Introduction

Stroke is the most common cause of disability in Western Countries, and its lifetime risk is 1 in 6 for men and 1 in 5 for women. While managing acute stroke patients in hyperacute stroke units overall has modest benefits for short and long term outcome (e.g. 51% versus 47% independence and 29% versus 33% mortality), specific therapeutic options are limited. The first major option for treatment of ischaemic stroke was intravenous thrombolysis, paralleling its previous development in acute myocardial infarction.

However, while use in myocardial infarction was widespread in the 1990’s, it has only been widely used to treat acute stroke in the last ten years. This is probably because of the narrower therapeutic window and the more severe consequences of haemorrhagic complications in the brain. In addition, its benefits are actually relatively modest. In the first main randomised clinical trial on its use within three hours (NINDS), bearing in mind that in the first hour a stroke often spontaneously recovers – termed a TIA, good outcome (grades 0 to 1 on the Modified Rankin scale) were achieved in 39% versus 26% of patients receiving placebo, but with a symptomatic brain haemorrhage risk 6% greater than in the placebo group.

When delivered between 3 and 4.5 hours after stroke onset (ECASS III), the benefits on the same scale were 52% vs 45%, which gave a relative risk confidence interval range of 1.01 to 1.34 (p=0.04). In other words, this was only just statistically significant in a study of 821 patients. The risk of causing intracranial haemorrhage was 27% versus 17.6% (p=0.001). Thrombolysis caused major symptomatic brain haemorrhage in 2.4% versus 0.3% of placebo patients (p=0.008).

So it is not surprising that there has been a move, just like in cardiology a decade or two earlier, away from relying solely on intravenous thrombolysis and towards direct intra-arterial catheter treatment. The paper, Revolution in acute ischaemic stroke care: a practical guide to mechanical thrombectomy, summarises recent evidence in favour of this treatment and the infrastructure required to manage patients in this way. This Journal Club review discusses issues around acute stroke treatment and the ramifications for delivery of such a service.

The Published Review

The first mechanical thrombectomy devices were approved for use in 2004, but it was only technical developments, and probably the improved expertise that comes with experience, that led to positive results as shown by a spate of studies published after 2010 employing a new generation of devices.

The HERMES collaboration meta-analysis revealed that 46% of patients had a good outcome with functional independence (grades 0-2 on the Modified Rankin scale) compared with 26.5% on best medical treatment. Most of the patients in both groups received intravenous (iv) thrombolysis, since in most study protocols patients had iv thrombolysis before going on to have thrombectomy an hour or so later. Mortality and the risk of brain haemorrhage did not differ between the two groups. The benefit seemed still to be present in patients over 80, and when patients did not receive iv thrombolysis, though the numbers to test the latter were small. While the window for thrombectomy was within 6 hours, there may still be improved outcomes up to 7.3 hours after symptom onset, but in general faster intervention leads to greater benefit. At a Quality Adjusted Life Years (QALY) cost of £2500, the procedure would be considered by any political criteria to be cost-effective.

The Thrombectomy technique has a number of variations depending on the Neuroradiologist and on the particular nature and location of the thrombus. It may be done under general anaesthesia or local anaesthesia with sedation and anaesthetic support. A large gauge catheter is directed to the internal carotid via a femoral puncture, and an intermediate catheter inside it is directed to the Circle of Willis. Then a microcatheter inside the intermediate one serves as a guide wire to the actual clot. The microcatheter is then removed and a stent retriever is placed within the clot, and pulled back to draw the clot to the intermediate catheter. Suction is applied to this catheter to remove the clot entirely. Some techniques involve directly removing the clot by suction on the intermediate catheter. A balloon may be located on the distal end of the clot to prevent forward movement (a clinician would describe this as embolus, an undesirable occurrence). When removing the clot reveals a tight lumen, there is the further option to perform angioplasty or stenting to open the vessel. The same can apply to a carotid stenosis occurring in tandem with a more distal thrombus.

The main complications are technical, including vessel perforation (1.6%), other symptomatic intracranial haemorrhage (3-9%), subarachnoid haemorrhage (0.6 – 5%), arterial dissection (0.6 to 3.9%), or emboli distally (1-9%). In addition , there can be vasospasm or issues related to the puncture site. While the total incidence is 15%, not always is there any actual clinical adverse consequence.

