2023 Neurocritical Care Updates in Cerebrovascular Disease

RESCUE-Japan LIMIT (Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism-Japan Large Ischemic Core Trial) was the first randomized controlled trial (RCT) suggesting EVT benefit in 203 patients with large ischemic cores (ASPECTS [Alberta Stroke Program Early Computed Tomographic Score] 3–5).¹² While promising, there was no benefit beyond 6 hours or with ASPECTS 0 to 3 in a post hoc secondary analysis (not powered by the initial study) thus raising questions about subgroups applicability.¹³ ANGEL-ASPECT (Study of Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients With a Large Infarct Core)³ and SELECT2 (A Randomized Controlled Trial to Optimize Patient's Selection for Endovascular Treatment in Acute Ischemic Stroke)¹ expanded the time window of EVT benefit for patients with large cores; both were halted early for efficacy.

ANGEL-ASPECT randomized 456 patients in China (ASPECTS, 3–5 or infarct, 70–100 mL) within 24 hours of last known well to either EVT or medical management. The second interim analysis yielded benefit in primary outcome (90-day modified Rankin Scale [mRS] shift). Again, infarcts were moderate, not large. Unlike RESCUE-Japan LIMIT, a greater proportion (>60%) of patients were enrolled beyond 6 hours, and benefit was observed with EVT (odds ratio [OR], 1.55 [95% CI, 1.17–2.0]). There were higher odds of any intracranial hemorrhage (ICH) within 48 hours with EVT (OR, 2.07; P<0.001). Symptomatic hemorrhage and decompressive craniectomy were higher with EVT although this did not meet statistical significance. Edema and hemorrhage may thus be important in the larger core (>70 mL) subgroup. There was no mortality benefit at 90 days potentially reflecting the more moderate infarct volumes.

Similarly, SELECT2—an RCT of 352 patients across North America, Europe, Australia, and New Zealand—included patients with ASPECTS 3 to 5 but a smaller infarct core threshold (≥50 mL). Median infarct volumes were ≈80 mL. Subgroup analysis demonstrated EVT benefit across age, National Institutes of Health Stroke Scale scores, time from last known well, infarct volume (including ≥150 mL), and mismatch ratios. The rate of symptomatic ICH was low (≈1%) in both arms. Early neurological worsening was numerically (not statistically) higher with EVT; these patients had worse 90-day outcome. Although no definitive conclusions can be drawn, these patients may warrant close NCC monitoring and management.

TESLA (Thrombectomy for Emergent Salvage of Large Anterior Circulation Ischemic Stroke) was presented at the 2023 European Stroke Organization Conference as a pragmatic approach trial¹⁴ that used computed tomography (CT)-based infarct volumes (versus advanced imaging) for patient selection and expanded the inclusion threshold to ASPECTS 2 to 5. TESLA narrowly missed its primary end point; however, there were no safety concerns. A recently published meta-analysis of all 4 large core trials demonstrated that while symptomatic ICH was greater with EVT, clinical/outcome benefit persisted.²

Currently, the large core trials affirm that patients with moderate-large core (≈50–100 cm³) likely benefit from EVT. There remain unanswered questions about differences in hemorrhage rates between the studies and etiology of early neurological deterioration without hemorrhagic transformation (SELECT2). The lack of mortality benefit may reflect the moderate-large versus truly large core infarct volumes tested. Questions of “is there an infarct size that is ‘too big to treat’ with EVT?,” or “is noncontrast CT sufficient to triage patients?” remain. Results from both TESLA and LASTE (Large Stroke Therapy Evaluation; NCT03811769)¹⁵ will be informative and potentially revolutionize the EVT landscape once again, although there remains debate about this.

The relationship between BP and acute ischemic stroke, particularly after EVT, remains complex. An individual patient data analysis from 7 RCTs demonstrated a nonlinear association between admission systolic BP (SBP) and functional outcome, with an inflection point at 140 mm Hg.⁴ Patients with ≥140 mm Hg were associated with unfavorable outcome. There was no interaction with EVT; the authors note that elevated SBP should not dictate thrombectomy treatment decisions.

