Advances in Acute Stroke Treatment 2020

Introduction

In this past year, medicine has been dominated by the Covid19 pandemic. Acute stroke care and research has been affected both directly^{1, 2} and indirectly. We present a summary and commentary on advances published and presented in 2020 ending with observations on Covid19 and stroke.

Endovascular thrombectomy (EVT) in Middle and Low-Income Countries

EVT has been shown to be a highly effective treatment in high-resource countries. The RESILIENT Trial performed at 12 public hospitals in Brazil demonstrated that EVT is also highly effective in a health care system with more constrained resources.³ Infrastructure and support are needed for EVT in the developing world.

Acute Ischemic Stroke Thrombolysis and EVT

For a quarter century, thrombolysis has been a standard of care treatment for acute ischemic stroke. The withholding of intravenous alteplase seems anathema, but has now been challenged in patients with large artery occlusions arriving first at thrombectomy centres. The SKIP trial,⁴ examined 204 Japanese patients with middle cerebral artery (MCA) or internal carotid artery (ICA) occlusions, half of whom were randomized to treatment with intravenous alteplase (0.6 mg/kg) prior to EVT and half to EVT alone. The trial did not meet its primary outcome of non-inferiority. The DIRECT-MT trial⁵ enrolled 656 patients of whom half were randomized to intravenous alteplase (0.9 mg/kg) prior to EVT and half to EVT alone. The median time from randomization to groin puncture was 33.5 minutes. The trial met its non-inferiority margin (cOR 1.07, 0.81–1.40) with 36.4% in the EVT only group and 36.8% in the alteplase plus EVT group achieving mRS 0–2 at 90 days. Participants treated with EVT alone had lower percentages of successful reperfusion before thrombectomy (2.4% vs. 7.0%) and overall successful reperfusion (79.4% vs. 84.5%). Mortality at 90 days was 17.7% in the thrombectomy-alone group and 18.8% in the combination-therapy groups. In both trials, however, the non-inferiority margin was much larger than the minimal clinically important difference and so the trials were underpowered. Additional trials, MR-CLEAN-NoIV, SWIFT-DIRECT, and DIRECT-SAFE are ongoing.

A quarter of patients with ICA or M1-MCA occlusions in the INTERRSeCT study had thrombus migration into a distal segment resulting in poorer outcomes compared to complete recanalization or no change in recanalization. Registry data from California identified the challenge of distal embolization occurring in a quarter of patients resulting in distal emboli that were not possible to address with EVT.⁶ Both studies confirm data from the MR-CLEAN registry.⁷ Similarly, data from the ESCAPE trial showed early recanalization rates of only 6% in the EVT arm at a median of 50 minutes after the start of IV alteplase infusion. In the control arm, recanalization was observed, on CTA completed a median of ~4.5h after the start of intravenous alteplase infusion, in 37% of patients.⁸ The EXTEND-IA-TNK part 2 study compared two doses of tenecteplase, 0.25 vs. 0.4 mg/kg, among patients with large vessel occlusion, eligible for EVT.⁹ The primary outcome was early recanalization (not reperfusion) defined at the first angiographic run of the EVT procedure. There was no difference in outcome between the two doses but the study confirmed prior results from EXTEND-IA TNK part 1,¹⁰ of an early recanalization rate of 20% at an average of 46.5 minutes from treatment with tenecteplase to imaging. Finally, a pooled individual patient meta-analysis of trials examining patients with stroke-with-unknown-onset, who were selected by MR imaging (either DWI-FLAIR mismatch or MR perfusion imaging, showed that intravenous alteplase treatment was superior to placebo when assessed at 90 days.¹¹

Together these data provide empiric evidence and quantitative understanding of the in vivo mechanisms of intravenous thrombolysis, further demonstrating that patient selection is increasingly based on imaging and not time, and that thrombolytic agents require time to work. In a majority of patients with large vessel occlusion, thrombolysis alone will be unsuccessful during the critical time window when reperfusion will effectively salvage the ischemic tissue. In addition, thrombolysis can, in a minority of patients with large vessel occlusions, make the situation worse due to thrombus migration. Very rapid EVT possibly obviates any additional benefit of combined intravenous thrombolysis and EVT, but it remains unknown if an incremental benefit of combined therapy may emerge due to thrombolytic action on distal emboli, on incomplete reperfusion, on the microcirculation, or in situations where EVT proves to be unsuccessful. In contrast, a 20% target vessel recanalization rate within 45 minutes after thrombolysis is clinically meaningful, particularly in the drip and ship paradigm. Treatment with tenecteplase at 0.25 mg/kg (the dose seems settled now^{9, 12–14}) is not ready for widespread usage at present but more evidence will accrue from ongoing trials (TASTE, TEMPO-2, NORTEST-2, ACT, TWIST) over the next two years. The issue of withholding thrombolysis, is much less relevant when patients arrive at hospitals which do not perform EVT and so far the data do not justify withholding thrombolysis generally. At the end of 2020 it remains clear that the goal of acute ischemic stroke treatment is reperfusion as quickly as possible, whether that is achieved by going directly to EVT in selected patients or with combined thrombolysis and EVT in most patients.

