Abstract TP382: A Bayesian Network for Reasoning on Acute Ischemic Stroke Intervention

Section Editors: Marc Fisher MD Antoni Davalos MD The Food and Drug Administration (FDA) evaluates applications for new human drugs, biologics, and complex medical devices. Companies must obtain FDA approval to legally market these products. In August, the FDA gave Concentric Medical clearance to market its Merci Retriever system to “remove blood clots from the brain in patients experiencing an ischemic stroke.” Given that the FDA is charged with “protecting the public health by assuring the safety, efficacy, and security of… biological products and medical devices…, ” “advancing public health by helping to speed innovations that make medicines … more effective, safer, and more affordable,” and “helping the public get the accurate, science-based information they need to use medicines … to improve their health,”1 the FDA’s decision to approve the Merci Retriever system is of concern. The pathways to approval are reviewed by Felten et al in the accompanying article and are outlined in Figure 1. Figure 1. Potential pathways for device approval. The decision to approve the Merci Retriever was based on data from the MERCI (Mechanical Embolus Removal in Cerebral Ischemia) Trial; the approval was granted through the 510(k) process. The Merci Retriever system includes a flexible nickel titanium (nitinol) wire that obtains a helical shape once it is passed through the tip of the guidance catheter. In practice, the catheter/wire is passed distal to the thrombus, the catheter is removed, and the helical configuration assumed by the wire; the clot is then trapped in the helix and withdrawn from the vasculature (Figure 2). The 510(k) clearance means that the Merci Retriever was felt to be substantially equivalent to a predicate device. In this case, the predicate device was the Concentric Retriever, which itself received 510(k) clearance by the FDA in May 2001 for “use in …

Predicting outcome after endovascular treatment for acute ischemic stroke is challenging. We aim to investigate differences between predicted and observed outcomes in patients with acute ischemic stroke treated with endovascular treatment and to evaluate the performance of a validated outcome prediction score. MR PREDICTS is an outcome prediction tool based on a logistic regression model designed to predict the treatment benefit of endovascular treatment based on the MR CLEAN and HERMES populations. ESCAPE-NA1 is a randomized trial of nerinetide vs. placebo in patients with acute stroke and large vessel occlusion. We applied MR PREDICTS to patients in the control arm of ESCAPE-NA1. Model performance was assessed by calculating its discriminative ability and calibration. Overall, 556/1105 patients (50.3%) in the ESCAPE-NA1-trial were randomized to the control arm, 435/556 (78.2%) were treated within 6 h of symptom onset. Good outcome (modified Rankin scale 0-2) at 3 months was achieved in 275/435 patients (63.2%), the predicted probability of good outcome was 52.5%. Baseline characteristics were similar in the study and model derivation cohort except for age (ESCAPE-NA1: mean: 70 y vs. HERMES: 66 y), hypertension (72% vs. 57%), and collaterals (good collaterals, 15% vs. 44%). Compared to HERMES we observed higher rates of successful reperfusion (TICI 2b-3, ESCAPE-NA1: 87% vs. HERMES: 71%) and faster times from symptom onset to reperfusion (median: 201 min vs. 286 min). Model performance was good, indicated by a c-statistic of 0.76 (95%confidence interval: 0.71-0.81). Outcome-prediction using models created from HERMES data, based on information available in the emergency department underestimated the actual outcome in patients with acute ischemic stroke and large vessel occlusion receiving endovascular treatment despite overall good model performance, which might be explained by differences in quality of and time to reperfusion. These findings underline the importance of timely and successful reperfusion for functional outcomes in acute stroke patients.

A multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke caused by proximal arterial occlusion in the anterior circulation.

Various endovascular intraarterial approaches are available for treating patients with acute ischemic stroke who present with severe neurological deficits. Three recent randomized trials-Interventional Management of Stroke (IMS) III, Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE), and Synthesis Expansion: A Randomized Controlled Trial on Intra-Arterial Versus Intravenous Thrombolysis in Acute Ischemic Stroke (SYNTHESIS Expansion)-evaluated the efficacy of endovascular treatment of acute ischemic stroke and, after failing to demonstrate any significant clinical benefit of endovascular therapies, raised concerns and questions in the medical community regarding the future of endovascular treatment for acute ischemic stroke. In this paper, the authors review the evolution of endovascular treatment strategies for the treatment of acute stroke and provide their interpretation of findings and potential limitations of the three recently published randomized trials. The authors discuss the advantage of stent-retriever technology over earlier endovascular approaches and review the current status and future directions of endovascular acute stroke studies based on lessons learned from previous trials.

