Hemostasis and Fibrinolysis following Aneurysmal Subarachnoid Hemorrhage: A Systematic Review on Additional Knowledge from Dynamic Assays and Potential Treatment Targets
Seminars in thrombosis and hemostasis. 2021
Mortality after aneurysmal subarachnoid hemorrhage (aSAH) is augmented by rebleeding and delayed cerebral ischemia (DCI). A range of assays evaluating the dynamic process of blood coagulation, from activation of clotting factors to fibrinolysis, has emerged and a comprehensive review of hemostasis and fibrinolysis following aSAH may reveal targets of treatment. We conducted a systematic review of existing literature assessing coagulation and fibrinolysis following aSAH, but prior to treatment. PubMed, Embase, and Web of Science were searched on November 18, 2020, without time boundaries. In total, 45 original studies were eventually incorporated into this systematic review, divided into studies presenting data only from conventional or quantitative assays (n = 22) and studies employing dynamic assays (n = 23). Data from conventional or quantitative assays indicated increased platelet activation, whereas dynamic assays detected platelet dysfunction possibly related to an increased risk of rebleeding. Secondary hemostasis was activated in conventional, quantitative, and dynamic assays and this was related to poor neurological outcome and mortality. Studies systematically investigating fibrinolysis were sparse. Measurements from conventional or quantitative assays, as well as dynamic fibrinolysis assays, revealed conflicting results with normal or increased lysis and changes were not associated with outcome. In conclusion, dynamic assays were able to detect reduced platelet function, not revealed by conventional or quantitative assays. Activation of secondary hemostasis was found in both dynamic and nondynamic assays, while changes in fibrinolysis were not convincingly demonstrable in either dynamic or conventional or quantitative assays. Hence, from a mechanistic point of view, desmopressin to prevent rebleeding and heparin to prevent DCI may hold potential as therapeutic options. As changes in fibrinolysis were not convincingly demonstrated and not related to outcome, the use of tranexamic acid prior to aneurysm closure is not supported by this review.
How outcomes are measured after spontaneous intracerebral hemorrhage: A systematic scoping review
PloS one. 2021;16(6):e0253964
BACKGROUND AND PURPOSE Recovery after intracerebral haemorrhage (ICH) is often slower than ischemic stroke. Despite this, ICH research often quantifies recovery using the same outcome measures obtained at the same timepoints as ischemic stroke. The primary objective of this scoping review is to map the existing literature to determine when and how outcomes are being measured in prospective studies of recovery after ICH. METHODS We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials and Web of Science from inception to November 2019, for prospective studies that included patients with ICH. Two investigators independently screened the studies and extracted data around timing and type of outcome assessment. RESULTS Among the 9761 manuscripts reviewed, 395 met inclusion criteria, of which 276 were observational studies and 129 were interventional studies that enrolled 66274 patients. Mortality was assessed in 93% of studies. Functional outcomes were assessed in 85% of studies. The most frequently used functional assessment tool was the modified Rankin Scale (mRS) (60%), followed by the National Institute of Health Stroke Severity Scale (22%) and Barthel Index (21%). The most frequent timepoint at which mortality was assessed was 90 days (41%), followed by 180 days (18%) and 365 days (12%), with 2% beyond 1 year. The most frequent timepoint used for assessing mRS was 90 days (62%), followed by 180 days (21%) and 365 days (17%). CONCLUSION While most prospective ICH studies report mortality and functional outcomes only at 90 days, a significant proportion do so at 1 year and beyond. Our results support the feasibility of collecting long-term outcome data to optimally assess recovery in ICH.
Effects of various therapeutic agents on vasospasm and functional outcome following aneurysmal subarachnoid hemorrhage - Results of a network meta-analysis
World neurosurgery. 2021
INTRODUCTION Vasospasm and delayed ischemic neurological deficits (DIND) are the leading causes of morbidity and mortality following aneurysmal subarachnoid hemorrhage (aSAH). Several therapeutic agents have been assessed in randomized controlled trials (RCTs) for their efficacy in reducing the incidence of vasospasm and improving functional outcome. The aim of this network meta-analysis is to compare all these therapeutic agents for their effect on functional outcome and other parameters following aSAH. METHODS A comprehensive search of different databases was performed to retrieve RCTs describing the effect of various therapeutic approaches on functional outcome and other parameters following aSAH. RESULTS Ninety-two articles were selected for full text review and 57 articles were selected for the final analysis. Nicardipine prolonged released implants (NPRI) was found to be the best treatment in terms of favorable outcome (OR, 8.55; 95% CrI, 1.63 to 56.71), decreasing mortality (OR, 0.08; 95% CrI, 0 to 0.82), and preventing angiographic vasospasm (OR, 0.018; 95% CrI, 0.00057 to 0.16). Cilostazol was found to be the second-best treatment in improving favorable outcomes (OR, 3.58; 95% CrI, 1.97 to 6.57) and decreasing mortality (OR, 0.41; 95% CrI, 0.12 to 1.15). Fasudil (OR, 0.16; 95% CrI, 0.03 to 0.78) was found to be the best treatment in decreasing raised vessel velocity and enoxaparin (OR, 0.25; 95% CrI, 0.057 to 1.0) in preventing DIND. CONCLUSIONS Our analysis revealed that NPRI and Cilostazol were associated with the best chances to improve favorable outcome and mortality in patients with aSAH. However, larger multicentric studies from different parts of the world are required to confirm these findings.
