Advances in the Management of Stroke: A Panel Discussion

Educational Objectives

The goal of this program is to improve the medical and surgical management of stroke. After hearing and assimilating this program, the clinician will be better able to:

1. Compare the efficacy of tenecteplase and alteplase in patients with large-vessel occlusion.
2. Manage blood pressure in patients with acute ischemic stroke.
3. Identify the most common cause of hemorrhagic stroke in children.
4. Screen for unruptured intracranial aneurysms in patients with rare vascular diseases.
5. Discuss the clinical importance of the Curing Coma Campaign.

Summary

Update on Endovascular Therapy – Dr. Smith

Studies of basilar artery occlusion: a retrospective trial by Li et al (2022) reported better outcomes with endovascular therapy (EVT) than with control; Langezaal et al (2021) — conducted a randomized trial of patients 18 to 80 yr of age using EVT vs medical therapy at 6 to 24 hr; used the posterior circulation Acute Stroke Prognosis Early Computed Tomography score (ASPECTS) and found significant results with good outcomes (Modified Rankin Scores 0-3) in 49% of those treated with EVT vs 24% with medical therapy; the average time of stroke onset to revascularization was 790 min

Tenecteplase (TNK): tissue plasminogen activator (tPA) is a plasminogen activator made by endothelial cells; when it attaches to plasminogen (in the clot or circulation), it creates plasmin; plasmin is an enzyme that rapidly degrades fibrin and makes fibrin split products; TNK is a modified version of human tPA (alteplase) with less affinity for plasminogen activator inhibitors; TNK is more active, has a longer half-life, and is administered as a single bolus; Warach et al (2020) compared TNK with alteplase in randomized trials and found that TNK is better at opening up the large vessels and improving reperfusion scores; in a registry study assessing clinical use, no significant difference was seen between TNK and tPA, although TNK had some increase in functional outcomes (odds ratio of 2) and a trend toward lower mortality; a randomized multicenter trial found no significant difference and no differences in hemorrhage rate; Roaldsen et al (2023) looked at TNK vs best medical therapy in patients with “wake-up stroke” ≤4.5 hr of awakening, and found that TNK had good outcomes that trended better but were not superior; all these studies used TNK at 0.25 mg/kg

Increased dosage of TNK: a phase 3 trial (Kvistad et al [2022]) found that 0.4 mg/kg TNK leads to poorer outcomes and higher hemorrhagic rates; in early TNK trials, 1.2 mg/kg (the dose used for myocardial infarction) was noted to cause hemorrhages, and the dose was reduced to 0.9 mg/kg; a study in Japan showed that 0.6 mg/kg was safer, especially in Asian cohorts; TNK at a dose of 0.25 mg/kg is considered safe to administer for large-vessel stroke at the primary hospital, then the patient is transported to a comprehensive stroke center

Transportation of patients on TNK vs tPA: standard advanced life support (ALS) transportation cannot handle an infusion pump; if tPA is started at the sending hospital, infusion must be complete before transportation (delays EVT by 1 hr); because TNK is given as a bolus, ALS transportation can occur without delay; TNK is used off-label for this indication

EVT for large strokes: retrospective study — assessed patients with large-vessel occlusion (LVO) who underwent EVT at 6 to 24 hr; ASPECTS for the intercirculation starts at 10, with 1 point subtracted for each ischemic region in the middle cerebral artery territory; a lower score indicates a larger stroke; the study reported that, even with APSECTS of 0 (indicating a completely infarcted hemisphere) there was a marginal benefit (≈20% had good outcomes); for patients with ASPECTS ≤5, good outcomes were noted in ≤35%; longitudinal study by Shao et al (2023) — assessed LVO patients treated with thrombectomy; the subset who underwent EVT with a core volume >70 mL on computed tomography (CT) perfusion had almost 4-fold better odds of good neurologic outcomes (ie, Rankin score of 0-2); this patient population would otherwise have been treated with medical therapy alone; Huo et al (2023) — assessed patients with large core volume at <24 hr from when they were last known to be well, with poor ASPECTS (3-4) and high National Institutes of Health Stroke Scale scores; the primary outcome was met, with 1.37 odds of a better outcome; EVT does not appear to harm patients with large core strokes

