Dr Nicholas Evans is a Stroke Association Senior Clinical Lecturer (Assistant Research Professor) and Honorary Consultant in Stroke Medicine at the University of Cambridge and Addenbrooke’s Hospital. His research considers vascular ageing/atherosclerosis and the impact of frailty in cerebrovascular disease.
It is just over a decade since the first studies showed benefit from mechanical thrombectomy in acute ischaemic stroke. Since then, advances in imaging and procedural techniques have led to a rapid expansion in the pool of people eligible for thrombectomy. Time windows have extended, the amount of acceptable established infarct core has expanded, and we are continuing to explore thrombectomy in smaller and more distal vessels. Things look promising for maximising the benefit to the greatest number from these powerful reperfusion therapies.
However, there is one group who have been left behind. Many of the seminal thrombectomy trials – including MR CLEAN, SWIFT-PRIME, and ESCAPE – had strict criteria that excluded those with mild or moderate pre-stroke disability (defined as modified Rankin Score, or mRS, of >2 or >3 depending on the study). This meant that those living at home but requiring some support, particularly those with mRS 3 who required some assistance with activities of daily living but were able to walk independently, were excluded from most of the studies. Reflecting the lack of representation of these groups, our evidence base and guidelines frequently mean that such individuals are consequently not eligible for these powerful treatments. There is even less data available for individuals with frailty, which was typically not measured in the foundational studies.
This raises important questions: we are increasingly offering thrombectomies to those individuals at later time points and with large core infarcts, where benefit may be attenuated on the basis of established damage and time since stroke, but why does doing thrombectomy for someone with mild-moderate pre-existing disability and frailty give stroke clinicians pause for thought? Does this reflect evidence-based practice or inappropriate treatment nihilism for those with disability and/or frailty?
Therein lies the challenge for the stroke clinician on the frontline: the evidence for thrombectomy is clear for younger, more robust individuals with fewer co-morbidities; but most people we see are not in this cohort. Around one in four individuals presenting with stroke will have concurrent frailty, a figure that rises to three-quarters when you include those with a degree of pre-frailty. This proportion is likely to increase further with the ageing population, shortening health span, and anticipated rise in the number of strokes in the coming decades.
Speaking to stroke survivors with frailty, one of their biggest concerns is that they will not be considered for potent treatments that may increase the likelihood of recovering to their previous level of health. For individuals living at home – albeit often with a degree of frailty or disability – returning to this level is a highly desirable outcome both for the individual and wider society, representing health economic benefit compared to living with more marked post-stroke disability. Many have reported an appreciation that the benefit may be attenuated, but there remains strong support that we should still try for individuals with moderate disability and/or frailty if it increases the likelihood of getting home.
Hence, there is an urgent need to understand the risks and benefits of reperfusion therapies in this population. This topic has been identified as a research priority in the James Lind Alliance Priority Setting Partnership for Stroke and continues to garner interest at the international level (including the recent World Stroke Organisation Scientific Statement on Frailty in Stroke).
This systematic review and meta-analysis help to elucidate the relationship between pre-stroke frailty and outcomes after reperfusion therapies in hyperacute stroke. Across 11 studies with 194,699 participants, we found that pre-stroke frailty was common (being found in 37.2% of reperfusion cases) and was associated with increased mortality at 90 days and at 1 year (consistent with the effects of frailty in both stroke and across general medical conditions), but reassuringly not with increased peri-procedural complications or higher probability of living with post-stroke disability.
Such findings may provide some reassurance to clinicians that reperfusion therapies in these cohorts do not appear to be more risky or futile compared to non-frail individuals, and that a better appreciation of the association with short and longer-term mortality may facilitate more personalised shared decision-making.
Although this work provides some answers to guide our clinical management, there remain many unknowns. For example, frailty is a spectrum and a dichotomised approach is arguably too simple. Instead, taking the degree of frailty as a continuous measure, is there an inflexion point at which the procedure becomes futile? This then begs the question of how best to assess frailty in the acute setting. Furthermore, future research into the mechanisms underlying the relationships between frailty, inflammation, and changes within the brain that prime it for injury (so-called ‘brain frailty’) may well provide translational targets to improve clinical care.
The ageing population – and the associated rise in premorbid disability and frailty – means that time is running short for us to answer these important questions. Fortunately, research – including our own Frailty and Its Effects on Stroke Treatments and Outcomes (FIESTO) Study – is working to elucidate these mechanisms and relationships further in order to improve stroke care for these growing but underserved groups.
Further information on the FIESTO Study can be found here: https://www.stroke.org.uk/about-us/research/projects/fiesto-how-should-we-measure-frailty-and-its-impact-stroke-treatment
The systematic review published in Age and Ageing journal is: Treatment-modifying Effects of Frailty on Stroke Reperfusion Therapy Outcomes: A Systematic Review and Meta-analysis