While the 6 hour time window for thrombectomy is wider than for intravenous treatment, there are other selection criteria that are more strict:

• There should be a documented anterior circulation large vessel occlusion of the middle cerebral or carotid artery. (There is only limited evidence for efficacy in basilar occlusion.)
• There should be good collateral cerebral circulation.
• There should be relatively normal extracranial arterial anatomy from the technical viewpoint regarding passing the catheter.
• There should be significant clinical deficit at the time of treatment (but this parallels the criteria that should be applied also to intravenous thrombolysis), while acknowledging that a large vessel occlusion with minimal clinical deficit nevertheless incurs a significant risk of clinical deterioration.
• There should be a lack of extensive early ischaemic change on CT (according to the ASPECTS score a threshold of 5). The role of more advanced imaging, e.g. CT perfusion, to establish salvageable brain, is yet to be clarified.
• Consideration should be given to pre-stroke functional status and the potential of benefit.
• Patients should have had iv thrombolysis within 4.5 hours of symptom onset.

The authors report that there is little evidence on managing blood pressure around the time of the procedure. It is probably best to avoid lowering blood pressure unless it is greater than 220 mmHg systolic, or 200 mmHg systolic if evidence of clinical complications of hypertension.

Usually no specific anticoagulation is given around the procedure. Some interventionalists use a peri-procedure dose of heparin. Aspirin is avoided beforehand but patients can have their usual 300 mg aspirin dose starting 24 hours after their stroke. If a stent has been implanted, aspirin and clopidogrel are given together for the first 3-6 months.

Authors’ Conclusions

The authors emphasise the great benefits to be had in selected patients, and comment that the selection criteria may be broadened with future experience. In particular, cases of milder stroke with large vessel occlusions may prove to be good candidates or the time window may broaden and perhaps ignored altogether if advanced imaging reveals a reversible penumbra.

They highlight that the significant technical complication rate means that the procedure should be concentrated in centres that deal with a large number of cases to gain and maintain expertise. They describe two models: “drip and ship” where the patient is thrombolysed at a local HASU (or A&E resuscitation unit?) and ambulanced to the thrombectomy centre, versus “mothership”, where the patient is transferred straight to the thrombectomy unit.

Journal Club Comments

The 20% increased good outcome arising from mechanical thrombectomy on top of that from iv thrombolysis is impressive compared to the 13% reported for thrombolysis versus placebo.

While the selection criteria are more stringent, they are not very much more stringent than for thrombolysis alone; a middle cerebral artery occlusion is a common presentation of acute stoke, especially if it is more severe. The review estimated that 10% of acute stroke patients would be candidates. We suspect at most half that amount, given that in practice thrombolysis rates are 10%, and 5% in some centres.

The most striking issues for us were the very high degree of technical expertise required acutely for decision-making and performing the procedure, and the high technical complication rates that parallel the high levels of benefit. The Neuroradiologist appears to decide both before and during the procedure between a number of different technical options and items of equipment. The suspicion is that the complications, unlike the haemorrhage rates for iv thrombolysis, depend much less on blind luck than on user expertise.

We wondered about circumstances where there might be a contraindication to intravenous thrombolysis and yet not to thrombectomy; it does not appear that thrombolysis, or even antocoagulation or antiplatelet therapy, is actually required for the procedure, and intravenous thrombolyis is so short acting that it would not be protecting against new emboli resulting from the procedure. The trials were conducted according to a protocol of having received thrombolysis mainly for ethical reasons around not denying patients proven beneficial treatment.

However, for practical purposes, a poor candidate for thrombolysis is probably in general going to be a poor candidate for thrombectomy. It would nevertheless be interesting to see if the 20% benefit from thrombectomy overlaps with that from thrombolysis, or adds to it. In other words, could patients get a 20% benefit from thrombectomy alone, and not face the 6% risk of thrombolysis-induced brain haemorrhage?

As an aside to the discussion on benefits of stroke treatment, we noted the different slants that can be put on data. This has great practical consequences for the patient. So, returning for a moment to intravenous thrombolysis, at 3 to 4.5 hours after stroke, a clinician may explain to a patient (if they are not too dysphasic at the time), that they can deliver a treatment with an odds ratio of good outcome of 1.34. Or the clinician might more likely say there would be 34% better chance of recovery, or a third as much again better chance of recovery. Right?

