[b]Use of thrombolysis for acute ischaemic stroke[/b] With an estimated 4.5 million deaths per year worldwide and over 9 million stroke survivors, stroke has an overwhelming impact on public health. In the second of his two part series. Professor Kennedy Lees reviews the use of intravenous thrombolysis in acute ischaemic stroke, specifically in the elderly, and reviews major randomized and observational studies to date. Although stroke can affect anyone regardless of age, it is predominantly a disease of the elderly. Almost a quarter of all types of stroke occur in those greater than 85 years old and half occur in those over 70 years of age1. Statistics show that age also affects outcome after stroke and it is likely that elderly sufferers require greater care after a stroke than younger counterparts. Acute stroke services in the UK are currently limited and consequently over-burdened. Despite recent investment in health services, the stroke burden will increase with the ageing UK population. The recent launch of an intravenous thrombolytic therapy for acute ischaemic stroke in the UK may help relieve the burden by limiting disability. This feature will examine the use and benefits of intravenous thrombolysis for acute ischaemic stroke, with particular reference to elderly patients. Thrombolysis in the elderly Alteplase or recombinant tissue plasminogen activator (rt-PA) received its licence for acute ischaemic stroke in the UK in April 2003. It is the first (and only) licensed thrombolytic therapy for use in this indication. According to its product licence, alteplase should only be used by an experienced stroke physician within a specialist acute stroke centre and must be administered within three hours after the onset of symptoms. The use of rt-PA for acute ischaemic stroke in those over the age of 80 years continues to encounter resistance due to concerns over the increased risk of intracranial haemorrhage. Consequently, limited data are available on this sub-group, as their age would have been a factor for exclusion. This is a particular challenge to physicians, as stroke is primarily a disease of the elderly. For example, almost half of stroke sufferers in Rochester, Minnesota were over the age of 75 years with nearly one quarter affected being over 85 years1. Elderly stroke patients also tend to suffer more severe strokes, have a higher case-fatality rate and be more likely to require long-term institutional care. As the very old represent the fastest-growing segment of the elderly population in developed countries, it is important to weigh up the risks and benefits of rt-PA carefully to ensure physicians can make an informed decision about optimal treatment and to develop an appropriate healthcare strategy for dealing with this age group. The European Medicines Evaluation Agency (EMEA) licence for alteplase stipulates that it should not be administered to those patients aged over 80 years. This is probably based on an increasing risk of intracranial haemorrhage, coupled with the fact that older patients tend to have a worse overall prognosis after stroke. However, a secondary analysis of the National Institute of Neurological Disorder and Stroke (NINDS) trial found that elderly patients gain, on average, the same benefit from rt-PA treatment as younger patients without a higher risk of converting to symptomatic haemorrhage2. Similar results were obtained in part of the t-PA Stroke Survey, where acute ischaemic stroke patients aged over 80 years were compared with counterparts aged under 80 years. No evidence was found to support withholding t-PA treatment in appropriately selected patients (according to standard selection criteria) over the age of 80 years. The risks of intracerebral haemorrhage (fatal, symptomatic and total) were comparable, being three per cent, three per cent and seven per cent in the elderly age group and two per cent, six per cent and nine per cent in their younger counterparts3. A similar situation exists in other clinical circumstances such as myocardial infarction (MI): results from the GUSTO-I trial showed a higher risk of intracerebral haemorrhage in patients over 75 years4. However, aside from age, stroke physicians also need to take account of confounding factors that may contribute to a higher level of haemorrhage when selecting patients for thrombolysis, such as hypertension, prior use of oral anticoagulants such as warfarin and a history of cerebrovascular disease4. Despite the increased risk of haemorrhage, there is a greater overall mortality reduction in elderly patients thrombolysed for MI5, provided the risk-benefit ratio is otherwise satisfactory. As the major benefit of thrombolytic therapy for stroke is the increased likelihood of long-term independence, it may not be as advantageous to treat those who were already dependent prior to the acute event as less would be gained in terms of increased quality of life2. Optimal clinical