Blood pressure (BP) control: BEST II trial (2019) — Mistry et al assessed BP control after thrombectomy; when BP was divided into 3 tiers (<140 mm Hg, <160 mm Hg, and <180 mm Hg), there was a trend toward increased harm in the very low BP ranges (≈120 mm Hg systolic); ENCHANTED2/MT trial (2022) — Yang et al found no change in outcomes with actively lowering BP, although there was a slight trend toward poorer outcomes; because evidence is inconclusive, intensive BP-lowering after thrombectomy needs to be personalized

Brain Aneurysms and Endovascular Malformations – Dr. Ko

Aneurysmal subarachnoid hemorrhage (ASH): global prevalence of unruptured intracranial aneurysms (UIA) is ≈1 in 20 to 30 adults; generally benign in individuals with small aneurysms, but it is impossible to predict which individuals will go on to develop a devastating ASH; recent population-based studies show a decline in overall incidence, likely because of decreases in hypertension (HTN) and tobacco usage; mortality rates have also improved with better surgical techniques (eg, clips and coils) and neurointensive care, but morbidity remains high; ≈25% of patients die before they can reach the hospital; of those who survive hospital care, ≈33% have devastating neurologic consequences; incidence is highest in Japan, Finland, and parts of Latin America; women are more affected than men; in the United States, incidence is increasing in some populations; older age is a risk factor; Black patients have more consequences of disease compared with other races and ethnicities

Screening for UIA: imaging often detects incidental UIAs; screening is not usually performed unless there are risk factors; the population at highest risk for a familial form are those with ≥2 first-degree relatives; patients with autosomal dominant polycystic kidney disease should be screened, ie, before kidney transplantation; rare collagen vascular disorders (eg, Ehlers-Danlos type IV, mega-aortic syndrome, Loeys-Dietz syndrome, fibromuscular dysplasia) may feature aneurysms, but more commonly, UIAs are associated with abdominal aortic aneurysms and bicuspid aortic valves, but it is not known whether routine screening affects outcomes; other high-risk groups include individuals with long-standing smoking and HTN risk; screening has implications for patients concerned about their life expectancy and quality of life, and also has insurance implications

Incidental UIAs: evidence is lacking on follow-up for incidental findings; patients with treated UIA who have no recurrence after 2 yr are unlikely to have recurrence after 7 yr; interventionalists and surgeons typically stop monitoring treated aneurysms after a period of time; a meta-analysis by Chandra et al (2022) assessed UIAs ≤10 mm and found that 0.8% to 1.5% ruptured over a 3.7-yr follow-up period; the ideal frequency and duration of scanning is unknown; routine annual screening is not cost-effective in the United States

High-risk groups for screening: include younger patients (men <60 yr of age and women <65 yr of age) and those with patient-specific risk factors, eg, genetic predisposition, smoking, HTN; there is less utility in screening people >70 yr of age; aneurysm risk calculators assess 5-yr rupture risk or cumulative lifetime risk but are not perfect; several calculators that incorporate population and individual characteristics are available and can facilitate conversations about risk and shared decision-making; however, they do not incorporate other comorbidities, distinguish between symptomatic vs nonsymptomatic aneurysms, or include newer radiology findings (ie, growth noted on serial annual monitoring); newer technology, genetic knowledge, and biomarkers might help refine calculators

Balancing natural history of UIA with risks of treatment: most trials assess intervention for ruptured aneurysm; some data show that simple coiling or clipping for asymptomatic UIAs incurs a ≈4% risk for neurologic impairment; newer techniques — balloon-assisted treatments and therapies for wide-neck aneurysms are relatively new; with stent-assisted treatment, there is an additional risk with dual antiplatelet therapy, ie, bleeding complications in addition to procedural complications; flow diverters became available in 2011; new endovascular or endosaccular devices (eg, Woven EndoBridge) are also available; there are no good data that compare devices against each other or that note cost-effectiveness

