The Knowns and the Unknowns of Acute Ischemic Stroke Treatments for Patients With Pre-existing Disability and Dementia

Explanatory clinical trials test the efficacy of intervention, commonly in a small, specific population.¹ Pragmatic trials test the intervention in a broad, real-world, representative population.¹ Pragmatic trials have been historically under-utilized in acute stroke research. Non-pragmatic, explanatory clinical trials of intravenous thrombolysis and endovascular thrombectomy have led to historic advances in acute stroke treatment in the past quarter century. However, they have, by design, resulted in evidence gaps, and consequently clinical care gaps, for acute ischemic stroke patients in the real world who do not meet the stringent criteria for well-designed explanatory trials. One such important evidence gap that is in an urgent need of clarity is that of acute stroke treatments for ischemic stroke patients with a pre-existing disability and dementia. The primary goal of acute stroke reperfusion therapies is to reduce the stroke-related disability in the long term. Thus, disability scales, such as the Modified Rankin score (mRS) and Barthel Index are the most common primary outcomes used to determine the efficacy of such treatments.^{2, 3} In other words, acute stroke clinical trials are often enriched with patient populations that are free from disability at the baseline to allow demonstration of the best possible treatment effect in terms of disability reduction related to a therapy. As such, inclusion of patients who have a pre-existing disability into research studies of acute stroke therapeutics risks blunted treatment effect detection. In the real world, about a third of acute ischemic stroke patients have pre-existing disability and approximately one-tenth have a pre-existing dementia. The evidence gaps arising from exclusion of this large population from systemic studies of acute stroke reperfusion therapies has led to heterogenous clinical practice.⁴ These gaps are likely to perpetuate as researchers remain reluctant to include these patients in future clinical research. Systemic studies providing insights into ideal clinical outcome measure and differential treatment effects of acute stroke therapies specific to patients with a pre-existing disability or dementia are essential to bridge these gaps. This American Heart Association/American Stroke Association (AHA/ASA) scientific statement describes the current evidence and limitation thereof, of thrombolysis and thrombectomy for patients with pre-existing disability and dementia and outlines a roadmap for future research to steer the field towards inclusiveness.

Evaluating and accounting for pre-existing disability and dementia in the time-constrained acute stroke setting is complex, as highlighted in this statement. First, clinicians are largely relying on the proxy-account of severity and implications of the pre-existing impairment in the patient with acute stroke. Second, the definition of pre-existing disability or dementia in research studies (that often translates into clinical practice) is often arbitrary. For example, most studies dichotomously exclude patients based on pre-stroke mRS >2 or >1 and exact definition of dementia is often not specified. Further, these definitions do not consider comprehensive facets of impairment which can stem from a multitude of diseases or conditions. For example, impairments arising from cognitive dysfunction differ from those arising from cardiac or neuromuscular conditions. Third, the implications of the impairment resulting from pre-existing disability or dementia on a person’s life and society are difficult to understand in a hyperacute setting. A person living with an impairment may still lead a meaningful life and making important societal contributions that are worth maintaining. Squarely, there is a need to develop tools that allow clinicians to understand not only the severity of disability but also objectively evaluate causes and implications of pre-morbid impairment in hyperacute settings to facilitate patient-centered decisions. The authors summarize important characteristics for such a tool in the article's Supplement. They emphasize the need for discussions regarding patients’ wishes regarding acute stroke therapies in the stroke or primary prevention clinic, outside of hyperacute setting, and harmonizing electronic documentation of patients’ wishes. This approach, while attractive, is difficult for most patients, as acute stroke setting is the first point of contact with a particular healthcare facility and clinical care team.

