American Heart Association


Low-Dose Intravenous Alteplase in Stroke with Unknown Time Onset

Sohei Yoshimura, MD, PhD

Koga M, Yamamoto H, Inoue M, Asakura K, Aoki J, Hamasaki T, Kanzawa T, Kondo R, Ohtaki M, Itabashi R, et al. Thrombolysis With Alteplase at 0.6 mg/kg for Stroke With Unknown Time of Onset: A Randomized Controlled Trial. Stroke. 2020;51:1530–1538.

The guidelines of the American Heart Association/American Stroke Association recommend MRI to identify diffusion-positive FLAIR-negative lesions (DWI-FLAIR mismatch) for selecting patients who can benefit from IV alteplase in acute ischemic stroke (AIS) patients who awake with stroke symptoms or have unclear time of onset > 4.5 hours from last known well.1 The efficacy and safety of IV alteplase for these patients was revealed by the WAKE-UP trial.2

In the WAKE-UP trial, a favorable outcome defined by mRS 0 to 1 at 90 days was achieved in 53.3% in the alteplase group and 41.8% in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P = 0.02). The trial was stopped early for lack of funding, and there was numerically more death (4.1% vs 1.2%, P=0.07) and significantly more symptomatic intracranial hemorrhage (sICH) (2.0% vs. 0.4%, P= 0.15). So, there still have been some concerns about safety of the therapy.

Balancing Risk-Benefit for Non-Acute Vertebral Artery Occlusion Revascularization

María Gutiérrez, MD

Gao F, Sun X, Zhang H, Ma N, Mo D, Miao Z. Endovascular Recanalization for Nonacute Intracranial Vertebral Artery Occlusion According to a New Classification. Stroke. 2020;51:3340–3343.

Large vessel occlusion of the posterior circulation has devastating effects and carries high morbidity and mortality. One of the main causes for this stroke subtype is vertebral atherosclerosis. The optimal treatment for the non-acute intracranial vertebral artery occlusion (NA-ICVAO) in patients at high risk of stroke despite the best medical treatment remains unclear. Some case-report studies showed that endovascular recanalization (ER) is feasible. However, a large heterogeneity of perioperative outcomes and a high incidence of complications makes critical to identify which patients would benefit from intervention.

In this study, the authors aimed to define an angiographic classification to explore the feasibility and safety of endovascular recanalization for symptomatic atherosclerotic NA-ICVAO that might become a reference for patient selection and risk stratification in future trials. They retrospectively analyzed 50 patients with atherosclerotic NA-ICVAO that were treated with angioplasty and stenting. Patients were divided into 4 groups according to the following angiographic classification: type I (Figure 1A), the occlusion length is ≤15 mm; type II (Figure 1B), the occlusion length is >15 mm; type III (Figure 1C and 2), the occlusion length is >15 mm, and the tortuosity angle of the occluded segment is ≥45°; and type IV (Figure 1D), the occlusion extends to the epidural segment.

Illustration of the angiographic classification of nonacute intracranial vertebral artery occlusion.
Figure 1. Illustration of the angiographic classification of nonacute intracranial vertebral artery occlusion. A, Type I, the occlusion length is ≤15 mm. B, Type II, the occlusion length is >15 mm. C, Type III, the occlusion length is >15 mm, and the tortuosity angle of the occluded segment is ≥45°. D, Type IV, the occlusion extends to the epidural segment.

The median duration of occlusion was 45 days, and the median time from last symptom onset to endovascular treatment was 15 days. The overall technical success rate was 76%. The perioperative complication rate was 16% (8/50); vascular dissection occurred in 5 cases (4 asymptomatic and 1 mild stroke). One patient died of vascular perforation. Stroke or death beyond 30 days was 10.2% (5/49), 2 patients died (one for cerebral hemorrhage and another from ischemic stroke), 1 patient experienced severe ischemic stroke, and 2 patients had mild ischemic stroke. In angiographic follow-up, 4 patients developed in-stent restenosis and 3 developed reclusions.

Article Commentary: “Tenecteplase Thrombolysis for Acute Ischemic Stroke”

Burton J. Tabaac, MD

Warach SJ, Dula AN, Milling Jr TJ. Tenecteplase Thrombolysis for Acute Ischemic Stroke. Stroke. 2020;51:3440–3451.

This topical review takes a deep dive analysis into the literature as it pertains to Tenecteplase (tNK), a type of IV thrombolysis, in the treatment of acute ischemic stroke. A qualitative synthesis of published stroke trials is presented. Most interestingly is the argument, using meta-analysis, that tNK is superior in recanalizing large vessel occlusions (LVO) compared to Alteplase (tPA). This resonates with the vascular neurology world because the original prospective studies were unable to demonstrate superiority or non-inferiority of tNK on clinical outcome. As detailed, the current body of clinical trial evidence evaluating tNK relative to tPA points in the direction of superior early recanalization in LVO and non-inferior disability-free outcome at 3 months in favor of tNK.

