Management of Large-Core Infarct Ischemic Stroke

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1		Ibrahim Migdady	--	4274	2023-10-24 17:15:37	\|
2	Reference format revised.	Lindsay Dong	Meta information modification	4274	2023-10-25 03:27:35	\|

This entry is adapted from the peer-reviewed paper 10.3390/jcm12206641

The volume of infarcted tissue in patients with ischemic stroke is consistently associated with increased morbidity and mortality. Initial studies of endovascular thrombectomy for large-vessel occlusion excluded patients with established large-core infarcts, even when large volumes of salvageable brain tissue were present, due to the high risk of hemorrhagic transformation and reperfusion injury.

large-core infarcts malignant edema large-vessel occlusion endovascular therapy

1. Introduction

In the past two decades, the treatment of acute ischemic stroke has witnessed significant progress, mainly driven by the widespread use of recombinant intravenous tissue-plasminogen activator (tPA), the adoption of endovascular therapy (EVT), and advancements in the subacute-to-chronic phases of care. These developments have had a profound impact on patient outcomes, improving survival rates and reducing long-term morbidity. Consequently, there is a growing need for personalized approaches to acute and post-acute treatment in the hospital setting.

It is estimated that one-fourth of patients with large-vessel occlusion (LVO) strokes present with established large-core infarcts (LCI) ^[1]. Traditionally, patients with LCI were excluded from tPA and endovascular therapy trials due to concerns regarding the risks of hemorrhagic conversion, reperfusion injury, and the perceived limited benefits when a substantial portion of the brain had already experienced infarction. As a result, the primary focus of treatment for this patient subgroup has been on mitigating secondary injuries arising from cerebral edema, increased intracranial pressure, hemorrhagic conversion, and other in-hospital complications. Specialized neurocritical care has played a pivotal role in managing these patients, particularly in cases of complete middle-cerebral artery (MCA) infarcts, where early decompressive hemicraniectomy (DHC) demonstrates improved survival rates and functional outcomes ^[2]. Other commonly used management strategies for patients with LCI encompass meticulous blood pressure control, implementation of neuroprotective measures, identification and treatment of seizures, optimization of cerebral perfusion, support for collateral circulation of tissue-at-risk, and prevention of stroke recurrence.

2. Definition of Large-Core Infarct Ischemic Stroke

The volume of infarcted tissue can be measured on computed tomography (CT), CT-perfusion (CTP), magnetic resonance diffusion weighted imaging (MRI-DWI) or apparent-diffusion coefficient sequences (ADC) by applying the ABC/2 method ^[3], or through automated, commercially available CT and MRI analysis software ^[4]. The Alberta Stroke Program Early CT Score (ASPECTS), a score from 0 to 10 inversely correlating with the severity of MCA strokes, is also widely utilized, with ASPECTS < 6 regarded as an LCI. However, due to low inter-rater agreement, ASPECTS is increasingly being replaced by quantitative measurement of infarcted brain tissue using CT or MRI.

There is no agreed-upon definition of what constitutes an LCI; however, a strong relationship between initial infarct volumes and outcome has been well established. The cut-offs for the minimal infarct volume that constitutes a large infarct are derived from studies evaluating the impact of initial or final infarct volumes on clinical outcomes; the most common cut-off used in clinical trials ranges from 50 to 70 mL of infarcted brain tissue ^[5]^[6]. For example, in the pivotal DEFUSE-3 trial of thrombectomy for stroke within 6–16 h, patients with core infarct volume (measured on MRI-DWI) > 70 mL were excluded because prior studies had shown that initial MRI-DWI volume of infarcted tissue ≥ 70 mL results in poor clinical outcomes regardless of recanalization status ^[7].

