Michel Shamy

Endovascular Stroke Trials: Why We Must Enroll All Eligible Patients

Is it appropriate to enroll into a clinical trial (and hence randomize to either medical or endovascular therapy) a 45-year-old patient who presents within 3 hours of onset of disabling symptoms resulting from a left M1 occlusion? This is the question many of us have faced in the course of the past few months because multiple new trials of endovascular stroke therapy have been launched on the heels of the neutral Interventional Management of Stroke (IMS)-III, Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR-RESCUE), and Local Versus Systemic Thrombolysis for Acute Ischemic Stroke (SYNTHESIS) trials.1–3 The recently published IMS-III, MR-RESCUE, and SYNTHESIS trials have raised important questions related to efficacy of intra-arterial treatment. These trials have many flaws that have been eloquently discussed in some recent editorials and have raised interesting epistemological questions.4–6 Many neurologists, neurosurgeons, and interventional neuroradiologists have argued that randomization is unethical in such circumstances because patients like this one have the potential to do well with rapid recanalization but are likely to face a lifetime of disability without it. They support their argument by pointing out the potential flaws in the previous randomized studies and the poor natural history of the disease.4,5 In this article, we present a variety of perspectives on this question, reflecting the multiplicity of opinions within the stroke community. Ultimately, we think that these perspectives converge on the conclusion that we face a medical and ethical imperative to enroll our patients (even those who are young and with potentially devastating strokes) into clinical trials. Some critics of enrollment into endovascular stroke trials contend that endovascular therapy already amounts to the standard of care, and therefore, depriving patients of this treatment is negligent. Is this true? The standard of care may be …

Rapid Assessment and Treatment of Transient Ischemic Attacks and Minor Stroke in Canadian Emergency Departments: Time for a Paradigm Shift.

A majority of acute cerebrovascular syndromes are transient ischemic attacks (TIA) or minor ischemic strokes. They are often thought of and managed as though benign, but are in fact a warning of impending disabling stroke. The risk of stroke progression or recurrence is highest in the first hours to days from initial symptom onset, with a 6.7% risk at 48 hours and a 10% risk by 7 days after a TIA.1,2 The highest risk period is early, with a median time to a recurrence or progression event of 1 day; many events occur overnight after the initial ictus.3 Many strokes are preventable after a TIA. Rapid diagnosis and treatment reduces the risk of stroke by as much as 80%4,5 and significantly reduces mortality, long-term disability, and costs.6,7 The estimated annual cost avoidance in Canada from the rapid assessment and treatment of TIA is

RecoverNow: Feasibility of a Mobile Tablet-Based Rehabilitation Intervention to Treat Post-Stroke Communication Deficits in the Acute Care Setting

313.8 million (of which

Clinical Trials Involving Hypertension.

269.2 million are indirect costs).8 To be most effective, the diagnosis and treatment of all TIAs and minor strokes must recognize the natural biology of the condition and should ideally occur on the same day as the event. Currently, this is not consistently achieved in Canada. There are several overlapping challenges with TIA/minor stroke management, including (1) establishing an accurate diagnosis of brain ischemia quickly; (2) establishing accurate triage approaches to risk-stratify patients; and (3) establishing systems of care that expedite both the diagnostic evaluation and initiation of treatment. Rapid access to both brain and vascular imaging is a unifying component of the solution to all these challenges. The clinical diagnosis of TIA/minor stroke is not always straightforward because a …

How Patient Demographics, Imaging, and Beliefs Influence Tissue-Type Plasminogen Activator Use: A Survey of North American Neurologists.

Background Approximately 40% of patients diagnosed with stroke experience some degree of aphasia. With limited health care resources, patients’ access to speech and language therapies is often delayed. We propose using mobile-platform technology to initiate early speech-language therapy in the acute care setting. For this pilot, our objective was to assess the feasibility of a tablet-based speech-language therapy for patients with communication deficits following acute stroke. Methods We enrolled consecutive patients admitted with a stroke and communication deficits with NIHSS score ≥1 on the best language and/or dysarthria parameters. We excluded patients with severe comprehension deficits where communication was not possible. Following baseline assessment by a speech-language pathologist (SLP), patients were provided with a mobile tablet programmed with individualized therapy applications based on the assessment, and instructed to use it for at least one hour per day. Our objective was to establish feasibility by measuring recruitment rate, adherence rate, retention rate, protocol deviations and acceptability. Results Over 6 months, 143 patients were admitted with a new diagnosis of stroke: 73 had communication deficits, 44 met inclusion criteria, and 30 were enrolled into RecoverNow (median age 62, 26.6% female) for a recruitment rate of 68% of eligible participants. Participants received mobile tablets at a mean 6.8 days from admission [SEM 1.6], and used them for a mean 149.8 minutes/day [SEM 19.1]. In-hospital retention rate was 97%, and 96% of patients scored the mobile tablet-based communication therapy as at least moderately convenient 3/5 or better with 5/5 being most “convenient”. Conclusions Individualized speech-language therapy delivered by mobile tablet technology is feasible in acute care.

