This article reviews recent breakthroughs in the treatment of acute ischemic stroke, mainly focusing on the evolution of endovascular thrombectomy, its impact on guidelines, and the need for and ...implications of next-generation randomized controlled trials.
Endovascular thrombectomy is a powerful tool to treat large vessel occlusion strokes and multiple trials over the past 5 years have established its safety and efficacy in the treatment of anterior circulation large vessel occlusion strokes up to 24 hours from stroke onset.
In 2015, multiple landmark trials (MR CLEAN, ESCAPE, SWIFT PRIME, REVASCAT, and EXTEND IA) established the superiority of endovascular thrombectomy over medical management for the treatment of anterior circulation large vessel occlusion strokes. Endovascular thrombectomy has a strong treatment effect with a number needed to treat ranging from 3 to 10. These trials selected patients based on occlusion location (proximal anterior occlusion: internal carotid or middle cerebral artery), time from stroke onset (early window: up to 6-12 hours), and acceptable infarct burden (Alberta Stroke Program Early CT Score ASPECTS ≥6 or infarct volume <50 mL). In 2017, the DAWN and DEFUSE-3 trials successfully extended the time window up to 24 hours in appropriately selected patients. Societal and national thrombectomy guidelines have incorporated these findings and offer Class 1A recommendation to a subset of well-selected patients. Thrombectomy ineligible stroke subpopulations are being studied in ongoing randomized controlled trials. These trials, built on encouraging data from pooled analysis of early trials (HERMES collaboration) and emerging retrospective data, are studying large vessel occlusion strokes with mild deficits (National Institutes of Health Stroke Scale <6) and large infarct burden (core volume >70 mL).
Mechanical thrombectomy (MT)-mediated endovascular recanalization has dramatically transformed treatment and outcomes after acute ischemic stroke caused by a large vessel occlusion (LVO). Current ...guidelines recommend MT up to 24 hours from stroke onset in carefully selected patients based on favorable clinical and imaging parameters. Despite optimal patient selection and low complication rates with current recanalization technology, approximately 1 in 2 patients with LVO stroke do not achieve functional independence at 3 months. This ceiling effect of MT efficacy may be explained by ischemic core expansion into the ischemic penumbra before recanalization and neuronal loss occurring after recanalization. Factors affecting the efficacy of MT, or the degree of irreversible injury, include time from symptom onset to recanalization, collateral circulation status, and differences in neuronal vulnerability. The purpose of this brief review is to discuss potential targets for neuroprotection, present and future potential pharmacologic and nonpharmacologic agents, and the data available in the literature.
In experimental ischemia models, several authors reported that pharmacologic and nonpharmacologic agents are able to slow the progression of ischemic core expansion. However, in the era of unsuccessful recanalization of the occluded artery, several neuroprotective agents that were promising in the preclinical stage failed phase II/III clinical trials.
Providing neuroprotection before and after recanalization of an LVO may play an important role in improving outcomes in the era of MT. Neuroprotection is classically defined as a process that results in the salvage, recovery, or regeneration of neuronal (and other supporting CNS cell) structure or function. The advent of successful recanalization of acute LVO by MT in the majority of patients may spur the growth of effective neuroprotection.
Background and Purpose- Fast and slow progressors of infarct growth due to anterior circulation large vessel occlusion are commonly observed in clinical practice. We aimed to estimate the prevalence ...and temporal distribution of fast and slow progressors among anterior circulation large vessel occlusion patients diagnosed within 24 hours of stroke onset. Methods- Single-center retrospective study of all patients with anterior circulation large vessel occlusion who underwent baseline computed tomographic perfusion or magnetic resonance imaging within 24 hours of stroke onset. Prevalence was determined for fast progressors (ischemic core >70 mL, <6 hours of stroke onset) and slow progressors (ischemic core ≤30 mL, >6-24 hours of stroke onset). Results- One hundred eighty-five patients were included. The median time interval from stroke onset to baseline core imaging was 7.6 hours (interquartile range, 3.9-13.2), and median core volume was 17 mL (range, 0-405). Patients had core volume ≤70 mL in 72% of cases in the overall cohort. The prevalence of fast progressors was 25% (95% CI, 17%-37%) and reached 40% (95% CI, 24%-59%) between 3 and 4.5 hours after stroke onset. The prevalence of slow progressors was 55% (95% CI, 46%-64%) and was similar across time intervals beyond 6 hours after stroke onset. Conclusions- Most anterior circulation large vessel occlusion patients had small-to-moderate ischemic core volume, irrespective of early or delayed presentation within 24 hours of stroke onset. Fast progressors were highly prevalent between 3 and 4.5 hours after stroke onset.
