Reflection and Reaction

Approval of alteplase in Europe: will it change stroke management?

Leczenie trombolityczne jest najskuteczniejszą terapią udaru niedokrwiennego mózgu. Dotychczasowe wytyczne i rejestracja leku ograniczały stosowanie trombolizy do pacjentów, którym lek można by podać w ciągu 4,5 godz. od wystąpienia objawów, oraz osób w wieku 80 lat lub młodszych. Ponadto istnieje szereg innych ograniczeń wynikających z protokołów badań klinicznych, m.in. bardzo ciężkie i bardzo łagodne udary. Dostępne dane wskazywały na możliwą skuteczność terapii u pacjentów leczonych do 6 godz. od wystąpienia objawów i wykraczających poza inne obowiązujące dotychczas ograniczenia.

W ubiegłym roku ukazały się wyniki badania IST-3 (Third International Stroke Trial: Thrombolysis) przeprowadzonego właśnie u takich pacjentów oraz metaanaliza wszystkich dotychczas zakończonych badań klinicznych z uwzględnieniem badania IST-3. Wskazują one na możliwość korzystnego efektu trombolizy dożylnej u pacjentów wykraczających poza dotychczas obowiązujące kryteria, co zostało uwzględnione w polskich wytycznych leczenia udaru mózgu.

Thrombolysis is the most effective therapy for ischaemic stroke. The current guidelines and approvals have limited its use to patients available for treatment within 4.5 hours of onset and those aged 80 or less. There are also a number of other limitations derived from clinical trial protocols, i.e. minor and major strokes. The available evidence has indicated its possible efficacy in patients treated within 6 hours of onset and not fulfilling other limitations.

Last year, the results of the IST-3 (Third International Stroke Trial: Thrombolysis) and a meta-analysis of all available trials including IST-3 were published. They point out the possible benefit of thrombolysis in patients not meeting the current criteria, which has been acknowledged in the Polish guidelines for management of stroke.

The objective of this study was to determine the utility of computed tomography perfusion (CTP) scans in diagnosing acute ischemic stroke (AIS). CTP abnormalities in two contiguous supratentorial levels were correlated with diffusion weighted image (DWI) abnormalities on magnetic resonance imaging (the standard for stroke diagnosis) performed within 1 week in 422 suspected acute ischemic strokes. Of 157 AIS confirmed by DWI, 78 showed CTP abnormalities (sensitivity 49.7%). All of these examinations were performed with a mean of 35 min from the initial emergency department neurological examination. Excluding small non-vascular territory strokes left 77 AIS with a total volume of infarcted tissue of more than 5 cc by DWI. Of these, 71 showed CTP abnormalities (sensitivity 92.2%). Of the 265 patients without AIS, none showed CTP abnormalities (specificity 100%). CTP is a rapid, readily available and effective method of diagnosing AIS in clinical practice, particularly the major intracranial vessel strokes that result in a more devastating outcome.

Cerebral ischaemia is a major cause of disability and death globally and has a profoundly negative impact on the individuals it affects, those that care for them and society as a whole. The most common and familiar manifestation is stroke, 85% of which are ischaemic and which is the second leading cause of death and most common cause of complex chronic disability worldwide. Stroke survivors often suffer from long-term neurological disabilities significantly reducing their ability to integrate effectively in society with all the financial and social consequences that this implies. These difficulties cascade to their next of kin who often become caregivers and are thus indirectly burdened. A more insidious consequence of cerebral ischaemia is progressive cognitive impairment causing dementia which although less abrupt is also associated with a significant long-term disability.

Globally cerebrovascular diseases are responsible for 5.4 million deaths every year (1 in 10 of total). Approximately 3% of total healthcare expenditure is attributable to cerebral ischaemia with cerebrovascular diseases costing EU healthcare systems €21 billion in 2003. The cost to the wider economy (including informal care and lost productivity) is even greater with stroke costing the UK £7–8 billion in 2005 and the US$62.7 billion in 2007. Cerebrovascular disease cost the EU €34 billion in 2003. From 2005 to 2050 the anticipated cost of stroke to the US economy is estimated at US$2.2 trillion.

Given the global scale of the problem and the enormous associated costs it is clear that there is an urgent need for advances in the prevention of cerebral ischaemia and its consequences. Such developments would result in profound benefits for both individuals and their wider societies and address one of the world's most pre-eminent public health issues.

The underlying rationale for the introduction and application of thrombolytic agents is the lysis of an obliterating thrombus and subsequent re-establishment of cerebral blood flow by cerebrovascular recanalization. The characterization of potentially reversible versus irreversible loss of function is based on the concept of the ischemic penumbra. Neuroradiological intervention with intra-arterial or intravenous thrombolysis to date is the only life-saving therapy that has demonstrated benefit with regard to mortality and outcome, albeit not in a randomized trial. Educating the general public to regard stroke as a treatable emergency and training emergency caregivers in the use of thrombolysis can decrease these problems but demands a continuous effort. Healthcare institutions should be made aware of the potential in long-term cost savings, once stroke management is optimized and thrombolysis is more widely available. Patients and their relatives should be informed about the hazards of thrombolytic therapy and about its potential benefits and thus the risk of not being treated. Intra-arterial thrombolysis with or without devices and/or combination therapies such as GP IIb/IIIa inhibitors is under further investigation in the anterior circulation.

The aim of the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) was to assess the safety and efficacy of intravenous alteplase as thrombolytic therapy within the first 3 h of onset of acute ischaemic stroke. Under European Union regulations, SITS-MOST was required to assess the safety profile of alteplase in clinical practice by comparison with results in randomised controlled trials.

6483 patients were recruited from 285 centres (50% with little previous experience in stroke thrombolysis) in 14 countries between 2002 and 2006 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 type 2 within 24 h and mortality at 3 months. We compared mortality, the proportion of patients with symptomatic intracerebral haemorrhage as per the Cochrane definition, and functional outcome at 3 months with relevant pooled results from randomised controlled trials.

Baseline characteristics of patients in SITS-MOST were much the same as those in the pooled randomised controlled trials. At 24 h, the proportion of patients with symptomatic intracerebral haemorrhage (per the SITS-MOST protocol) was 1·7% (107/6444; 95% CI 1·4–2·0); at 7 days, the proportion with the same condition as per the Cochrane definition was 7·3% (468/6438; 6·7–7·9) compared with 8·6% (40/465; 6·3–11·6) in the pooled randomised controlled trials. The mortality rate at 3 months in SITS-MOST was 11·3% (701/6218; 10·5–12·1) compared with 17·3% (83/479; 14·1–21·1) in the pooled randomised controlled trials.

These data confirm that intravenous alteplase is safe and effective in routine clinical use when used within 3 h of stroke onset, even by centres with little previous experience of thrombolytic therapy for acute stroke. The findings should encourage wider use of thrombolytic therapy for suitable patients treated in stroke centres.