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June 26, 2016

Clinical prediction rules are key in tackling stroke

Outcomes can only improve if hospitals receive adequate resources to implement evidence-based practice

In his latest Clinical Update, Gary Culliton examines advances in the management of stroke patients, as well as the importance of stroke networks, treatment protocols and the adoption of standards.

Treatments for patients with acute strokes and transient ischaemic attacks (TIA) have developed considerably over the past 15 years. Management of stroke includes primary prevention, active management of the acute stroke phase, secondary prevention and rehabilitation.

Outcomes can only improve if hospitals receive adequate resources to implement evidence-based practice, said Prof Martin O’Donnell, Professor of Translational Medicine at NUIG and Associate Director of the Clinical Research Facility, Galway.

Prof O’Donnell is Principal Investigator of an international case-control study of risk factors for stroke (INTERSTROKE). Considerable work has been done by the HSE’s joint Clinical Leads Dr Peter Kelly and Prof Joe Harbison in advancing the agenda for management of acute stroke.

A stroke is either ischaemic or haemorrhagic. The clinical distinction between these subtypes is one of the most urgent aspects of acute stroke management and the key issue is the time from symptom onset to receipt of treatment. Assessment must be fast to determine if a TIA has occurred and to facilitate correct management (McArthur KS, BMJ 2011).

Early stroke
The danger of an early stroke may be as high as 30 per cent in certain high-risk TIA patients (Callaghan A, Arch Neurol 2011; Arsava E, Stroke 2011). The ABCD2 score tabulates the risk factors indicative of early stroke after TIA. This score identifies those at particular risk — those who need urgent, intensive, preventative measures (Rothwell P et al, The Lancet 2005). The overall individual clinical profile must also be taken into account.

ABCD2 is a clinical prediction rule that helps to classify and then triage patients who have had a TIA into those with high, intermediate and low risks of ischaemic stroke.

Patients who require very rapid evaluation are prioritised and management strategies are implemented.

Secondary prevention strategies are also important and diagnostic work must be done to exclude atrial fibrillation. Carotid endarterectomies in patients with TIA may be a very effective intervention to prevent stroke, said Prof O’Donnell. Even in very good centres, the rates of people who are eligible for — and who receive — thrombolysis are 15 to 20 per cent.

The high-profile FAST campaign is directed at getting people with ischaemic strokes into hospital as quickly as possible: “The time from symptom onset to receiving thrombolysis therapy is of critical importance to its efficacy,” said Prof O’Donnell.

All patients should ideally be managed within an acute stroke unit, a geographically-defined part of a hospital where staff — including physicians, nurses and therapists — have expertise in stroke care. The majority of recovery occurs within the first few months following a stroke, with the most rapid recovery happening in the first few weeks (NMIC Management of Stroke Bulletin, 2011).

If the Irish population’s blood pressure could be controlled and if all patients with atrial fibrillation could be identified — leading to the implementation of effective anti-thrombotic strategies — the incidence of stroke might be halved, Prof O’Donnell believed.

Anti-thrombotic therapy
Once diagnosed, the risk of stroke can be dramatically reduced by use of anti-thrombotic therapy (ATT). Identification of the danger of stroke in individuals with atrial fibrillation through risk factor analysis is one objective of the European Cardiology Society (ESC) guidelines for the management of atrial fibrillation (ESC Guidelines, Eur Heart J 2010).

Thrombolysis is very time sensitive and the model in many countries is to have regional stroke centres to which candidates for thrombolysis would be diverted. This is predicated on access and the geographical location of patients.

Thrombolysis requires clinical staff with expertise in administering it to patients with acute stroke and such expertise is required 24/7, in order to supervise care.

There is an independent benefit from implementing organised stoke care within each hospital in the country, said Prof O’Donnell.  An organised, geographically-dedicated stroke unit within a hospital delivers improvements in outcomes in patients with acute stroke, he said.

Thrombolysis is concerned with restoring blood flow to the part of the brain that has suffered an ischaemic stroke and clot-busting drugs are a key element in the acute management of ischaemic stroke: “Tissue plasminogen activator (TPA) is the thrombolytic agent which has been most rigorously evaluated and it is the medication that we use,” said Prof O’Donnell.

‘Anti-thrombotic therapy’ is an umbrella term covering anti-platelet therapy and anti-coagulant therapy and anti-thrombotic therapy is recommended in patients with atrial fibrillation who have a prior history of ischaemic stroke or TIA.

Anti-platelet therapy
Anti-platelet therapy is aimed at preventing recurrent clots. In the acute setting — within the first 48 hours of the anti platelet therapies — the agent that has been most rigorously evaluated is aspirin, including in two very large trials: the International Stroke Trial (IST) and the Chinese Acute Stroke Trial (CAST).