In regards to dosing, current clinical practice guidelines for stroke include IV tNK 0.25mg/kg recommended for LVO, based on phase 2 trial data with improved 3-month outcome relative to tPA. We have known, at least since 2012, that reperfusion and clinical outcomes with the use of tNK appear improved, and intracranial hemorrhage risk is not increased, as compared to alteplase.1 The paper cites a network meta-analysis of five randomized trials on tNK versus tPA that found better efficacy on clinical and imaging endpoints. The authors elaborate, there has been no evidence to support an advantage of the 0.4mg/kg dose relative to 0.25mg/kg in the treatment of ischemic stroke, adding, “Trials that directly compared the two doses tended to favor the 0.25mg/kg dose.” The National Institute of Neurological Disorders and Stroke Tenecteplase trial has since eliminated the 0.4mg/kg as being inferior, and EXTEND-IA-TNK (part 2) reported a higher number of symptomatic intracranial hemorrhage events in the 0.4mg/kg group relative to the 0.25mg/kg dosed patients.2 The ongoing NOR-TEST 2 trial may confirm whether there is any disadvantage of the 0.4mg/kg dose relative to standard dose tPA. Current randomized phase 3 trials are ongoing in an aim to answer the question of if tNK has decreased hemorrhagic risk, and if tNK can establish efficacy beyond the 4.5 hour time window.

Dual Antiplatelet Therapy: Shotgun or Aiming at Precision Targets?

Thomas Raphael Meinel, MD

Amarenco P, Denison H, Evans SR, Himmelmann A, James S, Knutsson M, Ladenvall P, Molina CA, Wang Y, Johnston SC, on behalf of the THALES Steering Committee and Investigators. Ticagrelor Added to Aspirin in Acute Nonsevere Ischemic Stroke or Transient Ischemic Attack of Atherosclerotic Origin. Stroke. 2020.

Short-term dual antiplatelet therapy (DAPT) has emerged as a powerful treatment option in patients with non-severe ischemic stroke or high-risk TIA.1 However, the efficacy of antithrombotic therapy might vary according to etiology of the ischemic event.2 Amarenco et al. aimed to investigate whether the efficacy and safety of DAPT with Aspirin plus Ticagrelor as compared to Aspirin differed in the subgroup of patients with minor stroke or TIA due to atherosclerotic vascular disease.

For this purpose, the authors conducted a substudy of the THALES trial including patients aged 40 years or older with non-severe non-cardioembolic ischemic stroke (NIHSS ≤5) or high-risk TIA (ABCD2-Score ≥6 or vascular stenosis ≥50% in the suspected vascular territory). Main exclusion criteria were atrial fibrillation, suspicion of cardioembolic cause, high bleeding risk and — importantly — planned carotid revascularization that required halting study medication within 3 days of randomization. or the main prespecified analysis, atherosclerotic ipsilateral stenosis was defined as presence of narrowing of the lumen of ≥30% ipsilateral to the ischemic event as assessed by CT- or MR-angiography or neurovascular ultrasound. The primary efficacy endpoint was time from randomization to the first subsequent event of stroke or death. The primary safety endpoint was occurrence of a severe bleeding event according to the GUSTO definition. 11,016 patients underwent randomization (roughly 50% representing a European and 40% Asian population).

World Stroke Day: The Long Journey of Revascularization Treatments for Ischemic Stroke: From Strict Patient Selection to Extending Time Windows

Raffaele Ornello, MD

Until the early 1990s, stroke was regarded as a disabling event with no cure. The NINDS trial of intravenous thrombolysis, published in 1995, changed the minds of stroke physicians and marked the rise of revascularization treatments for acute ischemic stroke. The initial criteria for patient selection were very strict. After that, more and more refined protocols were established, allowing the progressive extension of the therapeutic window and the loosening of selection criteria.

The last decade saw the rise of endovascular treatments. After the first unsuccessful trials, adequate protocols for the selection of patients with salvageable brain ischemic tissue led to success in recanalization treatments. Better use of brain neuroimaging led to refinements in patient selection, allowing the extension of time windows for treatments in eligible patients. Over the years, revascularization treatments for ischemic stroke spread over most hospitals in the world, allowing widespread access to treatments.

World Stroke Day: Interview with Dr. Anna Bersano on the Impact of the COVID-19 Pandemic on Stroke Care in Italy

Dr. Anna Bersano
Dr. Anna Bersano

An interview with Dr. Anna Bersano, MD, PhD, at the Cerebrovascular Unit of Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy, about the impact of the COVID-19 pandemic on stroke care in Italy.