The relationship between plasma D-dimer concentrations and acute ischemic stroke subtypes

To the Editor: We read with great interest the review from H.P. Adams1 who critically re-evaluates individual aspects of well-known and often-discussed studies on anticoagulation in acute stroke. These studies do not exhibit a net benefit of anticoagulant use with regard to the criteria safety, mortality, morbidity, prevention of stroke recurrence and late outcome. The author emphasized the differences among the individual studies with regard to sample sizes, time-to-start of therapy (extending up to 48 hours after stroke onset), protocols for dosages and controls of anticoagulants used and the route of administration leading to a distinct criticism of major meta-analysis published. In addition, prominent shortcomings such as the missing baseline brain imaging studies in the dominating IST and CAST trials and the lack of any efforts to differentiate among stroke subtypes with gross under representation of embolic mechanisms are mentioned. However, despite these shortcomings, H.P. Adams concludes that he sees no indication for anticoagulation in acute stroke and suggests the future role of anticoagulants will be very limited. In our view this conclusion is premature and not accepted by many “stroke experts” in institutions where advanced diagnostic techniques and neuro-monitoring are available. So far the albeit limited data available from these trials reveals statistically significant advantages of anticoagulation in the prevention of deep venous thrombosis, pulmonary …

Early recanalization of occluded vessels in acute ischemic stroke (AIS) either by intravenous thrombolysis or endovascular revascularization has been shown to be associated with improved clinical outcome and reduced mortality.1 Initial works on endovascular treatment (EVT) of AIS was published in the 1980s.2,3 Since then, the endovascular techniques for AIS treatment have tremendously improved, advancing from intra-arterial administration of thrombolytic drugs to first-generation mechanical thrombectomy devices (Merci clot retriever and Penumbra clot aspiration) and more recently to second-generation mechanical thrombectomy devices (stent-retrievers; Figure 1). Introduction of various tools and techniques in EVT for AIS will, for obvious reasons, affect the efficacy and safety. Figure 1. Evolution of endovascular techniques for acute ischemic stroke and clinical trials. IMS indicates Interventional Management of Stroke; MERCI, Mechanical Embolus Removal in Cerebral Ischemia; MR CLEAN, Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; PROACT, Prolyse in Acute Cerebral Thromboembolism; SWIFT, Solitaire With the Intention for Thrombectomy; and TREVO, Thrombectomy Revascularization of Large Vessel Occlusions in Acute Ischemic Stroke. On the other hand, intravenous thrombolysis was evaluated in several large randomized trials and was shown to improve clinical outcome at 90 days if treatment was initiated within 3 hours of stroke onset.4 Subsequently, the European Cooperative Acute Stroke Study (ECASS) III showed the benefit of intravenous thrombolysis between 3 and 4.5 hours.5 After establishing the efficacy of intravenous recombinant tissue-type plasminogen activator (r-tPA) in the treatment of AIS, EVT had to be evaluated against intravenous treatment. A long time elapsed before the results of the first randomized controlled trials were published in 2013 demonstrating no major difference between intravenous r-tPA treatment and EVT for AIS.6–8 Noteworthy, these trials had several limitations including the fact that all EVT were approved for use.9 …

See related article, pages 1826–1830. The goal of acute stroke evaluation is to determine not only stroke type (ischemic versus hemorrhagic) and localization (anatomical and vascular), but perhaps more importantly, to determine reversibility (presence of an ischemic penumbra that may be salvaged with acute therapy). Traditionally, neurologists have relied on history and neurological examination to provide much of this information. However, long experience has demonstrated that the neurological examination is imperfect at best in determining lesion localization and grossly limited in its ability to provide insights into the presence of penumbral tissue. This is evidenced by the only modest correlations between National Institutes of Health Stroke Scale (NIHSS) score and perfusion-weighted imaging lesion volume.1,2 The last decade has seen a striking growth in neuroimaging techniques that provide important real-time information about acute stroke pathophysiology. In the mid-1990s the advent of diffusion-weighted imaging revolutionized the role of MRI in acute stroke evaluation. Not …