Previously, we discussed an individual patient data meta-analysis where higher mean SBPs post-EVT were associated with unfavorable outcomes.^16,17 ENCHANTED2/MT ([Second Enhanced Control of Hypertension and Thrombectomy Stroke Study] a multicenter open-label blinded RCT) is now completed with 821 patients randomized to more (<120 mm Hg) versus less intensive (140–180 mm Hg) SBP control for 72 hours.⁵ Again, odds of worse primary outcome (ordinal mRS analysis) were greater with intensive treatment (OR, 1.37 [95% CI, 1.07–1.76]). Most patients achieved their target SBPs and Thrombolysis in Cerebral Infarction (TICI)-3 recanalization (83%–84%); thus, even with open large vessels, the risk of compromising the cerebral microcirculation may outweigh concerns of reperfusion injury. Caution against generalized BP reduction post-EVT and support for an individualized approach was supported by OPTIMAL-BP (Outcome in Patients Treated With Intraarterial Thrombectomy - Optimal Blood Pressure Control) and BEST-II (Blood Pressure After Endovascular Stroke Treatment II) presented at the 2023 European Stroke Organization Conference and International Stroke Conference. CRISIS-1 ([Intensive Control of Blood Pressure in Acute Ischemic Stroke After Endovascular Therapy on Clinical Outcome], NCT04775147; SBP, <120 versus 140 mm Hg) and HOPE ([Hemodynamic Optimization of Cerebral Perfusion After Endovascular Therapy in Patients With Acute Ischemic Stroke], NCT04892511; standard of care versus SBP, 140–160 mm Hg if TICI-2b versus SBP <140 mm Hg if TICI-2c/3) will be informative, particularly with the latter accounting for the potential importance of recanalization extent in subsequent hemodynamic requirements.

ENRICH (Efficacy and Safety of Early Minimally Invasive Removal of Intracerebral Hemorrhage) is the first surgical trial to suggest functional benefit of minimally invasive clot removal in ICH.¹⁸ Presented at the 2023 American Association of Neurological Surgeons conference, it is a Bayesian adaptive comparative effectiveness study that randomized patients with anterior basal ganglia (n=92) or lobar (n=208) ICH to minimally invasive trans-sulcal parafascicular surgery±guideline-based medical management within 24 hours of last known normal. The study enriched for lobar ICH when the stopping criterion for anterior basal ganglia ICH was met. The primary outcome (utility-weighted mRS) at 6 months demonstrated treatment benefit. Results (pending publication) suggest a promising therapy for improving patient outcomes at least in supratentorial lobar ICH.

INTERACT-3 (Third Intensive Care Bundle With Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial; international multicenter blinded RCT) in 7036 patients from predominantly low- and middle-income countries demonstrated benefit of a goal-directed care bundle that incorporated protocols for BP lowering, hyperglycemia, pyrexia, and anticoagulation.¹⁹ Most patients (≈82%) had deep ICH. The reduced odds of unfavorable functional outcome (OR, 0.86 [95% CI, 0.76–0.97]) were consistent across multiple sensitivity analyses.

Notwithstanding the benefit of goal-directed care bundles, death and disability was high in INTERACT-3 despite a high median presenting the Glasgow Coma Scale (score, 9). Neuroprognostication after ICH remains challenging and will evolve as treatments advance. A post hoc analysis of pooled individual data in severe ICH and IVH survivors (from CLEAR-III [Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III] and MISTIE-III [Minimally Invasive Surgery Plus Rt-PA for ICH Evacuation Phase III]) evaluated 1-year recovery trajectories and determined that ≈43% of patients with initially poor outcomes (30-day mRS score, 4–5) recovered to good outcome by 1 year (mRS score, 0–3).²⁰ By 1 year, 64.6% of these patients had returned home. Including granular data like preexisting conditions, hospital events, and response to therapy improved model discrimination (and identifies targets to improve long-term recovery). The study reminds us to sidestep self-fulfilling prophecies and allow for longer evaluation periods and nuanced discussions before neuroprognostication.