Interviewed by Francesca Tinelli, MCs, rare cerebrovascular disease fellow at Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Dr. Tinelli: First of all, I present you Dr. Anna Bersano, the neurologist I work with, and I would like to thank Anna for agreeing to do this interview. 

Anna is a stroke neurologist with long-term expertise in cerebrovascular diseases, particularly in genetics of monogenic and complex stroke diseases, combining research with an active practice as a vascular care neurologist. She coordinated several studies on genetics of stroke, such as the Lombardia GENS study on stroke monogenic disease and the SVE-LA study on genetics of small vessel disease and lacunar stroke. Recently, she implemented an Italian network for the study of Moyamoya disease named GE-NO-MA (Genetics of Moyamoya Disease) and an Italian network for the study of Cerebral Amyloid Angiopathy (SENECA project). 

Dr. Bersano: Thank you for discussing this relevant and critical topic in the current situation.

Dr. Tinelli: What is the correlation between SARS-CoV2 and cerebrovascular diseases?

Dr. Bersano: It is well known that SARS-CoV2 invades human respiratory epithelial cells through its S-protein and ACE2 receptor on human cell surface. Then, the virus can spread from the respiratory tract to the central nervous system, causing possible neurological complications. A recent study on 214 Chinese COVID-19 patients reported acute cerebrovascular events in 5.7% of COVID-19 patients. However, the exact relationship between SARS-CoV2 and stroke is unclear. Patients affected by COVID-19 have been observed to have a higher risk of cerebrovascular events, probably due to the activation of coagulation and inflammatory pathways, which lead to cardiovascular and thrombotic complications, or to cardioembolic causes.

Chaos About Treatment of Chaotic Heartbeat in Elderly Patients

Nurose Karim, MD

Okumura K, Akao M, Yoshida T, Kawata M, Okazaki O, Akashi S, Eshima K, Tanizawa K, Fukuzawa M, Hayashi T, et al. Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation. N Engl J Med. 2020.

Treatment of atrial fibrillation (AF) in the elderly population has always been challenging. Fragile age, multiple comorbidities, and fall risk put them as a red flag whenever a decision to anticoagulate them is made. Edoxaban is a direct oral factor Xa inhibitor. Studies have been done comparing low dose Edoxaban with warfarin and have found Edoxaban once-daily regimens noninferior to warfarin with respect to the prevention of stroke or systemic embolism and have been associated with significantly lower rates of bleeding and death from cardiovascular causes.1

The Edoxaban Low-Dose for EldeR CARE AF patients (ELDERCARE-AF) study is a phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study comparing the safety and efficacy of once-daily edoxaban 15 mg versus placebo in Japanese patients with NVAF ≥80 years of age who are considered ineligible for standard oral anticoagulant therapy.2

A Collateral Dialogue: Addressing Neuroanatomy of Posterior Circulation in Basilar Artery Occlusion

Saurav Das, MD

Kwak HS, Park JS. Mechanical Thrombectomy in Basilar Artery Occlusion: Clinical Outcomes Related to Posterior Circulation Collateral Score. Stroke. 2020;51:2045–2050.

The successful endovascular treatment (EVT) trials for large vessel occlusion (LVO) strokes have excluded patients with basilar artery occlusion (BAO). Recently, the results of the Basilar Artery International Collaboration Study (BASICS) were presented at the European Stroke Organization (ESO-WSO) virtual platform. The results, even though underpowered to show significant benefits of EVT <6 hours of BAO, were effective in patients with moderate to severe deficits (NIHSS > 10). The trial results have shifted the spotlight to the distinction in the neuro-anatomy of posterior-circulation vessels and collateral circulation in this part of the brain, etio-pathological mechanisms involved in large vessel disease in the posterior circulation, as well as appropriate patient selection based on symptom severity and time window from symptom onset. In this blog, I will discuss a retrospective study from South Korea relevant to this topic that was published in the July issue of Stroke.

