Alteplase not yet proven for acute ischaemic stroke

COMMENTARY

COMMENTARY

Alteplase not yet proven for acute ischaemic stroke See page 1245 The neutral results of the European Cooperative Acute Stroke Study II (ECASS II), published in this week’s Lancet, will be a great disappointment to clinicians managing patients with acute ischaemic stroke. It had been hoped that this trial would confirm the positive results of the studies done by the US National Institute of Neurological Disorders and Stroke (NINDS), which, together, found that alteplase (recombinant tissue plasminogen activator) significantly improved outcome.1 A positive ECASS II would have led to rapid licensing of alteplase in Europe and the recognition that there was, at last, a treatment for acute ischaemic stroke. ECASS II tested whether intravenous alteplase, given within 6 h of proven acute ischaemic stroke, could increase the proportion of patients having a “favourable” outcome at 3 months, judged as a Rankin scale score of 0 or 1. Alteplase increased this proportion from 36·6% to 40·3%, a non-significant absolute increase of 3·7% (relative increase 10%). This result replicates that of the first ECASS study, which also yielded neutral results.2 There are several reasons why ECASS II was not positive. First, the patients recruited had mild strokes— patients receiving placebo had low baseline National Institutes of Health stroke-scale scores and fared better than did the placebo group in the NINDS studies (table). Patients with mild stroke are less likely than those with more severe disease to benefit from acute therapy since many will improve spontaneously. Second, the primary outcome measure of “favourable” outcome (also used in NINDS) is unusual in stroke trials, which normally base it on independence (Rankin scale 0–2). Interestingly, a post-hoc analysis shows that ECASS II was “positive” when analysed with independence as the outcome

(absolute increase 8·3%). Lastly, ECASS II was too small, in common with ECASS I and NINDS. Although conventional sample-size calculations generate trials of about 800 people on the basis of 10% absolute improvements, they do not take into account the heterogeneity of stroke and the need to recruit patients of appropriate severity. Additionally, it may be unrealistic to expect that any drug treatment can improve outcome by as much as 10% (which suggests that the NINDS result was over-optimistic). Several continuing efficacy trials in acute stroke are recruiting 1500 or more patients to avoid these problems. What then is the future of alteplase? A reasonable starting position is that thrombolysis does work (an assertion supported by a recent Cochrane systematic review3) but that this point has yet to be proven beyond reasonable doubt. Since alteplase strikingly increases the risk of symptomatic intracerebral haemorrhage (ICH, table), but the patients likely to be affected cannot yet be identified, there should be no rush to license alteplase for acute ischaemic stroke (although in the USA it has been licensed for use within 3 h of onset of such stroke). What features, then, might a future trial have? It must be considerably larger than the NINDS and ECASS studies to compensate for heterogeneity of patients and the expectation that the benefit may be more modest than 10%. Of a total of 2400 patients, 1800 patients might be enrolled after conventional computed tomography scanning (to exclude primary ICH), to represent typical stroke practice and the pragmatic delivery of thrombolysis. An additional 600 patients might be recruited from stroke centres where patients can be selected on the basis that they have arterial occlusion and a perfusion-diffusion mismatch on magnetic resonance

Trials of alteplase in acute ischaemic stroke Total participants Dose of alteplase Time window Baseline NIHSS score Rankin 0–1 (%)* absolute benefit (%) Mortality at 90 days (%)* absolute benefit (%) Symptomatic ICH (%)*

NINDS

ECASS I

ECASS II

624 0·9 mg/kg 3h 14 vs 15 42·7† vs 26·5 +16·2 17·3 vs 20·5 +3·2 6·4 vs 0·6

620 1·1 mg/kg 6h 12 vs 13 35·7 vs 29·3 +6·4 22·4 vs 15·8 26·6 ..

800 0·9 mg/kg 6h 11 vs 11 40·3 vs 36·6 +3·7 10·5 vs 10·7 +0·2 8·8 vs 3·4

*Alteplase vs control. †This figure comes from NINDS parts I and II.