Medical therapy: not all UIAs require repair; risk factor modification (eg, treating HTN) and decreasing inflammation in vessel walls may be helpful; population studies show that administration of aspirin reduces the risk for rupture; a prospective randomized trial (PROTECT-U) is underway to assess whether 100 mg of aspirin and BP-lowering can make a difference

Arteriovenous malformation (AVM): a rare disease that typically affects young people; primarily associated with the morbidity and mortality of hemorrhage; often incidentally diagnosed during workups for headache and seizure; in the pediatric population, AVM is the most common cause of hemorrhagic stroke; ARUBA trial (2014) — Mohr et al reported that medical management of unruptured AVM is associated with less risk and longer survival compared with interventional therapy (endovascular, surgical, radiation [eg, Gamma Knife]); the risk for hemorrhage in this population was 2.2%; MARS trial (2014) — Kim et al followed patients with unruptured AVM for 10 yr; the study population is globally generalizable; untreated AVM has a higher rate of bleeding over the patient’s lifetime (ie, a higher cumulative incidence); the risk for hemorrhage with treatment increases immediately for the first year, then declines; the survival curves cross at 18 yr of age; the benefit of treatment is observed after 10 yr; counseling for unruptured brain AVM — must be individualized; younger patients may benefit from treatment; genetic predisposition — angiogenesis and genetic factors are associated with the formation of AVM, and inflammation tends to trigger rupture; 50% of somatic mutations in patients with sporadic (nongenetic) AVM are in the KRAS pathway, and the majority are in children; this seems to be associated with AVM formation (not with rupture)

Advances in Neurocritical Care – Dr. Hemphill

Intracerebral hemorrhage (ICH): has a high risk for mortality and morbidity; identifying management strategies has been challenging, although mortality and functional outcomes associated with ICH have been improving with the use of care packages (eg, guidelines); the guidelines are detailed and complicated, describing, eg, decisions on transfer, initial neuroimaging, medical therapy, coagulopathy reversal, surgery, and secondary prevention; the American Heart Association and American Stroke Association guidelines should form the basis for standardized hospital protocols and order sets (level 1 recommendation for patients with spontaneous ICH)

BP management for acute ICH: chronic HTN probably causes nontraumatic ICH in ≈60% of patients; even with other etiologies (eg, amyloid angiopathy, drug abuse, coagulopathy), 90% of patients are admitted to the hospital with acute HTN; the strongest recommendations do not provide a target BP but do state that variability is not favorable; a quick and protocolized approach (from emergency department to intensive care unit) needs to be followed to reach a target BP ≤1 hr

Class 2B recommendations for BP management: for patients with nonextreme HTN, set a target of 130 to 150 mm Hg (ie, a ceiling and a floor) to minimize variability; INTERACT trial (Anderson et al [2008]) — in patients with acute ICH, BP was lowered to a target of 180/140 mm Hg using various medications; the outcome of death or disability was almost statistically significant (3.6% difference); there was a statistically significant shift in overall functional outcome, but no difference in hematoma expansion; INTERACT2 trial (Arima et al [2015]) — conducted in the United States, Japan, China, and Europe; intravenous nicardipine was very effective at lowering BP but tended to overshoot the targets, ie, lowered BP too aggressively; there was no difference in outcome, but there was an increase in renal injury in the group with aggressive BP reduction to the lower threshold

Indications for surgery in patients with ICH: the only class 1 recommendation is for evacuation for cerebellar hemorrhage; STICH trials (Mendelow et al [2013]) — compared policies for early surgery vs conservative treatment for patients with supratentorial lobar ICH; there was 20% to 25% crossover between groups; surgery was delayed in those in the conservative group; the focus is shifting toward minimally invasive surgery