benefit is realized in those elderly patients who regain their independence following thrombolytic therapy. Major randomized studies to date Limited data exist on the use of intravenous thrombolysis in those over 80 years, because three of the early major trials excluded those aged over 80 years due to uncertainty over safety. The NINDS trial showed a statistically significant benefit in favour of rt-PA over placebo for patients treated within three hours of symptom onset. Half of patients treated with alteplase had achieved functional independence in daily living activities at three months, compared to 38 per cent in the placebo group6. Further analyses of the NINDS data have shown that the earlier thrombolytic treatment is administered, the more likely a favourable outcome for the patient7. ECASS-I8 also evaluated neurological outcomes at three months using a higher dose of alteplase with a maximum interval of six hours between onset to treatment. On intention-to-treat analysis, no benefit was seen in the alteplase-treated group compared to placebo, however after exclusion of a significant minority of patients (17 per cent) who had protocol violations, there was a significant difference between the study groups, in favour of alteplase. Thrombolysis thus improved functional and neurological outcomes, but only in patients with moderate to severe neurological deficit who exhibited neither haemorrhage nor extensive ischaemic changes on their CT scan9. ECASS-II was targeted at a narrower patient population than ECASS-I and used a lower alteplase dose (to match that used in the NINDS trial). In ECASS-II, treatment was to be administered within six hours of symptom onset. Patients were aged from 18–80 years, were chosen according to more meticulous CT eligibility criteria and were managed according to guidelines for strict blood pressure control. Again, neurological outcomes at three months were evaluated. The effect of the extended time window compared with the NINDS trial was explored a priori by randomizing patients into two blocks, for treatment within three hours or three to six hours from stroke onset. ECASS-II demonstrated that alteplase does not increase mortality or morbidity despite an increased risk of intracranial haemorrhage, consistent with NINDS data. However, despite excellent outcomes in the placebo group, trends were observed (though these were not significant p=<0.05) in favour of alteplase in most outcome measures. Whilst the results are not statistically significant on their own, they are consistent with the positive trends and benefits seen in the other trials. Therefore, the overall conclusion of the trial was that thrombolysis in a selected group of patients may lead to a clinically relevant improvement in outcome9. ECASS III is currently underway. This is a randomized placebo-controlled study to examine the efficacy and safety of using alteplase in patients three to four hours from onset of symptoms. This study may help to clarify the outer limit of the therapeutic time window. In view of the evidence in support of early treatment, this trial should not be used as a reason to delay patients’ admission to hospital or assessment. The ATLANTIS (Alteplase Thrombolysis for Acute Non-interventional Therapy in Ischaemic Stroke) trial’s overall objective was to test the efficacy and safety of alteplase when administered between three to five hours after stroke onset. Patients over the age of 79 years were excluded by the protocol. Alteplase was administered at the same dose used in NINDS and ECASS-II. The study found no significant alteplase benefit on the 90 day efficacy end points in patients treated between three and five hours10. Observational studies In contrast, the Standard Treatment with Alteplase to Reverse Stroke (STARS) Study results11, published in 2000, suggested that favourable clinical outcomes and a low rate of symptomatic intracranial haemorrhage could be achieved. STARS had no exclusion on age: the mean age was 69 years, with a range from 28–100 years. At 30 days after treatment, 35 per cent of patients treated with alteplase had a modified Rankin score (functional stroke scale and assessment tool – Table 1) of 0-1, with 43 per cent functionally independent (modified Rankin score 0-2). The median time from stroke onset to treatment was within the three hour time window, at two hours 44 minutes. The study found that an age of 85 years or younger was a predictor of independence following alteplase treatment12 but of course this is also consistent with the natural history of stroke. CASES The most extensive experience with alteplase and the most reassuring results, come from the Canadian Activase for Stroke Effectiveness Study (CASES) group in Canada. CASES was set up following the conditional licensing for alteplase in Canada in 1999 and is a prospective registry of patients treated with alteplase for acute ischaemic stroke. Similar to the Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST), the registry is designed to assess the effectiveness of alteplase and its safety (in the Canadian context) and also to further clarify the patients who are most likely to benefit from thrombolytic treatment. The study also hopes to gauge the potential value of predicting clinical outcome in alteplase-treated patients via a scoring system for acute CT scan changes (the ASPECT score). The study includes over 60 active centres in Canada and has published results on 944 of the 2000-plus patients enrolled to date. Results have shown a lower rate of symptomatic intracerebral haemorrhage (4.7 per cent) than that found previously, even though the level of stroke severity is similar (median National Institute of Health Stroke Score NIHSS score=15), with 30 per cent of patients having minimal or no neurological deficit and 46 per cent being independent at 90 days13. The participating centres were encouraged to have a strict treatment protocol in place that adhered to clinical guidelines, including 24-hour CT scanning availability and a physician with expertise in dealing with stroke. Thus, the conclusion from these preliminary results is that overall, thrombolytic therapy is safe and effective14. SITS-MOST Alteplase was launched under strict licensing guidelines that included a requirement to register patients within SITS-MOST. This is a European observational safety monitoring study co-ordinated by an independent group of academic stroke experts. It is an integral part of the Safe Implementation of Thrombolysis in Stroke International Thrombolysis Register (SITS-ISTR) that was set up to audit the safety and efficacy of routine therapeutic use of thrombolysis in acute ischaemic stroke. The main aim of SITS-MOST is to confirm that alteplase remains a safe treatment choice and will improve clinical outcome for those acute ischaemic stroke patients eligible for thrombolysis, when treatment is used outwith clinical trials. European stroke centres (including those in Iceland, Norway and Switzerland) who participate within SITS-MOST must have appropriate acute stroke facilities. Stroke physicians who use alteplase must also register within SITS-MOST and ensure that patients who receive thrombolysis have met the defined inclusion criteria for treatment and receive it within the three hour time window. Data on each patient are collected, evaluated and entered into SITS-MOST. Anonymized extracts of the data are available on-line (www.acutestroke.org) and in annual statistical reports, allowing comparison of analysis of national and international data, and for individual centres, an opportunity to compare local results with national and international outcomes. Conclusion Use of alteplase for ischaemic stroke is growing cautiously, as the number of specialist centres that are trained in its use increases and as they register for co-operation with the SITS-MOST audit. With further reports and analyses of existing trial data and of experience in non-trial centres across the world, gaps in our knowledge will gradually be filled. We can hope that with this and with new trials such as ECASS-III, the therapeutic window may be widened to allow a greater proportion of patients to benefit from this treatment, including the very old. Professor Kennedy Lees is Professor of Cardiovascular Medicine at University Department of Medicine and Therapeutics, Western Infirmary, Glasgow Links Return to Archive Main Page References 1. Brown RD, Whisnant JP, Sicks JD et al. Stroke incidence, prevalence and survival: secular trends in Rochester, Minnesota, through 1989. Stroke 1996; 27: 373–80 2. Elskind MSV. Stroke in the Elderly. Mount Sinai Journal of Medicine 2003; 70: 27–37 3. Tanne D, Gorman MJ, Bates VE et al. Intravenous tissue plasminogen activator for acute ischaemic stroke in patients aged 80 years and older. The tPA stroke survey experience. Stroke 2000; 31: 370–5 4. White HD, Barbash GI, Califf RM et al. Age and outcome with contemporary thrombolytic therapy. Results from the GUSTO-I trial. Circulation 1996; 94: 1826–33 5. McMechan SR, Adgey J. Age related outcome in acute myocardial infarction. BMJ 1998; 317: 1334–5 6. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. 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Intravenous Tissue-Type Plasminogen Activator for Treatment of Acute Stroke: The Standard Treatment with Alteplase to Reverse Stroke (STARS) Study. JAMA 283(9):1145–50 12. Albers GW, Bates VE, Clarke WM et al. Intravenous tissue-type plasminogen activator for treatment of acute stroke. Journal of the American Medical Association 2000; 283: 1145–50 13. Hill MD, Buchan AM. The Canadian Activase for Stroke Effectiveness Study (CASES): final results. 14. Hill M, Buchan AM and the CASES Investigators. Methodology for the Canadian Activase for Stroke Effectiveness Study (CASES). Can J Neurol Sci. 2001; 28: 232–8 This article is from www.gerimed.co.uk