In this study, the authors present data from 81 patients with acute BAO treated with EVT using manual aspiration or stent retriever at their institute in South Korea over a period of eight years from 2012 to 2019. Posterior circulation collaterals were graded using the Basilar Artery on CT Angiogram (BATMAN) score and posterior circulation collateral score (PC-CS). Both these scoring systems have a maximum possible score of 10 points. 64% of these patients achieved TICI 2b or 3 recanalization within a median time of 5.5 hours from symptom onset, and 37% of patients had good functional outcomes defined by a 3-month modified Rankin scale ≤ 2. When compared to patients with poor outcomes, the ones with favorable outcomes had lower baseline NIHSS (15 vs 7.5, p<0.01), a greater proportion of distal BAO (20% vs 63%,  p<0.01), and better posterior circulation collateral scores (5 vs 6,  p<0.01). The authors also compared these groups on a timeline of < 3hrs, 3-6 hrs, 6-12 hrs, and >12 hrs from symptom onset. Interestingly, the time to recanalization from symptom onset was not significantly different between the groups. Receptor operating characteristic (ROC) curve analysis for collateral scores yielded the highest area under the curve with a cut-off score of 6 for both BATMAN and PC-CS. Using these cut-offs, multivariate analysis revealed that NIHSS score <15 (odds ratio 8.49, P=0.004), PC-CS ≥6 (odds ratio 3.79, P=0.042), and distal BAO (odds ratio 3.67, P=0.035) were independent predictors of good clinical outcomes.

Figure 1. Schematic illustration of collateral scores.

Endovascular Thrombectomy With or Without Intravenous Alteplase: ESO-WSO Large Clinical Trials Webinar

Parneet Grewal, MD

ESO-WSO 2020 Large Clinical Trials Webinar
Presenter: Dr. Jianmin Liu (China)
Article: Yang P, Zhang Y, Zhang L, Zhang Y, Treurniet KM, Chen W, et al, for the DIRECT-MT Investigators. Endovascular Thrombectomy with or without Intravenous Alteplase in Acute Stroke. NEJM. 2020.

The goal of current therapeutic strategies for acute ischemic stroke with large vessel occlusion (LVO) is recanalization of the occlusion before irreversible damage has occurred. In this large multicenter, prospective, randomized, open-label trial with blinded outcome assessment, Dr. Jianmin Liu and his team aimed to answer the question of whether mechanical thrombectomy (MT) alone (thrombectomy alone group) would be non-inferior to combined treatment of IV-tPA and MT (combined group) in patients with LVO.  

This trial included patients ³ 18 years of age who presented to 41 pre-selected academic medical centers in China within 4.5 hours of symptom onset, had National Institutes of Health Stroke Scale (NIHSS) ³ 2 with imaging showing an LVO (intracranial segment of ICA, M1 or proximal M2 only). Any patients who did not meet American Heart Association/American Stroke Association guidelines for alteplase or MT were not included in the trial. The standard dose of tPA at 0.9 mg/kg was used, and the first-line strategy for MT was stent-retriever. Statistically, the trial was designed to provide 80% power (at a two-sided alpha level of 0.05) to determine a non-inferiority margin of 0.8. 656 patients were randomized in 1:1 fashion by a web-based system with 327 patients in the thrombectomy alone group and 329 patients in the combined group. The patient enrollment period was 17 months (February 23, 2018, to July 2, 2019). The baseline characteristics of patients were similar in both the groups with a median age of 69 years, median NIHSS score of 17, and median ASPECTS value of 9. The median duration from stroke onset to randomization was 167 minutes in the thrombectomy alone group and 177 minutes in combined group with time from randomization to groin puncture being 31 minutes and 36 minutes, respectively.

ESO-WSO Large Clinical Trials Webinar: BASICS

Rachel Forman, MD

I was happy to see that although the ESO-WSO 2020 annual meeting was postponed, we still had the opportunity to virtually hear the results of some recent large clinical trials. One of the five trials presented was the Basilar Artery International Collaboration Study (BASICS) presented by Dr. Wouter Schonewille from The Netherlands. Posterior circulation occlusions have been largely excluded from the main endovascular randomized control trials, so these results were highly anticipated. 

Many of us are familiar with the devastating effects of a basilar artery occlusion (BAO), and from a personal experience, some of these cases have been very challenging without having the guidance of large trials as we do with anterior circulation occlusions. The clinical presentations, stroke severity, and collateral patterns are inherently different. This trial was an international, multicenter, controlled trial with randomized treatment-group assignments investigating the efficacy and safety of endovascular therapy (EVT) plus best medical management (BMM) versus BMM alone <6 hours of estimated time of BAO. Patients were randomly assigned (1:1 ratio) to EVT+BMM or BMM alone and stratified according to: randomizing center, use of IVT, and NIHSS (<20 vs >20). The enrollment period was from 2011 through 2019. Patients were excluded with intracranial hemorrhage, extensive brainstem ischemia, or cerebellar mass effect/acute hydrocephalus. The calculated sample size was 300 patients assuming favorable outcome in 46% with EVT+BMM and 30% with BMM. Primary outcome was mRS <3 at 90 days. Secondary outcome measures included clinical outcomes (mRS 0-2 at 90 days and mRS distribution) and imaging outcomes (posterior circulation ASPECTS score at 24 hours and basilar artery patency at 24 hours).