The jury remains out on seizure prophylaxis after ICH. PEACH (Prevention of Epileptic Seizures in Acute Intracerebral Haemorrhage) randomized 50 patients to 500 mg levetiracetam every 12 hours versus placebo for 6 weeks.²¹ Only 48% of the recruitment target was reached, and the data were not powered for efficacy. Three of 19 patients in the levetiracetam group (16%) had electrographic seizures versus 10 of 23 in placebo (43%; OR, 0.16; P=0.043). Most patients had deep ICH, small hematoma volumes, and were predominantly mild (median Glasgow Coma Scale score, 15; interquartile range, 14–15) potentially decreasing the generalizability. The impact on clinical seizures and outcomes remains to be determined in future work with larger trials.

An unexpected overlap between Alzheimer disease and cerebrovascular NCC has emerged with the approval of several antiamyloid immunotherapies associated with ARIA. Although ARIA-edema/effusion and ARIA-hemorrhage have been reported in 6.5% to 80%, the incidence/risk varies. There is higher risk with specific immunotherapies, dose dependence, ApoE-ε4 haplotype, anticoagulation use, and baseline characteristics (preexisting cerebral amyloid angiopathy). Most cases remain mildly/asymptomatic; however, there have been rare reports of severe and fatal brain swelling and hemorrhage.^8,9,22–27 For treatment, cessation of immunotherapy has been combined with high-dose corticosteroids, serial imaging, and anticonvulsants if needed.^23,25 ARIA’s putative pathophysiology involves mobilization of Aβ deposits in the vasculature when they are bound by anti-Aβ antibodies, thus disrupting vascular integrity.²⁴ ARIA-edema/effusion and ARIA-hemorrhage frequently co-occur, suggesting mechanistic overlap; this continuum has been proposed previously as it relates to the sulfonylurea receptor-1—transient receptor potential cation subfamily M member-4 channel.^28,29 Understanding the relationship between Aβ plaques, ApoE-ε4, and other channels implicated in cerebral edema may guide development of targeted molecular therapy across several diseases in NCC.

The 2023 Neurocritical Care Society and AHA guidelines for ASAH presented several updates after an ≈10-year hiatus.^10,11 Here, we highlight some differences between guidelines bookending the past decade. The Neurocritical Care Society guidelines no longer target a specific BP before aneurysm treatment. Both societies recommend against statins, endothelin receptor antagonists, and antifibrinolytic therapy. The Neurocritical Care Society guidelines noted insufficient data to recommend for or against BP and cardiac output augmentation (including milrinone), triggers for interventional procedures, mineralocorticoid therapy, or a transfusion threshold >7 g/dL. AHA guidelines present similar data and delineate the lower class of recommendation and level of evidence while suggesting it is reasonable to augment SBP, cardiac output, and intra-arterial vasodilator therapy. AHA noted harm with phenytoin for seizure prevention/prophylaxis and the lack of benefit of antiseizure medications beyond 7 days in patients with seizures but without prior epilepsy. AHA guidelines emphasized the importance of health care systems/access, critical care bundles, trained nurses, and multidisciplinary teams. Core treatments like oral nimodipine and avoidance of hypervolemia were unaltered.

EARLYDRAIN (Outcome After Early Lumbar CSF-Drainage in Aneurysmal SAH) randomized 307 patients from 19 centers to standard care versus an additional lumbar drain (LD) after ASAH.³⁰ There was a reduced risk ratio of unfavorable outcome in the LD group (risk ratio, 0.73 [95% CI, 0.52–0.98]) and fewer secondary infarctions at discharge (risk ratio, 0.71 [95% CI, 0.49–0.99]). It is challenging to extrapolate these data to current practice where patients receive either LD or external ventricular drain (EVD) but rarely both; in EARLYDRAIN, 70.8% of patients in the LD group and 76.9% of patients in the standard group also had EVD. Although adjusted statistically, a greater proportion of patients in the LD group had a lower ASAH grade. Despite some of these challenges, there was marked color difference in EVD versus LD CSF when used simultaneously, supporting the hypothesis of erythrocyte sedimentation by weight and potentially easier removal by LD. It was reassuring that only 1 patient developed an increasing gradient of >5 mm Hg in intracranial pressure from EVD versus LD. While this RCT does not answer the question of whether LD alone is superior to EVD after ASAH (since majority of patients in the LD group received both), it appeared safe in conjunction with EVDs. An adequately powered RCT of LD in ASAH is needed. Importantly, these data are hypothesis generating regarding potential mechanisms of reduced cerebral ischemia and improved outcome in ASAH.