Thrombectomy 24 hours after stroke: beyond DAWN Desai, Shashvat M; Haussen, Diogo C; Aghaebrahim, Amin ...
Journal of neurointerventional surgery,
11/2018, Letnik:
10, Številka:
11
Journal Article
Recenzirano
Odprti dostop
The results of the DAWN trial support the benefit of thrombectomy in patients with anterior circulation large vessel occlusion (LVO) acute stroke presenting within 6-24 hours from time last known ...well (TLKW). We sought to evaluate the characteristics and outcomes of patients who met DAWN criteria but underwent thrombectomy beyond 24 hours of TLKW.
A retrospective review of endovascular thrombectomy databases at three comprehensive stroke centers was performed to identify all patients who received thrombectomy beyond 24 hours of TLKW and otherwise met the DAWN criteria. Baseline characteristics, efficacy, and safety outcomes were compared with patients in the DAWN trial intervention arm.
Twenty-one patients met the inclusion criteria. Rates of successful reperfusion (mTICI2b-3: 81% vs 84%, P=0.72), 90-day functional independence (modified Rankin Scale score 0-2, 43% vs 48%, P=0.68), and symptomatic intracranial hemorrhage (5% vs 6%, P=0.87) were comparable across the two groups.
Thrombectomy appears to be safe and feasible in patients with acute ischemic stroke due to LVO meeting all DAWN trial criteria but treated beyond 24 hours of TLKW with outcomes comparable to patients in the DAWN trial intervention arm. Further studies are warranted to validate these findings.
Interventional cardiology produced level 1 evidence recommending radial artery-first for coronary angiography given lower vascular complications. Neuroendovascular surgeons have not widely adopted ...the transradial approach. This prospective, single center, non-inferiority comparative effectiveness study aims to compare the transradial and transfemoral approaches for diagnostic cerebral angiography with respect to efficacy, safety and patient satisfaction.
Consecutive patients presenting for diagnostic cerebral angiography were selected to undergo right radial or femoral access based on date of presentation. Primary outcome was ability to answer the predefined diagnostic goal of the cerebral angiogram using the initial access site and was assessed with a non-inferiority design. Secondary outcomes included technical success per vessel, complications, procedure times and patient satisfaction.
A total of 312 patients were enrolled, 158 and 154 for right radial and femoral access, respectively. The diagnostic goal of the angiogram was achieved in 152 of 154 (99%) patients who underwent attempted femoral access compared with 153 of 158 (97%) patients who underwent radial access, confirming non-inferiority of the transradial approach. Secondary outcomes showed equivalent technical success by vessel, no major complications, and similar frequency of minor complications between the two approaches. In-room time was similar between approaches, though post-procedure recovery room time was significantly shorter for transradial patients. Patient satisfaction results significantly favored the radial approach.
In patients undergoing diagnostic cerebral angiography, transfemoral and transradial access achieve procedural goals with similar effectiveness and safety, though patients strongly prefer the radial approach. Findings support consideration of adopting a radial-first strategy for diagnostic cerebral angiography.
Addressing traumatic brain injury (TBI) heterogeneity is increasingly recognized as essential for therapy translation given the long history of failed clinical trials. We evaluated differential ...effects of a promising treatment (glibenclamide) based on dose, TBI type (patient selection), and imaging endophenotype (outcome selection). Our goal to inform TBI precision medicine is contextually timely given ongoing phase 2/planned phase 3 trials of glibenclamide in brain contusion.
Blinded randomized controlled preclinical trial of glibenclamide on MRI endophenotypes in two established severe TBI models: controlled cortical impact (CCI, isolated brain contusion) and CCI+hemorrhagic shock (HS, clinically common second insult).
Preclinical laboratory.
Adult male C57BL/6J mice (n = 54).
Mice were randomized to naïve, CCI±HS with vehicle/low-dose (20 μg/kg)/high-dose glibenclamide (10 μg/mouse). Seven-day subcutaneous infusions (0.4 μg/hr) were continued.