It is important to develop tools for evaluation of pre-stroke disability and dementia that facilitate objective and bias-free treatment decisions. The authors of this statement outline important ethical considerations such as ableism, optimism bias, ineffectual bias, catastrophe bias that are often subconscious but inherent when clinical teams make acute stroke treatment decisions. A recent survey study found that clinicians perceived that pre-stroke disabled patients treated with EVT have a higher rate of complications and lower rate of retaining their baseline function compared to EVT-treated patients without a pre-existing disability,⁴ supporting the notions of fragility bias and therapeutic nihilism. It is even more important to ensure that such tools facilitate shared decision making between patients/families and clinicians. Discussions of acute stroke treatments are inherently complex. Pre-existing disability and dementia add layers of complexity to these discussions. Thus, researchers interested in studying the juncture of pre-stroke impairment and acute stroke treatment should engage patient and patient caregivers to develop simplified mechanisms of shared acute stroke treatment decision making.

Next, the authors introduce an extremely important concept of intersectionality. Discussions of how pre-existing disability and dementia are accounted for in acute stroke research and clinical care are incomplete without being conscientious that the population with disabilities and dementia is disproportionately female and of ethnic/racial minority.^{5, 6} Further, disabled population is older than non-disabled population, even when accounting for age-related cognitive disabilities.⁷ Thus, exclusion of persons with disability from clinical research might perpetuate inequality of medical care for minority and marginalized patients.

In this statement, the authors provide a concise but comprehensive summary of the current evidence on intravenous thrombolysis and endovascular thrombectomy for acute ischemic stroke patients with a pre-existing disability/dementia. Majority of the studies are observational or registry-based. No randomized evidence has been generated regarding the treatment effect of acute stroke reperfusion therapies for these patients. Further, majority of the studies compare the outcomes of acute ischemic stroke patients undergoing acute treatments according to their pre-morbid disability/cognitive status. This is problematic in that, by definition, patients with pre-existing disability/dementia cannot gain function that is better than their baseline impairment. Several studies have addressed this issue by defining novel outcomes, such as no increase in disability. However, this is also problematic because non-granular outcome measures, such as the mRS, do not capture a wide spectrum of worsened or improved disability within each mRS category. Future studies can account for this by measuring other granular measures of disability and quality of life outcomes. However, prospective, high-quality data evaluating performance and validity of these novel outcome measures are urgently needed to allow routine inclusion of persons with pre-existing disability/dementia in acute stroke research. As outlined in this statement, evidence also suggests that patients with pre-existing disability and dementia experience a higher rate of post-stroke complications, mortality and a higher length of hospital stay.⁸ Counterbalancing these safety issues is important when considering acute stroke reperfusion treatments for this patient population. As the authors rightly note, a cost-effectiveness or cost-benefit analysis can help guide the clinical community in complex decision making by introducing economic benefit (or lack thereof) of treatment into the equation.

The authors recognize that the existing data are insufficient to provide firm treatment guidance on acute stroke reperfusion treatments for patients with pre-existing disability or dementia. This is noted in both American Heart Association/American Stroke Association and European Stroke Organization guidelines.^{9, 10} Rightly, the authors call on adopting a patients-centered and individualized approach to this decision-making and integrally involving patients/families. Shared decision-making discussions should incorporate highly beneficial nature of acute stroke reperfusion therapies for patients without pre-existing disability,¹¹ uncertainty of benefit due to lack of high-quality data for patients with pre-existing disability/dementia, and potentially high rate of post-stroke complications among pre-stroke disabled patients when compared with those without pre-stroke disability. While this statement is primarily focused on therapeutic decisions in hyperacute stroke setting, the authors recognize the differential delivery of post-stroke clinical and rehabilitative care for persons with a pre-existing disability and the necessity to account for the effect of this heterogeneity in patient outcomes.

In conclusion, the AHA/ASA scientific statement “Endovascular treatment and thrombolysis for acute ischemic stroke patients with Pre-morbid Disability and Dementia” calls timely attention to the complex issue of clinical care and research gaps in acute treatment of ischemic stroke patients with a pre-existing disability/dementia. Besides summarizing it, the authors outline the limited applicability of the current evidence on the subject. The suggested roadmap for acute stroke research inclusive of persons’ pre-stroke functional limitations will hopefully serve as a valuable guidance and will be a step towards reducing disparities of acute stroke care through pragmatic clinical research.