Well then solve the problem so Intracranial Hemorrhage does not occur. Have you NO BRAINS AT ALL?
Intracranial Hemorrhage After Reperfusion Therapies in Acute Ischemic Stroke Patients
Abstract
Reperfusion therapies are the mainstay of acute ischemic stroke (AIS) treatments and overall improve functional outcome. Among the established complications of intravenous (IV) tissue-type plasminogen activator (tPA), intracranial hemorrhage (ICH) is by far the most feared and has been extensively described by seminal works over the last two decades. Indeed, IV tPA is associated with increased odds of any ICH and symptomatic ICH responsible for increased mortality rate during the first week after an AIS. Despite these results, IV tPA has been found beneficial in several pioneering randomized trials and improves functional outcome at 3 months(NOT GOOD ENOUGH; Survivors want 100% recovery, NOT THIS IMPROVES CRAPOLA.). Endovascular therapy (EVT) combined with IV tPA for AIS patients consecutive to an anterior circulation large-vessel occlusion does not increase ICH occurrence. Of note, EVT following IV tPA leads to significantly higher rates of early reperfusion than with IV tPA alone, with no difference in ICH, which challenges the paradigm of reperfusion as a major prognostic factor for ICH complications. However, several blood biomarkers (glycemia, platelet and neutrophil count), clinical factors (age, AIS severity, blood pressure management, diabetes mellitus), and neuroradiological factors (cerebral microbleeds, infarct size) have been identified as risk factors for ICH after reperfusion therapy. In the years to come, the ultimate goal will be to further improve either reperfusion rates and functional outcome, while reducing hemorrhagic complications. To this end, various approaches being investigated are discussed in this review, such as blood-pressure control after reperfusion or the use of new antiplatelet agents as an adjunct to IV tPA and exhibit reduced hemorrhagic potential during the early phase of AIS.
Introduction
To date, reperfusion therapies represent the mainstay of acute ischemic stroke (AIS) treatments (1, 2). Reperfusion can be performed pharmacologically by the use of intravenous recombinant human tissue-type plasminogen activator (IV tPA; alteplase, Boehringer Ingelheim, Germany) within the first 4.5 h after stroke onset (3), and since 2015, by endovascular therapy (EVT) in case of an anterior circulation large-vessel occlusion (LVO) (4). These different treatments have been found effective in reducing 3 month neurological disability(NOT GOOD ENOUGH; Survivors want 100% recovery, NOT THIS REDUCING CRAPOLA.). Indeed, in a meta-analysis of individual data from randomized controlled trials (RCTs), at 3 months, 32.9% of patients with IV tPA within 3 h after AIS onset had a modified Rankin Scale score 0–1 vs. 23.1% of the placebo group (5). Similarly, EVT following IV tPA vs. IV tPA alone in a setting of LVO of the anterior circulation significantly reduced disability at 3 months (4).
However, these treatments are by no means entirely free of complications, with intracranial hemorrhage (ICH) the most feared. Hemorrhagic complications after reperfusion therapies include a broad spectrum of severity between small petechial hemorrhagic infarcts (HIs) to parenchymal hematomas (PHs) (6–8). ICH, especially with PH, is associated with increased morbidity and mortality (9, 10). This explains in part why ICH and especially symptomatic ICH (sICH) are mandatory safety outcomes of most AIS RCTs. Nevertheless, the ICH description remains challenging, given its several different classifications and timeframe assessment (8). sICH and asymptomatic ICH after AIS have been differentiated, but the prognostic significance of asymptomatic ICH remains largely unknown. In this review, we discuss the implications of ICH after IV tPA and EVT. After examining the different clinical, radiological, and biological baseline characteristics associated with increased ICH occurrence, we review possible modifiable factors and future therapeutic approaches.
ICH After Intravenous TPA Therapy
Background
The serine protease tPA is mainly synthesized in endothelial cells and scarcely present in blood in the physiological condition. It converts the proenzyme plasminogen into plasmin. The active form of plasmin cleaves fibrin strands into small fibrin degradation products leading to fibrinolysis. This fibrinolysis cascade is tightly regulated under physiological conditions. Especially, at a physiological concentration, tPA can only activate plasminogen into plasmin when associated with fibrin, thus forming the ternary fibrinolysis complex responsible for a highly local fibrinolysis activation (11). However, numerous studies of IV tPA therapy for acute myocardial infarction have found that with tPA in the therapeutic concentration range, plasminogen can also be converted to plasmin in contact with circulating fibrinogen owing to the incomplete fibrin specificity of tPA. Therefore, plasmin can degrade fibrinogen, thus leading to a corresponding fibrinogen consumption and the formation of fibrinogen products (12, 13). The formation of fibrinogen degradation products with anticoagulant properties, called fibrinogen degradation coagulopathy, was linked to a surplus of hemorrhagic complications in acute myocardial infarction studies (14). In a recent study of AIS patients receiving IV tPA, 20% of patients showed fibrinogen degradation coagulopathy defined as a fibrinogen level decrease ≥200 mg/dL at 6 h after IV tPA infusion, which was associated with increased rate of hemorrhagic complications (15).