Serial MRI (3 hr, 6 hr, 24 hr, and 7 d) measured hematoma and edema volumes, T2 relaxation (vasogenic edema), apparent diffusion coefficient (ADC, cellular/cytotoxic edema), and 7-day T1-post gadolinium values (blood-brain-barrier BBB integrity). Linear mixed models assessed temporal changes. Marked heterogeneity was observed between CCI versus CCI+HS in terms of different MRI edema endophenotypes generated (all p < 0.05). Glibenclamide had variable impact. High-dose glibenclamide reduced hematoma volume ~60% after CCI (p = 0.0001) and ~48% after CCI+HS (p = 4.1 × 10-6) versus vehicle. Antiedema benefits were primarily in CCI: high-dose glibenclamide normalized several MRI endophenotypes in ipsilateral cortex (all p < 0.05, hematoma volume, T2, ADC, and T1-post contrast). Acute effects (3 hr) were specific to hematoma (p = 0.001) and cytotoxic edema reduction (p = 0.0045). High-dose glibenclamide reduced hematoma volume after TBI with concomitant HS, but antiedema effects were not robust. Low-dose glibenclamide was not beneficial.
High-dose glibenclamide benefitted hematoma volume, vasogenic edema, cytotoxic edema, and BBB integrity after isolated brain contusion. Hematoma and cytotoxic edema effects were acute; longer treatment windows may be possible for vasogenic edema. Our findings provide new insights to inform interpretation of ongoing trials as well as precision design (dose, sample size estimation, patient selection, outcome selection, and Bayesian analysis) of future TBI trials of glibenclamide.
Sulfonylurea receptor 1 (SUR1) is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) protein superfamily, encoded by Abcc8, and is recognized as a key mediator of central nervous ...system (CNS) cellular swelling via the transient receptor potential melastatin 4 (TRPM4) channel. Discovered approximately 20 years ago, this channel is normally absent in the CNS but is transcriptionally upregulated after CNS injury. A comprehensive review on the pathophysiology and role of SUR1 in the CNS was published in 2012. Since then, the breadth and depth of understanding of the involvement of this channel in secondary injury has undergone exponential growth: SUR1-TRPM4 inhibition has been shown to decrease cerebral edema and hemorrhage progression in multiple preclinical models as well as in early clinical studies across a range of CNS diseases including ischemic stroke, traumatic brain injury, cardiac arrest, subarachnoid hemorrhage, spinal cord injury, intracerebral hemorrhage, multiple sclerosis, encephalitis, neuromalignancies, pain, liver failure, status epilepticus, retinopathies and HIV-associated neurocognitive disorder. Given these substantial developments, combined with the timeliness of ongoing clinical trials of SUR1 inhibition, now, another decade later, we review advances pertaining to SUR1-TRPM4 pathobiology in this spectrum of CNS disease-providing an overview of the journey from patch-clamp experiments to phase III trials.
The therapeutic focus in acute ischemic stroke over the last 2.5 decades has been to balance the benefits of rapid reperfusion therapy with the risks of treatment-related complications. Both ...intravenous thrombolytics and endovascular thrombectomy are proven to substantially improve outcomes in a time-dependent manner. Each minute saved in achieving successful reperfusion grants an additional week of healthy life and may salvage up to 27 million neurons. The current approach to patient triage is inherited from the preendovascular thrombectomy era of stroke care. Current workflow concentrates on stabilization, diagnosis, and decision-making in the emergency department, followed by thrombolysis if eligible and subsequent transfer to the angiography suite as needed for further treatment. Multiple efforts have been directed toward minimizing the time from first medical contact to reperfusion therapy including prehospital triage and intrahospital workflow. Novel approaches for stroke patient triage such as the direct to angio approach, (also referred to as One Stop Management) are currently in development. The concept was initially introduced as several single-center experiences. In this narrative review article, we will consider various definitions of direct to angio and its variants, discuss its rationale, review its safety and efficacy, assess its feasibility, and delineate its limitations. Further, we will address methods to overcome these limitations and the potential impact of emerging data and new technologies on the direct-to-angio approach.