### Case A 68-year-old right-hand-dominant man was brought to the hospital because of a speech disturbance and right arm and leg weakness. He awoke with these deficits and was last known to be symptom-free when retiring to bed the previous evening 8 hours earlier. His past medical history was notable for coronary heart disease, the patient having underwent coronary artery bypass surgery 7 years previously for unstable angina, but he had no known history of myocardial infarction. He also had hypertension and hyperlipidemia, and smoked 1 pack of cigarettes daily for more than 40 years. He had no history of calf claudication. His hypertension was being treated with a diuretic and β-adrenergic receptor blocker. He was also prescribed 325 mg of aspirin daily and an HMG CoA-reductase inhibitor (statin); however, his wife remarked that he often forgot to take his medications. His last total cholesterol was 240 mg/dL, with LDL cholesterol of 130 mg/dL. He had a strong family history of coronary heart disease after the age of 50. He had no known drug allergies. #### Physical Examination The patient’s blood pressure was 195/100 mm Hg in both arms, with a regular pulse of 90 bpm. His weight was 225 lb (body mass index: 31.4 kg/m2). His lungs were clear to auscultation. Cardiac examination showed a laterally displaced point of maximum impulse with an S4 gallop and a soft nonradiating systolic murmur at the base. His abdomen was obese without organomegaly and no abdominal bruits were detected. He had no rashes and no joint deformities. The left superficial temporal artery pulse was stronger than the right. There were soft bilateral anterior cervical bruits, left louder than right, but no supraclavicular bruits. There were bilateral femoral bruits. Radial pulses were 2+ and symmetric. Dorsalis pedis and posterior tibial pulses were 1+. …

Background and Purpose: Red cell distribution width (RDW) has been recognized as a prognostic marker in cardiovascular diseases and stroke. Increased RDW is predictive of poor outcome and mortality in acute ischemic stroke patients. However, the underlying mechanisms are not fully understood. We aimed to explore the association between RDW, collateral flow, infarct volume growth, final infarct volume (FIV), and clinical outcomes in acute stroke patients with large artery atherosclerosis. Methods: This is a single-center retrospective cohort study based on a prospective registry of consecutive acute ischemic stroke patients within 6 hours of onset. Acute ischemic stroke identified with anterior circulation large artery atherosclerosis (LAA) with complete baseline and follow-up imaging (Non-contrast CT, CT Angiography, Perfusion CT) as well as clinical profiles were enrolled. Collaterals was assessed using the volume ratio between delay time (DT) >3s and DT>6s lesions. Baseline infarct core volume was defined by relative cerebral blood flow<30%. FIV was calculated by manually drawing regions of interest on the follow-up images. Infarct volume growth was determined from FIV minus baseline infarct core volume. A good functional outcome was defined as a 3-month modified Rankin Score of 0-2. The relationship between RDW, collaterals, infarct volume growth, FIV and clinical outcomes were evaluated using multivariate models. Results: A total number of 100 patients were included in this study. Multivariate adjusted general linear models revealed that increased RDW was associated with poorer collaterals (multivariate adjusted coefficient -0.11, 95% CI -0.20 — -0.02, p=0.02) and increased infarct volume growth (multivariate adjusted coefficient 0.06, 95% CI 0.03 — 0.08, p<0.001). No significant relationship was found between RDW and FIV (multivariate adjusted coefficient 0.08, 95% CI -0.01 — 0.13, p=0.08), RDW and clinical outcomes (multivariate adjusted OR 1.66, 95% CI 0.44 — 6.28, p=0.46) probably due to the small sample size. Conclusion: For patients with LAA stroke, high RDW was associated with poorer collateral flow and increased infarct volume growth, which may explain the predictive value of RDW and poor functional outcomes in acute stroke.

Time Is Brain

Acute stroke is a major component of neurology and one of few neurologic emergencies. Despite many efforts to increase treatment of acute ischemic stroke, we are still not able to treat a significant percentage of patients with intravenous tPA, typically because of time restrictions. Unfortunately, many patients do not present to medical attention within the short window for tPA administration. In addition, there are numerous contraindications for tPA, which make more patients ineligible. Endovascular treatment for acute ischemic stroke may help to expand the number of patients treated by extending the time window beyond the 3 to 4.5hour constraints of IV tPA, and including patients with tPA contraindications such as use of oral anticoagulants. However, several recent studies have raised questions regarding the utility and efficacy of these procedures. These studies should not discourage endovascular treatment of acute stroke, but should lead us to ask more questions and be proactive in seeking answers, and should make us carefully select the patient population to receive the treatment. Future studies should take advantage of the lessons learned from these recent trials, including the importance of using vascular imaging for inclusion criteria, and of utilizing the latest and most advanced devices and techniques. Endovascular therapy will continue to evolve into what will hopefully be a clinically significant alternative therapy for acute ischemic stroke.

Evaluating Age, Sex, Racial, and Ethnic Representation in Acute Ischemic Stroke Trials, 2010 to 2020: A Systematic Review and Meta-Analysis.

Image-guided vascular recanalization in acute stroke.

The impact of recanalization on ischemic stroke outcome: A clinical case presentation