3. Thrombolysis for Large-Core Ischemic Stroke

Patients with LCI have been historically excluded from the most pivotal trials of intravenous tPA for acute stroke treatment within 4.5 h of symptom onset. In the first trial to establish efficacy of tPA in acute ischemic stroke (NINDS trial 1995), initial stroke volumes were not assessed or used in the inclusion criteria ^[8]. The first European Cooperative Acute Stroke Study (ECASS 1) trial was the first to establish the improved safety and efficacy of tPA when given to patients without extended infarcts on initial CT ^[9]. In the subsequent ECASS trials, patients were excluded from enrollment if they presented with severe stroke, defined as a National Institutes of Health Stroke Scale (NIHSS) score >25 or a stroke involving >1/3 of the MCA territory on initial CT due to a concern for increased risk of symptomatic intracerebral hemorrhage (sICH) ^[10].

Because patients with LCI are systematically excluded from receiving tPA, substantial limitations in the literature pertaining to the safety and efficacy of IV tPA in LCI exist, and the exact infarct volume that increases risk of hemorrhagic conversion after IV tPA has not been thoroughly studied in randomized clinical trials and has only been evaluated in underpowered, retrospective studies. Recent studies have evaluated the safety of tPA in the era of EVT. In a retrospective analysis of 398 patients enrolled in the Stroke Thrombectomy Aneurysm Registry (STAR) who had baseline ASPECTS ≤ 5, LVO, and underwent EVT, there was no difference in the rates of symptomatic intracerebral hemorrhage (sICH) between patients who received IV tPA and those who did not (13.1% vs. 16.9%, p = 0.306) ^[11].

4. Endovascular Thrombectomy for Large-Core Ischemic Stroke

Patients presenting with established LCI represent a management challenge. Despite the potential for improvement in disability, serious concerns exist regarding the futility of recanalization when there is no salvageable brain tissue and there is risk of reperfusion injury, which can lead to sICH and potentially worsened outcomes ^[12]. This is especially true in patients who present in the late window of acute ischemic stroke.

In 2015, five pivotal trials demonstrated efficacy of EVT for patients presenting with anterior-circulation LVO (MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND IA) ^[13]^[14]^[15]^[16]^[17]. In all of these trials, there was planned exclusion or unplanned under-representation of patients presenting with established LCI on initial imaging, with volume assessment most often relying on non-perfusion imaging or ASPECTS. For example, in MR-CLEAN, the trial allowed inclusion of patients with low ASPECTS; however, only 28 patients had a baseline ASPECTS 0–4, and the subgroup analysis was underpowered to detect significant difference in outcome (adjusted common OR, 1.09 [95% CI, 0.14 to 8.46]) ^[13]. In ESCAPE, patients with initial ASPECTS < 6 were excluded ^[14]. In REVASCAT, patients with ASPECTS < 7 on initial CT or <6 on initial DWI-MRI were excluded ^[15]. In SWIFT-PRIME, patients were excluded if there was involvement of >1/3 of the MCA territory on initial CT or MRI, if ASPECTS < 6 or if infarct volume in other territories was >100 cc ^[16]. In ESCAPE-IA, patients with ischemic core > 70 mL on CTP were excluded.

The rationale for exclusion of patients with LCI from EVT trials was subsequently challenged by several observational studies showing the potential benefit and low risk of harm in carefully selected patients. In a pre-specified subgroup analysis of SELECT ^[1], a multicenter, observational prospective study of imaging modalities used to select for anterior circulation EVT, of 105 patients with large ischemic core (defined as ASPECTS of ≤5 on non-contrast CT or volume of ≥50 mL), 31% of those who were treated with EVT achieved functional independence (90-day mRS 0–2) compared to 14% of those treated with medical management only (OR, 3.27 [95% CI, 1.11–9.62]; p = 0.03). In addition, EVT was associated with less infarct growth (44 vs. 98 mL; p = 0.006) and smaller final infarct volume (97 vs. 190 mL; p = 0.001) compared to medical management alone. Notably, every hour of treatment delay was associated with a 40% reduction in the odds of functional independence. There was a numerically higher but not statistically significantly different rate of sICH with EVT (13% vs. 7% p = 0.51), but no difference in neurological worsening at 24 h or mortality at 90 days. As expected, patients with larger initial infarct volumes had lower odds of functional independence; the odds of a good outcome declined by 42% for each 10 mL increase in stroke volume on CTP. Only 10 patients with EVT had infarct volumes >100 mL, none of whom achieved good functional outcomes ^[1].