However, the benefit of aspirin in an acute setting is modest: it delivers a 10 per cent reduction in major vascular events. Aspirin is used — unless there is a clear contraindication — in patients presenting with TIAs. Other agents include clopidogrel.

The importance of preventative therapy following a TIA has been shown in a number of studies

The importance of preventative therapy following a TIA has been shown in a number of studies and many such patients can be managed as outpatients by a local TIA service. The Early use of eXisting PREventive Strategies for Stroke (EXPRESS) study from Oxford showed that early intervention with secondary prevention strategies appeared to reduce the risk of more completed stroke in the future.

Prof O’Donnell’s group has published Phase One findings from INTERSTROKE, an epidemiological study looking at the key causes of stroke in different regions of the world. Risk factors were examined in a population of 6,000 participants in 22 countries, half of whom had stroke and half of whom did not. Ninety per cent of the population-attributable risk was associated with 10 risk factors and hypertension was the most important risk factor for both of the main stroke subtypes — ischaemic and haemorrhagic: “It is also the risk factor which is most modifiable,” said Prof O’Donnell. Blood pressure management is recommended, with regular reviews, with the aim of establishing control and ensuring patients stick to drug therapy regimes (Graham I et al, 2011).

In high-risk patients with atrial fibrillation, anti-coagulant therapy is more effective than anti-platelet therapy,” said Prof O’Donnell. The traditional anti-coagulant therapy used has been warfarin and it remains the most common. However, warfarin requires regular blood testing and patients must watch what they eat and monitor the medications they take. Novel anti-coagulants have emerged recently that do not have these limitations and they are more convenient and their use is likely to become more widespread. Dabigatran is used in Ireland in patients with atrial fibrillation.

Thrombin inhibitors
Three thrombin inhibitors have been evaluated in large-scale, controlled trials. Over the last two years, all of them have been compared to warfarin in patients with atrial fibrillation. Dabigatran is a direct thrombin inhibitor (Connolly SJ et al, RE-LY trial. NEJM 2010) and Rivaroxaban (Patel et al, ROCKET trial, NEJM, 2011) and apixaban (Granger et al, ARISTOTLE trial, NEJM 2011) are both Factor Xa inhibitors. Prof O’Donnell was involved in the AVERROES trial (Connolly et al, NEJM 2011), which compared apixaban to aspirin in people who were not candidates for warfarin.

“The evidence appears to be there that these medications worked similarly in patients who did not have a previous history of stroke and those who did. These medications are gaining traction in countries such as Canada, where they have been licensed for longer,” said Prof O’Donnell. “One of the more important findings of the INTERSTROKE Phase One trial was the significance of the cardiac disorder atrial fibrillation.”

Detecting atrial fibrillation and putting patients on effective therapies is associated with a dramatic reduction in the risk of stroke. Research by Prof O’Donnell’s group suggested that if patients with atrial fibrillation received anti-coagulant therapy, such as well-controlled warfarin, the severity of stroke appeared to be less, if they did experience a stroke.

Atrial fibrillation appeared to be a more important risk factor in high-income countries in Europe and North America and this is also suggested in other research, which showed that between 20 and 30 per cent of patients with ischaemic stroke had atrial fibrillation. Atrial fibrillation becomes more common the older people get and the age of stroke onset is older in Western countries.

Lipids are a risk factor for ischaemic stroke and treatments that reduce cholesterols — such as statins — have also been shown to reduce the risk of stroke (O’Donnell M et al, The Lancet 2010; Rothwell P et al, The Lancet 2011).

Co-ordinated care ‘can cut deaths’

Stroke is the third-most common cause of death and the most common cause of acquired major physical disability in Ireland and there is considerable evidence that co-ordinated stroke care can reduce death and levels of disability for stroke survivors.

“Strokes may be prevented. Warning signs are often ignored and simple population educational measures can be very effective in reducing the number of victims,” said consultant cardiologist

Dr Brian Maurer

. “Care of the acute stroke victim begins in the ambulance, continues through thrombolysis, early recognition and assessment in the accident and emergency departments, stroke unit and the provision of internationally-acceptable levels of ongoing care. Such a service could save up to 350 lives a year and substantially reduce the number of those suffering from major disability.”

All patients should be reviewed immediately by a physician expert in stroke, the Irish Heart Foundation guidelines state, and initial assessment should include a complete history and physical examination, including a neurological examination.

Admitting clinicians should seek to investigate, determine and record possible underlying cardiovascular causes, localisation of the cerebral area likely to have been affected, and treatable risk factors.