (OR) 2.11, 95% confidence interval (CI) 1.33 -3.55; 90 -180 minutes: OR 1.69; 95% CI 1.09 -2.62) and suggested a benefit up to 4.5 hours.4 The ECASS III trial found tPA to be effective when provided up to 4.5 hours after stroke onset (OR 1.34, 95% CI 1.02 -1.76, p=0.04). There was a significant increase in symptomatic intracranial haemorrhage (2.7% v. 0.3%), but no significant effect on mortality. In another study the SITS investigators compared 664 patients with ischaemic stroke treated between 3 and 4.5 hours with 11 865 patients treated within 3 hours.5 There were no significant differences between the 3 -4.5-hour cohort and the 3-hour cohort for any outcome measures, confirming that tPA remains safe when given between 3 and 4.5 hours after the onset of symptoms in ischaemic stroke patients who otherwise fulfil the European summary of product characteristics criteria. A systematic review of four trials, including ECAS III, confirmed that tPA given between 3 and 4.5 hours after stroke onset is associated with an increased chance of favourable outcome (OR 1.31, 95% CI 1.10 -1.56, p=0.002) with no significant difference in mortality compared with placebo, thus strengthening the evidence that treatment with tPA in the 3 -4.5-hour window is beneficial and should therefore be considered for stroke patients who present during this time window.6
The recommendation for the use of IVI tPA within 4.5 hours of onset of ischaemic stroke in the new South African guideline is the same as in the guidelines of other countries including the USA, Canada, the European Union, Scandinavia and Australia. The evidence shows that IVI tPA treatment benefits selected patients but should be delivered in well-equipped and skilled emergency units and/or stroke units with adequate expertise and infrastructure for monitoring, rapid assessment and investigation of acute patients. Such patients should be offered treatment with tPA provided the potential risks and benefits are explained to them and their attendant families. Collaboration is recommended between clinicians in pre-hospital services, emergency medicine, neurology and neuroradiology for prompt identification of potentially eligible patients, patient selection, audit and quality improvement initiatives.
1. Wardlaw JM, Murray V, Berge E, del Zoppo G. Thrombolysis for acute ischaemic stroke. Stroke 2010;41:e445-e446. [ Links ]
2. Wahlgren N, Ahmed N, Da´valos A, et al.; SITS-MOST Investigators. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITSMOST): an observational study. Lancet 2007;369:275-282. [published correction appears in Lancet 2007;369:826] [ Links ]
3. National Institute for Health and Clinical Excellence. Altepase for the treatment of acute ischaemic stroke (TA 122). London: NICE, 2007; updated 2010. [ Links ]
4. Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768-774. [ Links ]
5. Wahlgren N, Ahmed N, Dávalos A, et al. Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study. Lancet 2008;372:1303-1309. [ Links ]
6. Lansberg MG, Bluhmki E, Thijs VN. Efficacy and safety of tissue plasminogen activator 3 to 4.5 hours after acute ischemic stroke. A meta-analysis. Stroke 2009;40:2438-2441. [ Links ]