Minimally invasive surgeries: MISTIE III (2019) — in a large clinical trial, Hanley et al placed a catheter into the clot and instilled 1 mg of thrombolytic therapy every 8 hr; they stopped administering tPA when the hematoma volume was <15 mL; mortality improved, but functional outcome did not; in a prespecified analysis, patients in whom the hematoma was removed did better and had less elevated intracranial pressure; surgeon and site experience were associated with better evacuation; for ischemic stroke, the use of better devices, systems of care, practitioners, and patient selection are essential; this is likely the case with minimally invasive surgery for ICH

Prognostication: clinicians often use the current neurologic examination (ie, phenotype), demographics (ie, age, medical comorbidities), anatomy, or modeling (ie, International Mission for Prognosis and Clinical Trials [IMPACT] model for traumatic brain injury or ICH score); care is limited in patients with a poor prognosis who might actually recover; the endotype (ie, underlying mechanism) of coma and impaired consciousness, and the capacity of the brain to recover, are often not considered; using functional MRI in minimally conscious patients months after hospitalization shows that some were aware; among patients who are unresponsive because of different diseases, 1 in 7 have activation (cognitive-motor dissociation) on machine-learning electroencephalography with spoken commands; these individuals are more likely to recover

Curing Coma Campaign: a platform to focus the science of acute disorders of consciousness on identifying and testing therapeutic interventions; promotes recovery of consciousness through early intervention and long-term support across the spectrum of disorders of consciousness; the first Scientific Advisory Council meeting focused on endotyping and biomarkers (eg, neuroimaging) to enable the start of proof-of-concept clinical trials (eg, classification mechanisms, trajectory of recovery, potential therapies); the COME-TOGETHER survey (2022) assessed variability in defining coma because precise numbers are not known; the COMPOSE study will assess incidence and outcomes of coma; standards are being set to standardize research; clinicians should assume a coma is treatable until proven otherwise