Subsequently, three randomized control trials evaluated EVT for LCI. A trial conducted in Japan was among the first to enroll patients with LCI ^[18]. In the RESCUE-Japan LIMIT trial, Yoshimura et al. randomized 203 patients presenting with LCI (defined as ASPECTS 3–5 on CT or DWI-MRI) within 6 h of stroke onset; 101 received EVT plus medical care and 102 received medical care alone. EVT resulted in more than double the odds of good functional outcome, defined as mRS 0–3 (31% vs. 12.7%). The trial also showed similar rates of sICH within 48 h but higher rates of any intracranial hemorrhage in the EVT group.

Subsequently, the SELECT-2 trial was designed and recently completed ^[19]. SELECT-2 was a randomized, open-label international clinical trial that randomized patients with LCI (defined as ASPECTS 3-5 on non-contrast CT or ≥50 mL on CTP or DWI-MRI) to EVT plus medical care vs. medical care alone. The trial was stopped early after enrolling 352 patients (178 to EVT plus medical care and 174 to medical care only) due to efficacy. Patients in the EVT arm were significantly more likely to shift their 90-day mRS towards better outcomes and had significantly higher rates of functional independence (relative risk 2.97); the rates of sICH in the two groups were very low and there was no difference in mortality.

At the same time as the SELECT-2 trial was published, the ANGEL-ASPECT trial was completed in China ^[20], which randomized 456 patients presenting with LCI > 6 h from onset (defined as ASPECTS 3-5 on non-contrast CT or infarct volume 70–100 mL on DWI-MRI). The trial was stopped early due to efficacy; EVT resulted in a significant shift of the mRS towards better outcomes. The rate of any ICH was significantly higher in the EVT group (49.1% vs. 17.3%); however, there was no significant difference in the rate of sICH. The rate of sICH was numerically higher for the EVT group (6.1% vs. 2.07%). There were no significant differences in rates of hemicraniectomy or death.

5. Neurocritical Management of Large-Core Ischemic Strokes

5.1. Blood Pressure

Under normal circumstances, the resistance imparted by cerebral arterioles is the main determinant of local cerebral blood flow. In a process known as cerebral autoregulation, these arterioles modulate their smooth muscle tone in response to upstream blood pressure and local metabolic rate ^[21]. Ischemia leads to appropriate dilatation of cerebral arterioles. At the point of maximal arteriolar dilation, cerebral blood flow becomes heavily reliant on systemic arterial blood pressure, such that a minimal reduction in cerebral perfusion pressure can accelerate neuronal loss. This concept forms the basis for the approach of permissive hypertension in patients presenting with acute ischemic stroke before recanalization. With prolonged or severe ischemia, the arterioles are injured, which results in impairment of autoregulation. If recanalization occurs, this may increase the risk of reperfusion injury.

Several prior studies have suggested a U- or J-shaped relationship between blood pressure and clinical outcomes after ischemic stroke, indicating that both high and low blood pressures after stroke are associated with worsened outcomes. In an analysis of >17,000 patients enrolled in the International Stroke Trial (IST) with confirmed ischemic strokes, early death increased by 17.9% for every 10 mm Hg below a systolic blood pressure (SBP) of 150 mm Hg and by 3.8% for every 10 mm Hg above 150 mm Hg ^[22].

Therefore, it is logical to conclude that the degree of recanalization matters when deciding optimal blood pressure goals after recanalization. However, the exact blood pressure goal remains much debated. Evidently, blood pressure has been shown to spontaneously decrease more significantly and earlier in patients with successful recanalization than in those with unsuccessful recanalization ^[23]. In a post-hoc analysis of 3631 stroke patients treated with EVT and enrolled in the SITS-TBYR registry ^[24], higher SBP in the first 24 h in patients with successful recanalization (mTICI 2b-3) was independently associated with less functional independence (defined as mRS 0–2 at 3 months), more sICH, and mortality.