EVT in Minor Ischemic Stroke, Basilar Artery Occlusion and Parenteral Antiplatelet Agents

Two cohort studies and a meta-analysis examining whether patients with mild symptoms (typically NIHSS 0–5) and a proximal large vessel occlusion should be treated with EVT reported similar outcomes between patients treated medically and those treated with EVT.^15–17 Randomized trials are underway to assess this question but it will always be more challenging to show a treatment effect on clinical outcomes when symptoms are mild given the ceiling effects on outcome scores. Selection of the specific populations of patients with LVO and only minor symptoms who will benefit from EVT remains an important research goal.

Large registries suggest the EVT is superior to medical therapy for basilar artery occlusion,¹⁸ but this has not yet been shown in trials. The open-label BEST trial randomized patients with basilar artery occlusion to EVT and best medical management versus best medical management alone. The trial was terminated early after 131 patients because of poor recruitment and high frequency of cross-over. In the intention-to-treat analysis, there was no evidence of a difference in the proportion of participants with mRS 0–3 at 90 days according to treatment (28 [42%] of 66 patients in the intervention group vs 21 [32%] of 65 in the control group; adjusted odds ratio [OR] 1·74, 95% CI 0·81–3·74).¹⁹ Further data from the BASICS trial have also reported a neutral outcome, with a trend toward better outcomes in the EVT group for those with higher NIHSS (Schonewille W. Personal communication and presented at ESOC-WSC 2020). Discrepancy in outcomes between cohort studies and randomized trials suggest both that selection bias exists in the cohort studies and that we have yet to identify the target subgroup of basilar artery occlusion patients who stand to benefit from EVT.

Intravenous or intra-arterial tirofiban as an adjunct prior to or as rescue treatment during EVT treatment has received ongoing attention, particularly in Asia but no data from larger randomized trials are available yet.^{20, 21} Mechanistically, the benefits of parenteral antiplatelet agents may follow the same paradigm as that seen in acute coronary syndromes and be of most utility in large vessel occlusion stroke due to intracranial atherosclerotic disease.

Cytoprotection and Adjuvant Therapies for Ischemic Stroke Reperfusion

The evolution of treatments for ischemic stroke due to LVO has resulted in a true human ischemia-reperfusion model, the same model in which pre-clinical demonstration of cytoprotection (or neuroprotection) has been proven for multiple compounds. The ESCAPE-NA1 trial assessed the peptide, nerinetide (previously called NA-1, TatNR2b9c), among 1105 patients with anterior circulation LVO undergoing EVT.²² The trial stratified randomization by alteplase treatment but was neutral overall. However, there was an alteplase-by-nerinetide treatment interaction, such that patients in the alteplase stratum showed no benefit, but patients in the no-alteplase stratum showed a 9.5% absolute risk benefit (RR = 1·19, CI₉₅ 1·01 to 1·41). This was a post-hoc test of interaction but was biologically supported by pharmacokinetic studies which suggest that there was an indirect effect of alteplase on cleavage of nerinetide in vivo. If the results can be confirmed in the ESCAPE-NEXT trial, this will give hope to other compounds that are being developed using the same paradigm. These include the modified activated protein C molecule, 3K3A-APC, which has already undergone assessment in the phase 2 Rhapsody study.²³ Simple molecules such as high-dose uric acid^{24, 25} may be assessed in future trials.

Intracerebral Hemorrhage (ICH)

ICH remains the most challenging stroke type. STOP-AUST randomized 100 patients with acute ICH <70 cc, a spot sign on CT angiography to receive intravenous tranexamic acid 1 g over 10 min followed by 1 g over 8 h or matching placebo, started within 4·5 h of symptom onset and within 1 hour of the qualifying CT scan.²⁶ There was no observed difference in the primary surrogate outcome of hemorrhage growth [OR = 0·72, CI₉₅ 0·32–1·59]. A post-hoc analysis of the ATACH-2 study reported that dropping the blood pressure by very large absolute amounts (>220 mmHg systolic down to <140mmHg systolic) may result in both poorer neurological outcomes and a greater chance of acute renal failure.²⁷ However, a subgroup of patients (about 1/3^rd of the trial population), treated within 2 hours of onset showed reduced hematoma growth and better outcomes with intensive blood pressure lowering comparing to control.²⁸ New studies are planned for ICH that will focus on the ultra-early treatment window, including a return to the assessment of recombinant factor VIIa within two hours of onset.¹