Readings

Anderson CS, Huang Y, Wang JG, et al. Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet Neurol. 2008;7(5):391-399. doi:10.1016/S1474-4422(08)70069-3; Arima H, Heeley E, Delcourt C, et al. Optimal achieved blood pressure in acute intracerebral hemorrhage: INTERACT2. Neurology. 2015;84(5):464-471. doi:10.1212/WNL.0000000000001205; Bameri O, Salarzaei M, Parooie F. KRAS/BRAF mutations in brain arteriovenous malformations: A systematic review and meta-analysis. Interv Neuroradiol. 2021;27(4):539-546. doi:10.1177/1591019920982810; Chandra RV, Maingard J, Slater LA, et al. A meta-analysis of rupture risk for intracranial aneurysms 10 mm or less in size selected for conservative management without repair. Front Neurol. 2022;12:743023. Published 2022 Feb 17. doi:10.3389/fneur.2021.743023; de Rooij NK, Linn FH, van der Plas JA, et al. Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends. J Neurol Neurosurg Psychiatry. 2007;78(12):1365-1372. doi:10.1136/jnnp.2007.117655; Hanley DF, Thompson RE, Rosenblum M, et al. Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial [published correction appears in Lancet. 2019 Apr 20;393(10181):1596]. Lancet. 2019;393(10175):1021-1032. doi:10.1016/S0140-6736(19)30195-3; Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998;351(9118):1755-1762. doi:10.1016/s0140-6736(98)04311-6; Huo X, Ma G, Tong X, et al. Trial of endovascular therapy for acute ischemic stroke with large infarct. N Engl J Med. 2023;388(14):1272-1283. doi:10.1056/NEJMoa2213379; Jordan LC, Hillis AE. Hemorrhagic stroke in children. Pediatr Neurol. 2007;36(2):73-80. doi:10.1016/j.pediatrneurol.2006.09.017; Kawano H, Hirano T, Inoue M, et al. Tenecteplase versus alteplase for large vessel occlusion recanalization (T-FLAVOR): Trial protocol [published correction appears in Eur Stroke J. 2023 Mar;8(1):404]. Eur Stroke J. 2022;7(1):71-75. doi:10.1177/23969873211070455; Kim H, Al-Shahi Salman R, McCulloch CE, et al; MARS Coinvestigators. Untreated brain arteriovenous malformation: patient-level meta-analysis of hemorrhage predictors. Neurology. 2014;83(7):590-597. doi:10.1212/WNL.0000000000000688; Kvistad CE, Næss H, Helleberg BH, et al. Tenecteplase versus alteplase for the management of acute ischaemic stroke in Norway (NOR-TEST 2, part A): a phase 3, randomised, open-label, blinded endpoint, non-inferiority trial. Lancet Neurol. 2022;21(6):511-519. doi:10.1016/S1474-4422(22)00124-7; Langezaal LCM, van der Hoeven EJRJ, Mont'Alverne FJA, et al. Endovascular therapy for stroke due to basilar-artery occlusion. N Engl J Med. 2021;384(20):1910-1920. doi:10.1056/NEJMoa2030297; Li C, Wu C, Wu L, et al. Basilar artery occlusion Chinese endovascular trial: protocol for a prospective randomized controlled study. Int J Stroke. 2022;17(6):694-697. doi:10.1177/17474930211040923; Mendelow AD, Gregson BA, Rowan EN, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial [published correction appears in Lancet. 2013 Aug 3;382(9890):396] [published correction appears in Lancet. 2021 Sep 18;398(10305):1042]. Lancet. 2013;382(9890):397-408. doi:10.1016/S0140-6736(13)60986-1; Mistry EA, Sucharew H, Mistry AM, et al. Blood pressure after endovascular therapy for ischemic stroke (BEST): A multicenter prospective cohort study. Stroke. 2019;50(12):3449-3455. doi:10.1161/STROKEAHA.119.026889; Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet. 2014;383(9917):614-621. doi:10.1016/S0140-6736(13)62302-8; O'Connor S, Kim ESh, Brinza E, et al. Systemic connective tissue features in women with fibromuscular dysplasia. Vasc Med. 2015;20(5):454-462. doi:10.1177/1358863X15592192; Roaldsen MB, Eltoft A, Wilsgaard T, et al. Safety and efficacy of tenecteplase in patients with wake-up stroke assessed by non-contrast CT (TWIST): a multicentre, open-label, randomised controlled trial. Lancet Neurol. 2023;22(2):117-126. doi:10.1016/S1474-4422(22)00484-7; Shao Y, Chen X, Wang H, et al. Large mismatch profile predicts rapidly progressing brain edema in acute anterior circulation large vessel occlusion patients undergoing endovascular thrombectomy. Front Neurol. 2023;13:982911. Published 2023 Jan 4. doi:10.3389/fneur.2022.982911; Tanaka K, Yamagami H, Yoshimoto T, et al. Endovascular therapy for acute ischemic stroke in patients with prestroke disability. J Am Heart Assoc. 2021;10(15):e020783. doi:10.1161/JAHA.121.020783; Tanswell P, Modi N, Combs D, et al. Pharmacokinetics and pharmacodynamics of tenecteplase in fibrinolytic therapy of acute myocardial infarction. Clin Pharmacokinet. 2002;41(15):1229-1245. doi:10.2165/00003088-200241150-00001; Warach SJ, Dula AN, Milling TJ Jr. Tenecteplase thrombolysis for acute ischemic stroke. Stroke. 2020;51(11):3440-3451. doi:10.1161/STROKEAHA.120.029749; Yang P, Song L, Zhang Y, et al. 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Disclosures

For this program, the members of the faculty and planning committee reported nothing relevant to disclose. Dr. Smith's lecture includes information about the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Smith, Dr. Ko, and Dr. Hemphill were recorded at The 56th Annual Recent Advances in Neurology, held February 15-17, 2023, in San Francisco, CA, and presented by University of California, San Francisco, School of Medicine. For more information on further CME activities from this presenter, please visit Cme.ucsf.edu. Audio Digest thanks the speakers and the University of California, San Francisco, School of Medicine for their cooperation in the production of this program.

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