A post-hoc analysis of eight MR-CLEAN registry sites showed that higher maximum systolic pressures within 6 h following EVT was associated with worse functional outcome (adjusted common OR per 10 mm Hg increment, 0.93, [95% CI 0.88–0.98]) and a higher rate of sICH (adjusted OR, 1.17, [95% CI 1.02–1.36]). Importantly, the association between minimum SBP and functional outcome was non-linear with an inflection point at 124 mm Hg; rates of minimum SBP lower and higher than the inflection point were associated with worse functional outcomes ^[25]. While several studies confirmed the concept that higher post-EVT blood pressures are associated with worsened outcomes, others challenged it. The recent BP-TARGET trial showed that intensive SBP lowering to a range of 100–129 mm Hg within 1 h post-EVT did not result in a significant reduction in sICH at 24–36 h compared to a standard SBP target of 130–185 mm Hg; however, the study was not sufficiently powered to detect differences in functional outcome ^[26].

More recently, two RCTs demonstrated the lack of benefit in intensive BP lowering after successful EVT and the possibility of harm. BEST-II was an open-label, phase 2, futility-design RCT which aimed to determine whether lower SBP targets after successful EVT (with goals of <140 mm Hg or <160 mm Hg) compared with a higher target of ≤180 mm Hg met pre-specified criteria for futility ^[27]. Primary outcomes included infarct volume at 36 h and utility-weighted mRS at 90 days. The final infarct volumes suggested a trend toward benefit in the lower SBP target group; however, this may have been mediated by a lower baseline infarct volume in the group targeting SBP < 140 mm Hg. The point estimate of treatment effect on the utility-weighted mRS was in the direction of harm, with a 0.0019 reduction in the utility-weighted mRS score for each mm Hg reduction in the SBP target; p-value for futility was 0.93. Although the criteria for futility were not met, the trial suggested a low probability of benefit from lower SBP targets after endovascular therapy if tested in a future larger trial.

Unfortunately, the majority of the studies discussed above did not analyze the effect of the final infarct volume on blood pressure goal after EVT. In patients with LCI without EVT or tPA, acute blood pressure lowering is typically avoided for the first few days unless it is greatly elevated (>220/120), while patients who receive tPA are maintained below 180/105 for the first 24 h ^[28]. Achieving these targets typically requires a temporary discontinuation of home antihypertensive regimens, followed by their re-initiation 24–48 h after stroke onset. Patients with certain comorbid conditions such as myocardial infarction, heart failure, and aortic dissection will require lower blood pressure targets.

Hypotension is uncommon at the time of stroke and typically suggests the presence of an underlying medical condition. It is crucial to avoid hypotension and promptly correct it, as low blood pressure is also linked to an unfavorable outcome ^[22]^[25]. On occasion, augmenting blood pressure in carefully selected patients with vessel occlusions and otherwise normal blood pressure is attempted in order to enhance cerebral perfusion through collateral circulation or a partially occluded vessel; however, this practice is controversial, it has not been proven in clinical trials, it may be associated with increased cerebral edema and myocardial injury, and there is limited data on the chronic effects of augmented perfusion ^[29].

5.2. Hemorrhagic Transformation

Hemorrhagic transformation (HT) is one of the most feared complications of acute ischemic stroke due to the associated increased risk of morbidity and mortality, typically occurring within 2 weeks of stroke onset. Ischemic injury leads to disruption of the blood–brain barrier. HT is commonly classified radiographically into hemorrhagic infarction (HI) or parenchymal hematoma (PH) based on CT appearance, in a widely used classification system that was first introduced by the ECASS investigators ^[30]. HI is characterized by CT evidence of scattered distribution of areas of high attenuation (i.e., petechial hemorrhages) at the infarct margin (HI1) or throughout the infarct without mass effect (HI2). PH is defined as a homogeneous region of circumscribed high attenuation (i.e., parenchymal hematoma) involving either ≤ 30% if the infarcted area (PH1) or >30% with mass effect (PH2) ^[31].