Wrong! The odds ratio is the ratio of good versus bad outcome in the treated group over the ratio of good to bad outcome in the untreated group. What layperson would describe things in those terms – terms that deliberately magnify the benefit? The relative risk, i.e. the ratio of a good outcome in the treated group versus that in the untreated group, is what most laypeople would understand, and the figure is 1.16. Even then, this does not mean that 16% more patients have a good outcome. From the actual figures, 52% versus 45%, 7% more patients get a good outcome, which is considerably different from 34%, and not so favourable when at the same time there are 10% more patients getting brain haemorrhages (or should we say 53.4% more likely?!), though only 2.5% (700% more likely!!) of these haemorrhages are giving them a much bigger stroke than they otherwise would have had.

What I would say at 3 to 4.5 hours after stroke onset is:

“We have a treatment available to dissolve clots in the brain that when given at this time after a stroke probably overall improves the chances of a good recovery, but which has risks of causing bleeding, including a brain haemorrhage that may make your stroke worse not better. Overall out of 100 people, on average 7 extra patients will get a good recovery from their stroke when they have the treatment, about 90 will be no different and 3 will be significantly worsened.”

And if the stroke is relatively mild, or one of those where one suspects the patient might be significantly better come the following morning regardless, one really wonders how much the patient stands to gain and whether to take that 2.5% risk of a much worse stroke instead.

The point about dysphasia is a serious one; can one ethically obtain proper consent to deliver a treatment that is definitely going to result in some people suffering additional permanent disability if not death? Even without dysphasia, lying semi-paralysed under a ticking clock is probably a situation, both for the patient and relatives, where choice, let alone informed consent, is an illusion. When consenting for emergency surgery, one generally has at least the impression that the benefits are an order of magnitude greater than the risks, or that a poor outcome without intervention is inevitable.

Another example of statistics and the all-important magical 0.05 p-value relates to the original comment about acute stroke units. The differences from general ward care are surprisingly modest, but it is always quoted from the Stroke Unit Trialists’ Collaboration Cochrane review in 2009 that stroke significantly reduces mortality. A group, Sun et al., (2013) did their own analysis and actually looked at the data. There was a discrepancy in the number of deaths in the control group in the largest study, the Athens trial: 121 deaths versus 127. On contacting the Cochrane review author, they were told that there was an “error which will be corrected in the next update”; on doing the sums to correct the “error”, Sun found that the p value for significant reduction in mortality shifted across the magical 0.05 threshold from 0.03 to 0.06. So there is no clear evidence that stroke units reduce mortality…

If one looks objectively at the data:

• Thrombectomy leads to 20% more good outcomes, which may replace rather that add to that from intravenous thrombolysis and with no higher risk of brain haemorrhage.
• Thrombolysis alone leads to 13% more good outcomes, if given within a very restricted window of 3 hours after stroke onset, but with a significant risk of brain haemorrhage and other complications.
• Stroke units, which also treat the other 90% of strokes, lead to 4% better outcomes, a figure of uncertain clinical significance.

Regarding stroke units, it is possible that it is the 10% who are candidates for intervention that are contributing largely to that 4% improvement, along with those with haemorrhagic stroke getting surgical input or neurological stroke mimics getting fast-tracked to more appropriate acute care. And if general wards treating the other 90% had more focus on early swallow assessments and actually feeding nil-by-mouth patients nasogastrically within 48 hours, would that single measure not improve outcome?

The initial decision to perform thrombectomy is highly technical and requires a neurointerventional radiologist, the procedure obviously requires a neuroradiologist, and therefore the consent should probably be taken by the neuroradiologist, as well as a the post-procedure ward round and early outpatient follow-up. The neuroradiologist requires the support of an anaesthetist during the procedure, and perhaps around the procedure as an intensivist. The technical skill required to write a thrombolysis prescription is negligible; that to perform a highly challenging emergency procedure, to minimise technical complications arising from mistakes and to deal with those complications when they do arise, will make or break the success of thrombectomy and the success of the stroke service. Does it not seem that acute stroke care has shifted from a medical to a “surgical” speciality? Instead of a “mothership”, could we have a Neuroemergency Unit, a Neuro ITU next to a catheter lab, centred around the Neuroradiologist managing the patients with acute stroke patients who are going to benefit from intervention, as well as patients with subarachnoid haemorrhage. They would have support from anaesthetists, stroke physicians/neurologists and neurosurgeons, with stroke physicians and allied health professionals taking on the subsequent rehabilitation role?