The natural history of AIS by itself is associated with the occurrence of delayed ICH, usually called hemorrhagic transformation or hemorrhagic infarction. In the European Cooperative Acute Stroke Study (ECASS) 3 trial, the frequency of any ICH in the placebo group reached 17.6%, with 3.5% being sICH according to the National Institute of Neurological Disorders and Stroke (NINDS) definition (3). Notably, the ICH risk in the setting of AIS without IV tPA therapy remains low, with mainly small petechial HIs associated with baseline stroke severity (16) but with limited, if any, impact on 3 month functional outcome in the ECASS 1 and 2 trials (17–19). These HIs were statistically independent of tPA use in the ECASS 1 and 2 trials and had a paradoxical lower proportion in the tPA group as compared with the placebo group (8). Thus, this ICH could be mainly due to the natural history of AIS and not the IV tPA use (19–22). In the late 1980s and early 1990s, when IV tPA was not approved for AIS and primary management was restricted to clinical monitoring, these HIs were frequently described (43%) and usually associated with severe AIS criteria such as brain edema, mass effect, blood–brain barrier disruption, and baseline neurological severity (22). In the setting of LVO AIS, the proportion of these HIs could even reach 50%, and they were associated with early hypodensities on baseline computed tomography (CT) scans (20). The pathophysiological mechanisms underlying HI development are still not elucidated. Reperfusion has long been cited as a main causal factor for the occurrence of HIs or ICH in general, along with blood pressure or hyperglycemia (23). However, this paradigm is now clearly questioned because of the lack of increased ICH risk observed after EVT-induced reperfusion, as discussed below.
ICH and sICH Definitions
As the most severe complication of IV tPA, ICH defined in the setting of AIS is crucial because it involves key safety outcomes in RCTs and may help neurologists in the everyday management of AIS. ICH can be defined clinically (symptomatic vs. asymptomatic), radiologically (HIs vs. PHs) but also within the timeframe of assessment (early vs. late) (8). The notion of sICH in the setting of AIS was first introduced by Levy et al., requiring contemporaneous neurological worsening or a new mass effect on brain CT scan (24, 25). In the NINDS trial (parts 1 and 2), the clinical aspect of ICH was taken into account by the notion of a “temporally related neurologic deterioration,” without further details (6, 8). The Prolyse in Acute Cerebral Thromboembolism (PROACT) II trial, assessing the efficacy of intra-arterial prourokinase for AIS, was the first trial to specifically define the meaning of clinical deterioration after treatment, as an increase from baseline of four points in the National Institutes of Health Stroke Scale (NIHSS) score (8, 26). Because several conditions may increase the NIHSS score in the setting of AIS (e.g., epilepsy, mass effect, ischemic lesion growth), further trials specified ICH as the presumed responsible cause of neurological deterioration (≥4 points in NIHSS score). The rationale for distinguishing sICH and asymptomatic ICH is prognosis. First, and as mentioned above, asymptomatic ICH usually involves HI lesions as opposed to PH lesions, without any impact on 3 month functional outcome (19). However, this last point must be considered with caution in light of recent studies highlighting the association between asymptomatic ICH after EVT and worse clinical outcome (27, 28). Second, such distinction provides a practical and useful tool for RCTs to assess the safety related to IV tPA use (8).
The radiological distinction was introduced in the early 1990s and first distinguished HI and PH on follow-up CT scan (7). These lesions were used in the NINDS study as “acute infarction with punctate or variable hypodensity/hyperdensity, with an indistinct border within the vascular territory” for HIs and “typical homogeneous, hyperdense lesion with a sharp border with or without edema or mass effect” for PHs (29). In the ECASS trials, these definitions were implemented and improved with the distinction between HI1 and HI2 and PH1 and PH2 (Table 1). Therefore, the ECASS definition includes the ICH mass effect that was not considered in the NINDS definition (<30% or ≥30% of the infarct area with or without space-occupying effect) depending on the PH type. PH1 is associated with risk of early neurological deterioration but not disability or death (19). In contrast, PH2 is strongly associated with early neurological deterioration but also with 3 month disability and death (19). In the ECASS 1 trial, PH1 was not associated with neurological deterioration, disability, or death, but PH2 was strongly associated with early neurological deterioration [odds ratio (OR) = 32.3, 95% confidence interval (CI) = 13.4–77.7] and 3 month death (OR = 18, 95% CI = 8.05–40.1) (30). As discussed below, PH2 is strongly associated with tPA use and increases with tPA dose (3-fold for 0.9 mg/kg and 3.6-fold for 1.1 mg/kg) (8). Given its tremendous clinical significance, the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) definition used local or remote PH2 on the 22 to 36 h posttreatment CT scan as a surrogate marker for sICH (Table 1) (31). More recently, the ECASS 4, the Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND), and the Echoplanar Imaging Thrombolytic Evaluation trials also used PH2 for defining sICH, when associated with an increase of four points in NIHSS score (32). Finally, the ICH and sICH classifications may differ regarding the timeframe of evaluation. In brief, the NINDS, PROACT II, and ECASS 1 trials assessed early ICH within 36 h after stroke onset (6, 8, 17, 26). In contrast, other trials considered a delayed timeframe for ICH assessment: within 7 days (3, 33). As discussed, delayed assessment could result in poorer correlations with tPA use, notably owing to its known short half-life and also in the context of EVT (8). In this context, the Heidelberg bleeding classification was developed during the XII Thrombolysis Symposium on Thrombolysis, Thrombectomy and Ischemic Stroke treatment with the aim to propose a revised classification that specifies, in a single format, ICH topography (intraparenchymal, subdural, and subarachnoid, to take into account EVT devices complications); localization (within the infarct or remote); symptomatic or asymptomatic aspects; and type of ICH (HI1, 2; PH1, 2) to harmonize everyday practice and RCT designs (Tables 1, ,2)2) (25). In the Heidelberg Classification, PH2 is considered a distinct entity from other ICHs owing to its pronounced impact on functional outcome and death. Details are also provided in the original publication to help the clinician distinguish the types of PH (25).
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