Due to concerns regarding inter-rater reliability, the absence of reporting on other types of HT (including subarachnoid hemorrhage, intraventricular hemorrhage, and remote parenchymal hemorrhage), the lack of clinical criteria, and the absence of patients who underwent EVT in the original ECASS trials, alternative classification systems have been introduced that aim to differentiate clinically significant HT from purely radiographic findings and also take into account the impact of EVT. One such classification system is the Heidelberg Bleeding Classification ^[32], in which sICH is defined as a new intracranial hemorrhage detected on brain imaging and associated with neurologic deterioration (defined as an increase ≥ 4 in the total NIHSS or ≥2 points in one NIHSS subcategory) ^[32].

Risk factors for post-tPA sICH include older age, greater stroke severity, hyperglycemia, hypertension, heart failure, kidney disease, atrial fibrillation, use of antiplatelet and anticoagulant agents, and white matter changes on brain imaging, among others ^[33]. While there are several sICH prediction scores available, they should not be utilized to justify withholding thrombolytic therapy ^[34]. It is important to consider that patients with the highest predicted risk of sICH are also the most likely to have poor outcomes if thrombolytic therapy is not administered.

Close neurologic monitoring and early diagnosis of HT is important to prevent further complications. Therefore, serial neurological examinations in a neurocritical care unit or acute stroke unit are recommended, and emergent brain imaging (CT) in the event of new headaches, nausea, vomiting, or neurological deterioration, especially in the first 24 h after tPA, is critical for early recognition ^[28]^[34]^[35]. When symptomatic HT occurs within 24 h of tPA (or in the setting of hypofibrinogenemia), reversal of tPA is warranted. As soon as sICH is identified, serum fibrinogen level should be checked, followed by empiric administration of 10 units of cryoprecipitate.

5.3. Malignant Cerebral Edema

5.3.1. Diagnosis and Monitoring

Malignant cerebral edema (MCE) is characterized by accumulation of cytotoxic edema which leads to progressive clinical deterioration. Without treatment, it imparts a very high risk of herniation and death. Most often, this develops after large infarcts in the MCA territory (equivalent to ≥1/2–2/3). Infarctions from MCA branch occlusions typically do not result in MCE or clinically significant mass effect necessitating DHC ^[36].

By definition, any patient with an LCI might be at risk for MCE, which occurs in 10–78% of patients with MCA infarction ^[37], but could also occur in other territorial infarcts ^[38]. Established risk factors for MCE include younger age, larger infarct volume (≥1/2 MCA territory), higher admission NIHSS, poor collateral flow, midline shift >3.7–5 mm in the first 24–48 h and unsuccessful recanalization with tPA or EVT ^[39]^[40]^[41]^[42].

5.3.2. Management of MCE

The management of MCE is tailored towards the prevention of secondary brain injury due to tissue displacement from mass effect. Several medical interventions are often attempted in a deteriorating patient with MCE; however, none have been systematically shown to improve neurological outcomes. These interventions include general ICP-lowering measures, such as head of bed elevation, transient hyperventilation, cerebrospinal fluid diversion, osmotic therapy, and sedation ^[43].

Hyperosmolar therapy is the mainstay of medical therapy in patients with cerebral edema, including those with MCE ^[43]. Mannitol and hypertonic saline are the most commonly used agents, which exert their effect by creating an osmotic gradient to move water from the cerebral interstitial tissue to the cerebral vasculature. This requires an intact blood–brain barrier (BBB), and thus hyperosmolar therapy predominantly reduces the volume of normal, uninfarcted tissue ^[44]^[45]. Although both are effective at acutely reducing ICP, neither has been shown to improve functional outcomes or mortality after stroke ^[46]^[47]^[48]^[49].

