Therapeutic thrombolysis for acute ischaemic stroke

What is good for heart attacks is still not good enough for brain attacks

Therapeutic thrombolysis for acute myocardial infarction is standard practice, but not so for ischaemic stroke, the “brain attack” equivalent of heart attack. This is partly because stroke is more complicated: intracerebral haemorrhage must be excluded by imaging, and more vascular pathologies than atheroma underly ischaemic stroke (for example, intracranial small vessel disease and embolism from the heart). Furthermore, coronary care units make research on heart attacks relatively easy, whereas research on acute stroke still often takes place in general medical wards. With stroke units, this will be less of a problem. Research on strokes is woefully underfunded in comparison to research on heart attacks.1 But, if thrombolytic “unblocking the pipes” works for acutely occluded coronary arteries, it should work for acutely occluded brain arteries, provided reperfusion does not make matters worse by increasing cerebral oedema and haemorrhagic transformation. As usual, the balance of benefit and risk is best determined by randomised trials—facts, not opinions and theories.

Here again there is a difference between heart attack and brain attack. For the former, about 60 000 patients have been randomised in trials of thrombolysis,2 for the latter just 5675. What evidence from trials there is in stroke is summarised in a Cochrane review.3 Thrombolysis increases the risk of intracranial haemorrhage about four times, but if recombinant tissue plasminogen activator is given within three hours of the onset of symptoms, patients are less likely to be left dead or dependent (from about 60% to 50%, a relative risk reduction of 36%). So why not just give recombinant tissue plasminogen activator, at least to those patients who are prepared to trade an immediate risk for long term benefit? There are at least two good reasons for caution.

Firstly, the evidence about the three hour window of opportunity for recombinant tissue plasminogen activator is based on only 957 patients, two thirds of them from one trial from the National Institute of Neurological Disorders.4 Experience tells us that relying on one positive trial to alter treatment policy is unwise, and that meta-analysis of a small number of trials (nine in this case) is an uncertain art. To change the treatment of acute stroke radically all around the world requires the reassurance of consistent results in several trials with much larger sample sizes, as happened for heart attack.

Secondly, we need information from a much wider range of patients. Just 42 patients in the recombinant tissue plasminogen activator trials were over 80, and only a few had lacunar strokes. We do not know if the risk-benefit ratio applies to the increasing number of patients already taking antithrombotic drugs for prevention, and uncertainty prevails about how to interpret “hypodensity” on computerised tomography (with its considerable observer variability) in deciding whether to treat or not. Finally, it may well be that the time window is longer than three hours for suitable patients. This is a complicated business. To know what sort of patients are most likely to benefit, or be harmed, will require reasonably sophisticated modelling of baseline factors, only one of which we know about so far—more than or less than three hours from onset of symptoms. This will require several thousand more randomised patients. There are bound to be some “under three hour patients” who should not be treated, and some “more than three hour patients” who should be—but who are they?

Finally, from a statistical perspective, the estimate of treatment effect is imprecise (confidence intervals are wide, and heterogeneity for some outcomes is significant).3 Thus matters have not really progressed since the publication of the trial from the National Institute of Neurological Disorders in 1995. Although enthusiasts and sceptics have debated the need for more data, recombinant tissue plasminogen activator has failed to have the impact on outcome after acute stroke anticipated in the results of the trial from the National Institute of Neurological Disorders.

Even among enthusiasts such as ourselves, it has proved very difficult to implement thrombolysis, requiring rapid triage in emergency departments, five consultant neurologists and stroke physicians on an on-call rota, very rapid access to computerised tomography, and multidisciplinary after care. Others find it equally difficult, some find it impossible, in the United Kingdom and elsewhere.5 Disagreement between enthusiasts and sceptics has played into the hands of conservative health service managers who, rightly, want more evidence before funding hyperacute stroke services. Advocating more trials does not mean that existing results cannot be believed—far from it. It simply means we need much more detail.

Fortunately, more evidence from randomised trials will emerge, but not for several years, from IST3, ECASS3, EPITHET, and DIAS trials. In the meantime, recombinant tissue plasminogen activator is being licensed in Europe, but patients treated within the licence must be recorded—although registering use of recombinant tissue plasminogen activator will not add to the randomised evidence.

Sadly for patients with stroke, the heart attack doctors are not just in the lead, they are out of sight evaluating and now establishing intra-arterial chemical and physical approaches to unblocking the pipes—fast. Maybe brain doctors have been a bit too clever, deflected into seeking the holy grail of neuroprotection—expensive and, so far, unsuccessful. Basic plumbing should come first.