Fallibility: a new perspective on the ethics of clinical trial enrollment

The author replies: In response to Araki and Miyoshi: of the 668 patients who were enrolled in MONALEESA-2, 68 were treated in Asian countries.1 In a preplanned analysis of efficacy and safety in this subgroup, the hazard ratio for progression-free survival with ribociclib plus letrozole, as compared with placebo plus letrozole, was 0.30 (95% confidence interval, 0.13 to 0.66).1 The safety profile for ribociclib plus letrozole among Asian patients was consistent with that observed in the full population.1 Of note, the incidence of grade 3 or 4 neutropenia among the Asian patients was 71% in the group receiving ribociclib plus letrozole versus 0% in the group receiving placebo plus letrozole, a finding that did not differ significantly from that among nonAsian patients (58% and 1%, respectively).1 A clinical trial investigating ribociclib plus letrozole involving Japanese patients is ongoing (ClinicalTrials.gov number, NCT02333370). In response to de Gramont et al.: we did not collect data regarding breast-cancer molecular subtypes (as determined locally) during the MONALEESA-2 trial. Preplanned analyses of tumor biomarkers that may be correlated with treatment response or resistance (including Ki-67 and other markers) are ongoing.

A Novel Neuroscience Intermediate-Level Care Unit Model Retrospective Analysis of Impact on Patient Flow and Safety

Background and Purpose— Understanding physician decision making is increasingly recognized as an important topic of study, especially in stroke care. We sought to characterize the process of acute stroke decision making among neurologists in the United States and Canada from clinical and epistemological perspectives. Methods— Using a factorial design online survey, respondents were presented with clinical data to mimic an acute stroke encounter. The history, examination, computed tomographic (CT) scan, CT angiogram, and CT perfusion were presented in sequence, and respondents rated their diagnostic confidence and likelihood of treatment with tissue-type plasminogen activator after each element. Patient age, race, sex, and CT perfusion imaging results were randomized, whereas the rest of the clinical presentation was held constant. Results— We collected 715 responses, of which 473 (66%) were complete. Diagnostic certainty and likelihood of treatment with tissue-type plasminogen activator rose incrementally as additional clinical data were provided. Diagnostic certainty and treatment likelihood were strongly influenced by the clinical history and the CT scan. Other factors such as physicians’ personal beliefs or biases were not influential. Respondents’ accuracy in interpreting CT angiographic and CT perfusion images was variable and generally low. Conclusions— Diagnostic certainty and likelihood of treatment with tissue-type plasminogen activator increase with additional clinical data, with the history being the most important factor for diagnostic and treatment decisions. Respondents had difficulty in interpreting the results of CT perfusion scans although they had little impact on treatment decisions. We did not identify treatment bias based on patient age, race, or sex.

A Case Study in the History of Neurology

The ethical principle of ‘equipoise’, introduced in 1974, represents the most widely influential justification for the enrollment of patients into randomized clinical trials. However, definitions of equipoise vary, and its terms are not universally accepted. In this paper, we suggest a new way of approaching the ethics of clinical trial enrollment, which we call fallibility. The principle of fallibility argues that all physician opinions are sufficiently uncertain to warrant investigation, and that the ethical justification for any trial becomes a question of its epistemic validity, by which we mean the strength of its hypotheses and methods. The principle of fallibility can be translated into practice through the virtues of humility, skepticism and caring. While we cite recent examples from stroke medicine to demonstrate the limitations of equipoise, we propose that fallibility may offer a more general means of addressing the controversies that arise surrounding randomized controlled trials in many disciplines of medicine.

Decision Making and the Limits of Evidence A Case Study of Acute Stroke in Pregnancy

Background and Purpose: Neurointensive care units have been shown to improve patient outcomes across a variety of neurological and neurosurgical conditions. However, the efficacy of less resource-intensive intermediate-level care units to deliver similar care has not been well studied. The purpose of this study is to evaluate the impact of neurocritical specialist comanagement on patient flow and safety in a neuroscience intermediate-level care unit. Methods: Our intervention consisted of the addition of a physician with critical care experience as well as training in neurology, anesthesiology, or intensive care to a neuroscience intermediate-level care unit to comanage patients alongside neurology and neurosurgery staff during weekday daytime hours. A retrospective analysis was performed on prospectively collected data pertaining to all patients admitted to the unit over a 3-year period, 1 year before our intervention and 2 years after. Patient statistics including wait times to admission, length of stay (LOS), and mortality were reviewed. Results: Following the intervention, there were significant reductions in wait times to unit admission from both the emergency department and postanesthetic care unit, as well as reductions in the average LOS. No significant safety concerns were identified. Conclusion: This study has demonstrated that the optimization of a neuroscience intermediate-level care unit involving comanagement of patients by a neurocritical specialist can reduce wait times to admission and lengths of stay, with preserved safety outcomes.

Should CT Angiography be a Routine Component of Acute Stroke Imaging

We review the case of a young man who developed a constellation of symptoms and signs—bizarre behavior, seizures, abnormal movements, and autonomic instability—that evaded diagnosis at the time of presentation. We use this case to explore the way medical knowledge changes over time. Despite the dramatic advances in our understanding of neurological diseases in recent decades, physicians tend to approach diseases and diagnoses as if they were immutable. Our case reinforces how the diagnosis and treatment of disease are determined by an ever-changing historical context driven by the rapid expansion of medical knowledge. We discuss the implications of this realization and present strategies for navigating the boundaries of knowledge, both in practice and in principle.