Several randomized clinical trials have evaluated the efficacy of DHC compared to maximal medical therapy in patients with MCE or large, space-occupying hemispheric infarction ^[2]. These include DECIMAL (2007) ^[50], DESTINY (2007) ^[51], HAMLET (2009) ^[52], Slezins et al. (2012) ^[53], Zhao et al. (2012) ^[54], HeADDFIRST (2014) ^[55], DESTINY II (2014) ^[56], and HeMMI (2015) ^[57]. These trials varied in their inclusion criteria regarding age and baseline functional status, infarct size, time to surgery, definition of standard medical management, and primary outcomes. They were also limited by small sample size, absence of blinding, exclusion of older patients, and lack of reporting regarding withdrawal of life-sustaining treatment and mortality outcomes. Despite these limitations, these trials established the benefit of early DHC on mortality and improving functional outcomes. In a pooled analysis of the three original trials (DESTINY, DECIMAL, and HAMLET) including patients ≤ 60 years old and treated within 48 h, the number needed to treat (NNT) was 4 to achieve a mRS ≤ 3 (absolute risk reduction [ARR] = 23%), 2 to achieve a mRS ≤ 4 (ARR = 51%), and 2 to survive irrespective of mRS (ARR = 50%) ^[58]. A subsequent pooled analysis of all eight trials ^[2] showed substantial improvement in the chance of favorable outcomes (mRS ≤ 3) at 1 year, even after adjustment for age, sex, baseline stroke severity (NIHSS), presence of aphasia, and time from stroke onset to randomization (adjusted OR, 2.95 [95% CI 1.55–5.60], p = 0.001) and significant reduction in mortality (1 year adjusted OR 0.16 [95% CI 0.10–0.24], p < 0.001). Among patients 60–82 years old, there remains a clear survival benefit, but the majority of survivors achieve a mRS of 4 or 5 ^[59]. The optimal timing of DHC within the first 48 h is based off the RCTs discussed above. Only HeADDFIRST, HeMMI and HAMLET allowed randomization after 48 h; a subgroup analysis in HAMLET found no benefit of DHC on neurological outcomes or mortality when performed after 48 h ^[52].

5.3.3. Unproven and Emerging Therapies for MCE

Over 1000 experimental therapies have been investigated for neuroprotective properties following ischemic stroke, both in preclinical and clinical studies, with no evidence of meaningful benefits in humans ^[60]. In the context of MCE due to LCI, corticosteroids have been examined with no conclusive benefit on mortality or functional outcomes ^[61]. Barbiturates might be effective at reducing ICP through lowering metabolic demand; however, they are associated with serious adverse effects and have not been shown to improve outcomes ^[62]. Temperature control has been of interest for decades; several early observational studies and small randomized trials described potential beneficial effects of therapeutic hypothermia as a neuroprotective measure in MCE with or without DHC ^[63]^[64]^[65]^[66]; however, recent data have shown potential for harm. Neugebauer et al. ^[67] randomized 50 patients aged 18–60 years with MCE who were treated with DHC within 48 h to receive moderate hypothermia within 12 h of DHC (33.0 ± 1.0 °C, maintained for 72 h) or standard of care. The trial was stopped early (short of the projected plan to include 324 patients) due to safety concerns; 12 of 26 patients (46%) in the hypothermia group and 7 of 24 patients (29%) receiving standard care had at least one serious adverse event within 14 days (OR, 2.05 [95% CI, 0.56–8.00]; p = 0.26); after 12 months, rates of serious adverse events were 80% in the hypothermia group and 43% in the standard care group (hazard ratio, 2.54 [95% CI, 1.29–5.00]; p = 0.005). There was no difference in 14-day mortality or 12-month functional outcome between the two groups. Whether there is a subset of patients who may benefit from therapeutic hypothermia, such as those who are not candidates for DHC, remains uncertain ^[64]. Trials of intravascular hypothermia in patients receiving EVT are underway ^[68]^[69].

6. Seizures

Stroke is the most common cause of seizures and epilepsy in older adults, accounting for approximately one-third of new-onset seizures and epilepsy in individuals ≥ 65 years old ^[70]. Post-stroke seizures can be classified into two categories: early seizures (or acute symptomatic seizures), occurring within the initial week after stroke, and late seizures (or remote symptomatic seizures), which manifest after the first week. Notably, the risk of seizures persists beyond the acute phase, progressively increasing and often leading to the development of epilepsy months to years following the stroke ^[71]^[72]. The emergence of early post-stroke seizures can be attributed to various factors, including neuronal damage resulting from hypoxia, metabolic dysfunction, reperfusion injury, glutamate excitotoxicity, and disruption of the BBB. The onset of late seizures and post-stroke epilepsy is associated with gliotic scarring, chronic inflammation, altered synaptic plasticity, and other neurodegenerative processes that collectively contribute to the epileptogenic process ^[73].

