Peter U Heuschmann
Darius G Nabavi
Department of Neurology
University of Muenster
Stroke is currently the second leading cause of death and the seventh leading cause of disability worldwide.(1) The majority of strokes are caused by an occlusion of a cerebral vessel by a blood clot. Intravenous treatment of ischaemic stroke patients with recombinant tissue plasminogen activator (tPA) according to published guidelines to dissolve the blood clot is an approved acute therapy in ischaemic stroke patients in the USA, Canada and the EU.
Evidence from RCTs
A recent pooled analysis of six randomised controlled trials (RCTs) on tPA use in ischaemic stroke patients demonstrated safety and efficacy of tPA administration within three hours from symptom onset.(2) In addition, it has been shown that quicker tPA treatment increases the odds of favourable three-month outcome.(2) Pooled data also suggest a potential benefit of tPA administration beyond the three-hour time window, possibly up to 4.5 hours after stroke onset.(2) The rate of substantial intracerebral haemorrhage (ICH), however, is higher in patients treated with tPA. For example, in the NINDS (National Institute of Neurological Disorders and Stroke) trial, 6.4% of patients suffered from symptomatic ICH during the first 36 hours after tPA treatment, compared with 0.6% in the placebo group.(3)
Frequency in community settings
Despite promising evidence from the RCTs, only 1.6–2.7% of all ischaemic stroke patients treated in community hospitals and 4.1–6.3% of patients treated in specialised stroke centres currently receive tPA in routine clinical care.(4) There might be several explanations for this finding. The narrow time-window for starting tPA treatment within three hours after symptom onset seems to be the greatest barrier for implementing thrombolytic therapy to patients in routine care to a greater extent.(5)
In addition, delays in prehospital and intrahospital management processes, such as transport to the hospital or time to neuroimaging, have also been shown to prevent delivery of tPA in community settings.(6) Finally, the concerns of the treating physician about the balance between risks and benefits of tPA treatment for an individual patient might also influence the proportion of patients receiving thrombolytic therapy in routine care.(7)
Effectiveness in routine clinical care
Numerous studies on the effectiveness of thrombolysis outside the setting of clinical trials have been published in the past few years. Many of these studies could replicate the favourable outcome of patients treated with tPA reported in RCTs.(8) However, a recent overview on the safety of published open-label studies on tPA use reveals a potential correlation between percentage of protocol violations and mortality rates in clinical practice.(9) In addition, there is evidence that administration of tPA in routine clinical care might be more effective in centres experienced in tPA use, as an inverse relationship between the number of patients treated with tPA per hospital per year and the risk of inhospital death was found.(4)
New approaches are claimed to improve further the effectiveness of thrombolytic therapy in community settings. One approach might be to develop more qualified stroke centres and to implement effective ways to get stroke patients into these centres as soon as possible(10) – for example, by using helicopter transport systems.(11)
Another approach could be to initiate a close collaboration between hospitals less experienced in tPA use and specialised stroke centres, by building regional treatment networks(12) or by using telemedical consultation services. A first promising experience in southern Germany demonstrated that tPA could be administered safely in small rural hospitals in the context of a telemedical network, yielding to complication rates in community hospitals similar to those observed in clinical trials.(13)
Some challenges remain in the treatment of ischaemic stroke patients with thrombolytics. First, more studies are needed on a potential benefit of tPA treatment beyond three hours from stroke onset.(2) Secondly, further evidence is required to identify which patients are most likely to benefit from tPA treatment.(14)
Finally, future studies on thrombolysis in acute stroke should also consider carefully the new advances in diagnostic technology – for example, taking into account the presence and the extent of an infarction as well as the size and location of the arterial occlusion prior to treatment.(10)
- Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet 1997;349:1269-76.
- 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;363:768-74.
- 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;333:1581-7.
- Heuschmann PU, Kolominsky-Rabas PL, Roether J, et al. Predictors of in-hospital mortality in patients with acute ischemic stroke treated with thrombolytic therapy. JAMA 2004;292:1831-1838.
- Kleindorfer D, Kissela B, Schneider A, et al. Eligibility for recombinant tissue plasminogen activator in acute ischemic stroke: a population-based study. Stroke 2004;35:e27-9.
- Kwan J, Hand P, Sandercock P. A systematic review of barriers to delivery of thrombolysis for acute stroke. Age Ageing 2004;33:116-21.
- Katzan IL, Sila CA, Furlan AJ. Community use of intravenous tissue plasminogen activator for acute stroke: results of the brain matters stroke management survey. Stroke 2001;32:861-5.
- Kaste M. Thrombolysis: what more does it take? Stroke 2005;36:200-2.
- Graham GD. Tissue plasminogen activator for acute ischemic stroke in clinical practice: a meta-analysis of safety data. Stroke 2003;34:2847-50.
- Caplan LR. Treatment of acute stroke: still struggling. JAMA 2004;292:1883-5.
- Silliman SL, Quinn B, Huggett V, et al. Use of a field-to-stroke center helicopter transport program to extend thrombolytic therapy to rural residents. Stroke 2003;34:729-33.
- Wang DZ, Rose JA, Honings DS et al. Treating acute stroke patients with intravenous tPA. Stroke 2000;31:77-81.
- Audebert HJ, Kukla C, Clarmann VC, et al. Telemedicine for safe and extended use of thrombolysis in stroke: the Telemedic Pilot Project for Integrative Stroke Care (TEMPiS) in Bavaria. Stroke 2005;36:287-91.
- Wardlaw JM, Sandercock PA, Berge E. Thrombolytic therapy with recombinant tissue plasminogen activator for acute ischemic stroke: where do we go from here? A cumulative meta-analysis. Stroke 2003;34:1437-42.
American Stroke Association
EUSI: The European Stroke Initiative