Cortical Venous Sinus Thrombosis (CVST)

CVST is the least common form of stroke and randomized data on CVST management, both acute and chronic, are sparse. The TOACT study (n=67), assessing endovascular treatment (mechanical with or without local thrombolytic drug infusion) vs. best medical care was conducted in Europe and China.²⁹ There was no difference in outcomes at 1 year with two-thirds of the population in both groups achieving mRS 0–1 (relative risk ratio, 0.99; CI₉₅, 0.71–1.38). Given its low prevalence relative to other stroke types, continued global collaboration on CVST trials is needed.

Covid19

While some initial case reports suggested that a pro-thrombotic state occurs in some patients with Covid19 that may manifest as large vessel occlusion, population-based data have yet to report an increased incidence of ischemic stroke.^{30, 31} In fact, stroke admissions may have fallen overall.^{32, 33} Finally, we recommend several publications that have addressed acute stroke care process to maximize safety for patients and health care personnel.^34–37

Abbreviations and Acronyms

LVO

large vessel occlusion

EVT

endovascular thrombectomy/treatment

ICH

intracerebral hemorrhage

CVST

cerebral venous sinus thrombosis

CT

computed tomography

MR

magnetic resonance

DWI

diffusion weighted imaging

FLAIR

fluid attenuated inversion recovery

CTA

CT angiography

NIHSS

National Institutes of Health Stroke Scale

RESILIENT

Randomization of Endovascular Treatment With Stent-retriever and/or Thromboaspiration vs. Best Medical Therapy in Acute Ischemic Stroke Due to Large VEssel OcclusioN Trial

SKIP

Randomised study of endovascular therapy with vs without intravenous tissue plasminogen activator in acute stroke with ICA and M1 occlusion

DIRECT-MT

Direct Intra-arterial Thrombectomy in Order to Revascularize AIS Patients With Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals: a Multicentre Clinical Trial

MR-CLEAN NoIV

Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands No IV thrombolysis study

SWIFT-DIRECT

Solitaire^™ With the Intention For Thrombectomy Plus Intravenous t-PA vs DIRECT Solitaire^™ Stent-retriever Thrombectomy in Acute Anterior Circulation Stroke

DIRECT-SAFE

Randomized Controlled Trial of DIRECT Endovascular Clot Retrieval vs Standard Bridging Thrombolysis With Endovascular Clot Retrieval Within 4.5 Hours of Stroke Onset

INTERRSeCT

Identifying New Approaches to Optimize Thrombus Characterization for Predicting Early Recanalization and Reperfusion With IV Alteplase and Other Treatments Using Serial CT Angiography study

BEST

Acute Basilar Artery Occlusion: Endovascular Interventions vs Standard Medical Treatment

BASICS

Basilar Artery International Cooperation Study

ESCAPE

Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimizing CT to recanalization times study

ESCAPE-NA1

Extension of Stroke Care by Added neuroProtection to Endovascular treatment

ESCAPE-NEXT

Efficacy and Safety of Nerinetide in Participants With Acute Ischemic Stroke Undergoing Endovascular Thrombectomy Excluding Thrombolysis

EXTEND-IA TNK

Extending the Time for Thrombolysis in Emergency Neurological Deficits - Intra-Arterial Using Intravenous Tenecteplase study

TASTE

Tenecteplase Versus Alteplase for Stroke Thrombolysis Evaluation Trial

TEMPO-2

Multicentre, Prospective Randomized Open Label, Blinded-endpoint (PROBE) Controlled Trial of Thrombolysis With Low Dose Tenecteplase (TNK-tPA) Versus Standard of Care in Minor Ischemic Stroke With Proven Acute Symptomatic Occlusion

NORTEST-2

Norwegian Tenecteplase Stroke Trial 2: A Randomised Trial of Tenecteplase vs. Alteplase in Acute Ischemic Stroke

ACT

Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke: QuICR & OPTIMISE Registry Based Pragmatic Randomized Controlled Trial

TWIST

Tenecteplase in Wake-up Ischaemic Stroke Trial (TWIST). A Randomised-controlled Trial of Thrombolytic Treatment With Tenecteplase for Acute Ischaemic Stroke Upon Awakening

TOACT

Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis study

STOP-AUST

Spot Sign and Tranexamic Acid On Preventing ICH Growth - AUStralasia Trial

ATACH-2

Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 study