Risk factors for post-stroke seizures include younger age, increased stroke severity, cortical involvement, and anterior circulation infarcts ^[72]. Patients with LCI are at an especially high risk of both early- and late-onset seizures ^[74]. There is conflicting data on whether reperfusion therapies increase the risk of post-stroke seizures ^[75]^[76]^[77]. The routine prophylactic administration of ASMs in the primary prevention of post-stroke epilepsy is not recommended due to the lack of evidence regarding efficacy and potential for harm. Evidence suggests that some ASMs (especially phenytoin and benzodiazepines) may hamper mechanisms of neural plasticity that are essential to recovery after stroke ^[78]^[79]^[80]^[81].

7. Anticoagulation Initiation in Large-Core Infarcts

The need to determine optimal timing for starting anticoagulant (AC) therapy in patients with LCI often arises when there is a clinical indication for early initiation or re-initiation of AC, such as atrial fibrillation, mechanical heart valve, cardiac thrombus, deep vein thrombosis, or pulmonary embolism. The risk of symptomatic HT with anticoagulation versus the risk of recurrent ischemic stroke or other systemic thromboembolism without AC must be carefully weighed ^[82]. Predictors for HT include large volume infarct, previous intracranial hemorrhage, thrombocytopenia, mechanical thrombectomy, and cerebral microhemorrhages ^[83]. The choice of AC depends on the indication for AC and patient-specific comorbidities; however, direct oral anticoagulants (DOACs), including apixaban, rivaroxaban, edoxaban, and dabigatran, are preferred in most clinical settings due to the reduced risk of intracerebral hemorrhage ^[84].

The timing of AC initiation has been extensively studied. In a meta-analysis (2007) of seven trials (4624 patients) comparing IV unfractionated heparin or low-molecular-weight heparin (LMWH) initiated within 48 h of a cardioembolic stroke versus other treatments (aspirin or placebo), IV anticoagulation was associated with an increase in symptomatic intracerebral hemorrhage (2.5% vs. 0.7%, OR 2.89 [95% CI: 1.19–7.01]), without statistically significant reduction in recurrent ischemic stroke within 7 to 14 days (3.0 vs. 4.9%, OR 0.68 [95% CI: 0.44–1.06]) ^[85]. The Early Recurrence and Cerebral Bleeding in Patient with Acute Stroke and Atrial Fibrillation (RAF) study showed that in patients with acute ischemic stroke and atrial fibrillation, a high CHA2DS2-VASc score, high NIHSS, large ischemic lesions, and choice of oral anticoagulant (OAC) independently led to greater risk of both recurrent ischemic stroke and major bleeding at 90 days; the best time for initiation of OAC was between 4 and 14 days from ischemic stroke ^[86]. Subsequently, the American Heart Association/American Stroke Association guidelines (2018) recommend starting OAC within 4 to 14 days after an acute ischemic stroke for most patients, with a further delay for patients with HT ^[87].

8. Goals of Care

The prognosis and long-term outcomes of patients with LCI depend on various factors, including age, baseline functional status, the efficacy of reperfusion therapies, the success of DHC, development of HT, and other hospital-related complications. The majority of patients with LCI sustain at least mild to moderate disability, with high rates of depression, cognitive dysfunction and anxiety ^[88]; therefore, conversations about long-term outcomes are typically conducted with families to establish the patient’s personal goals and to set realistic expectations. It is recommended to adopt an individualized approach when engaging in discussions about care goals. Acceptable levels of disability to patients and families vary, necessitating an individualized evaluation of what constitutes a “favorable” or “unfavorable” outcome based on patient-specific objectives and acceptable functional levels.

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