Background
Acute ischemic stroke (AIS) is a major contributor toward healthcare-associated costs and services. Symptomatic intracranial hemorrhage (sICH) and early neurologic decline (END), defined ...as a National Health Institute Stroke Scale score decline of ≥ 4 within 24 h (with or without sICH), remain major concerns when administering intravenous tissue plasminogen activator (IV tPA) despite improved functional neurologic outcomes with its use. Given these risks, current guidelines recommend comprehensive stroke care (most often in an intensive care unit setting) for 24 h posttreatment. However, a number of patients may remain stable after IV tPA and thus not require such intensive resources. We sought to determine causes of END, along with timing and predictors of both sICH and END, to identify patients at lower risk of neurological deterioration and those suitable for earlier transition to a lower level of care.
Methods
This present study analyzed patients with AIS that presented within 4.5 h of being last seen well and received IV tPA. Baseline demographic, clinical, and radiographic findings were collected. Outcomes included END from any cause, parenchymal hemorrhage (PH1 or PH2), sICH, and mortality at 90 days.
Results
A total of 1238 patients with AIS without acute treatment of large vessel occlusion received IV tPA. 9.4% (116) had presence of any degree of ICH on noncontrast computed tomography head and 7.4% (91) experienced associated END. 2.7% (33) of patients experienced sICH, while 6.7% (83) experienced asymptomatic ICH. Of the patients with END, 63.7% did not have ICH. Predictive factors at presentation for END included an older age (72.6 ± 16.1 vs. 69.1 ± 14.8,
p
= 0.03), history of tobacco use (odds ratio OR 2.1 1.1–4.3,
p
= 0.04), and hyperlipidemia (OR 1.7 1.1–2.8,
p
= 0.02), along with the presence of an untreated large vessel occlusion (OR 2.1 1.4–3.1,
p
= 0.02). Most END occurred within a mean time of 242 ± 251 min (4 ± 4 h). Because of the small proportion of patients suffering from sICH (33), predictors could not be determined; however, for patients with any ICH, predictive factors included an older age (74.6 ± 12.4 vs. 68.8 ± 15.1,
p
= 0.001), higher baseline National Health Institute Stroke Scale score (14.6 ± 7.3 vs. 10.8 ± 7.9,
p
= 0.002), and higher baseline glucose levels (155.1 ± 87.5 vs. 140.4 ± 70.5,
p
= 0.04).
Conclusions
In this study, only a small proportion suffered from either sICH and/or END, typically within 12 h of tPA administration. These findings may support earlier deescalation of higher acuity monitoring in clinically stable post-IV tPA patients without large vessel occlusion.
The pandemic caused by the novel coronavirus disease 2019 (COVID-19) has led to an unprecedented paradigm shift in medical care. We sought to evaluate whether the COVID-19 pandemic may have ...contributed to delays in acute stroke management at comprehensive stroke centers.
Pooled clinical data of consecutive adult stroke patients from 14 US comprehensive stroke centers (January 1, 2019, to July 31, 2020) were queried. The rate of thrombolysis for nontransferred patients within the Target: Stroke goal of 60 minutes was compared between patients admitted from March 1, 2019, and July 31, 2019 (pre-COVID-19), and March 1, 2020, to July 31, 2020 (COVID-19). The time from arrival to imaging and treatment with thrombolysis or thrombectomy, as continuous variables, were also assessed.
Of the 2955 patients who met inclusion criteria, 1491 were admitted during the pre-COVID-19 period and 1464 were admitted during COVID-19, 15% of whom underwent intravenous thrombolysis. Patients treated during COVID-19 were at lower odds of receiving thrombolysis within 60 minutes of arrival (odds ratio, 0.61 95% CI, 0.38-0.98;
=0.04), with a median delay in door-to-needle time of 4 minutes (
=0.03). The lower odds of achieving treatment in the Target: Stroke goal persisted after adjustment for all variables associated with earlier treatment (adjusted odds ratio, 0.55 95% CI, 0.35-0.85;
<0.01). The delay in thrombolysis appeared driven by the longer delay from imaging to bolus (median, 29 interquartile range, 18-41 versus 22 interquartile range, 13-37 minutes;
=0.02). There was no significant delay in door-to-groin puncture for patients who underwent thrombectomy (median, 83 interquartile range, 63-133 versus 90 interquartile range, 73-129 minutes;
=0.30). Delays in thrombolysis were observed in the months of June and July.
Evaluation for acute ischemic stroke during the COVID-19 period was associated with a small but significant delay in intravenous thrombolysis but no significant delay in thrombectomy time metrics. Taking steps to reduce delays from imaging to bolus time has the potential to attenuate this collateral effect of the pandemic.
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