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COMMENTARY

scanning. Such selection would target thrombolysis at patients with clot to lyse and with potentially salvageable brain, and would prevent such therapy for those who cannot benefit but can still have an ICH. NINDS, ECASS I, and ECASS II did not screen patients by angiography or perfusion-diffusion scanning. A trial of 2400 patients in total would have a nominal power of 80% to find a clinically worthwhile absolute benefit of 6%. Since ECASS II suggested that giving alteplase within 6 h instead of 3 h did not increase hazard, this future trial should use a 6 h time window, thereby potentially benefiting far more patients. Patients with moderately severe stroke should predominate in the study, and the alteplase should be given intravenously at 0·9 mg/kg as in NINDS and ECASS II. Former debates about thrombolysis in acute ischaemic stroke have been about the relative merits of streptokinase and alteplase. A typical view is that streptokinase is dangerous since the three medium-sized “phase III” studies assessing it all showed an increased hazard related to intracranial bleeding.4-6 However, streptokinase has not been compared directly with alteplase, and the efficacy trials of streptokinase were not preceded by dose-ranging studies (unlike those of alteplase) so that the dose used, 1·5 MU, may have been excessive. Additionally, aspirin was used to varying degrees with streptokinase, whereas it was withheld for at least 24 h in NINDS and ECASS II. The Cochrane systematic review of thrombolysis provides tantalising, but indirect, evidence that aspirin may increase the risk of ICH in the presence of alteplase/streptokinase.3 Hence, streptokinase has been inadequately tested to date. However, much more development work (eg, doseranging studies) will have to be done to take streptokinase on, so there seems little further point doing so when a single large trial of alteplase should answer once and for all whether thrombolysis should be routinely used. Another issue to be sorted out in any trial of thrombolysis is how to manage hypertension during the acute phase of stroke. Both NINDS and ECASS II controlled hypertension before and during administration of alteplase,1,7 although there is no scientific basis for intervention,8 which has been challenged ethically.9 Further information on the management of hypertension in ECASS II is required. Finally, it is vital that doctors are trained in the interpretation of computed tomographic scans (as part of any training programme in stroke medicine,10 and as occurred in ECASS II), to minimise the risk that thrombolysis will be prescribed inaappropirately. I have received fees and expenses from Boehringer Ingelheim, which manufactures alteplase. I also act as consultant to other companies with an interest in acute stroke.

Philip Bath Division of Stroke Medicine, University of Nottingham, University Hospital, Nottingham NG7 2UH, UK 1

2

3

The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group . Tissue plasminogen activator for acute stroke. N Engl J Med 1995; 333: 1581–87. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with tissue plasminogen activator for acute hemispheric stroke; the European Cooperative Acute Stroke Trial (ECASS). JAMA 1995; 274: 1017–25. Wardlaw J,Yamaguchi T, del Zoppo G. Thrombolytic therapy versus control in acute ischaemic stroke. In: The Cochrane Library, Issue 4, Oxford: Update Software, 1998.

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Multicentre Acute Stroke Trial-Italy (MAST-I) Group. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet 1995; 346: 1509–14. 5 The Multicenter Acute Stroke Trial - Europe Study Group. Thrombolytic therapy with streptokinase in acute ischemic stroke. N Engl J Med 1996; 335: 145–50. 6 Donnan GA, Davis SM, Chambers BR, et al. Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. JAMA 1996; 276: 995–96. 7 Brott T, Lu M, Kothari R, et al. Hypertension and its treatment in the NINDS rt-PA stroke trial. Stroke 1998; 29: 1504–09. 8 Bath FJ, Bath PMW. What is the correct management of blood pressure in acute stroke? The Blood pressure in Acute Stroke Collaboration. Cerebrovasc Dis 1997; 7: 205–13. 9 Slyter H. Ethical challenges in stroke research. Stroke 1998; 29: 1725–29. 10 Bath PMW, Lees KR, Dennis MS, et al. Should stroke medicine be a separate sub-specialty of medicine with its own training? BMJ 1997; 315: 1167–68.

Is harmonic imaging now fundamental? See page 1264 In the past 10 years, there has been striking growth in the applications of echocardiography in adult and paediatric medicine. Doppler techniques, including colour flow mapping, permit the diagnosis and quantification of all types of valvular heart disease, in many instances obviating the need for invasive studies. Transoesophageal echocardiography has rapidly been established as the technique of choice for the diagnosis of acute aortic dissections and the planning of surgical repair of the mitral valve, and it is increasingly being used in the search for cardiac sources of emboli and in the stratification of embolic risk in patients undergoing elective cardioversion for atrial fibrillation. Advances in digital technology have permitted widespread use of echocardiography as an alternative to stress testing with nuclear perfusion imaging, both for the diagnosis of coronary artery disease and for the assessment of myocardial viability. Although the recent advances in ultrasound technology have expanded the indications for echocardiography to more esoteric diagnoses, the commonest reason for this investigation in adults is to get an answer to a fundamental question: “what is the ejection fraction?”1 Information on left-ventricular function is essential to the clinician who is caring for patients with symptoms thought to reflect cardiac disease, or patients with a clinical diagnosis of heart failure. In these instances, the estimation of ejection fraction with reasonable accuracy and reproducibility is key to proper therapy (eg, with inhibitors of angiotensin-converting enzyme).2 The assessment of systolic function by echocardiography depends on adequate visualisation of most, if not all, of the walls of the left ventricle. Despite the best efforts of experienced sonographers and the availability of highquality, state-of-the-art equipment, the images are, at times, technically inadequate for this purpose. Age, obesity, chronic lung disease, and recent thoracic surgery increase the likelihood of technically inadequate images. In today’s Lancet, Kenneth Caidahl and co-workers describe their investigation with a technical advance, harmonic imaging, which promises to reduce the frequency of inadequate echocardiographic studies in clinical practice. Harmonic imaging developed as a means of potentiating the effects of ultrasound contrast agents, and the term refers to the fact that the ultrasound received back by the imaging transducer is a multiple, or harmonic, of the ultrasound emitted. By properly filtering the returning signal, harmonic imaging greatly increases the signal-to-noise ratio of the received signal.3 1239