Subarachnoid Hemorrhage in Mechanical Thrombectomy for Acute Ischemic Stroke: Analysis of the STRATIS Registry, Systematic Review, and Meta-Analysis
Frontiers in neurology. 2021;12:663058
Background: The indications for mechanical thrombectomy in acute ischemic stroke continue to broaden, leading neurointerventionalists to treat vessel occlusions at increasingly distal locations farther in time from stroke onset. Accessing these smaller vessels raises the concern of iatrogenic subarachnoid hemorrhage (SAH) owing to increasing complexity in device navigation and retrieval. This study aims to determine the prevalence of SAH following mechanical thrombectomy, associated predictors, and resulting functional outcomes using a multicenter registry and compare this with a systematic review and meta-analysis of the literature. Methods: Data from STRATIS (The Systematic Evaluation of Patients Treated with Neurothrombectomy Devices for Acute Ischemic Stroke) registry were analyzed dichotomized by the presence or absence of SAH after thrombectomy. Only patients with 24-h post-procedural neuroimaging were included (n = 841). Multivariable logistic regression was performed to identify significant predictors of SAH. A systematic review and random-effects meta-analysis was also conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) protocol. Results: The prevalence of post-thrombectomy SAH was 5.23% in STRATIS with 15.9% (1.84% overall) experiencing neurological decline. Distal location of vessel occlusion (OR 3.41 [95% CI: 1.75-6.63], p < 0.001) and more than 3 device passes (OR 1.34 [95% CI: 1.09-1.64], p = 0.01) were associated with a higher probability of SAH in contrast to a reduction with administration of intravenous tissue plasminogen activator (tPA) (OR 0.48 [95% CI: 0.26-0.89], p = 0.02). There was a trend toward a higher discharge NIHSS (8.3 ± 8.7 vs. 5.3 ± 6.6, p = 0.07) with a significantly reduced proportion achieving functional independence at 90 days (modified Rankin Score 0-2: 32.5% vs. 57.8%, p = 0.002) in SAH patients. Pooled analysis of 10,126 patients from 6 randomized controlled trials and 64 observational studies demonstrated a prevalence of 5.85% [95% CI: 4.51-7.34%, I (2): 85.2%]. Only location of vessel occlusion was significant for increased odds of SAH at distal sites (OR 2.89 [95% CI: 1.14, 7.35]). Conclusions: Iatrogenic SAH related to mechanical thrombectomy is more common with treatment of distally-situated occlusions and multiple device passes. While low in overall prevalence, its effect is not benign with fewer patients reaching post-procedural functional independence, particularly if symptomatic.
Time and Predictors of Treatment for Aneurysmal Subarachnoid Haemorrhage (ASAH): A Systematic Review
International journal for quality in health care : journal of the International Society for Quality in Health Care. 2021
BACKGROUND Aneurysmal subarachnoid haemorrhage (aSAH) is a serious form of stroke, for which rapid access to specialist neurocritical care is associated with better outcomes. Delays in the treatment of aSAH appears to be common and may contribute to poor outcomes. We have a limited understanding of the extent and causes of these delays, which hinders the development of interventions to reduce delays and improve outcomes. The aim of this systematic review was to quantify and identify factors associated with time to treatment in aSAH. METHODS This systematic review was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines and was registered in PROSPERO (Reg No. CRD42019132748). We searched four electronic databases databases (MEDLINE, EMBASE, Web of Science, and Google Scholar) for manuscripts published from January 1998 using pre-designated search terms and search strategy. Main outcomes were duration of delays of time intervals from onset of aSAH to definitive treatment and/or factors related to time to treatment. RESULTS A total of 64 studies with 16 different time intervals in the pathway of aSAH patients were identified. Measures of time to treatment varied between studies (e.g. cut-off timepoints or absolute mean/median duration). Factors associated with time to treatment fell into two categories - individual (n=9 factors e.g. age, sex, clinical characteristics) and health system (n=8 factors, e.g. pre-hospital delay or presentation out-of-hours). Demographic factors were not associated with time to treatment. More severe aSAH reduced treatment delay in most studies. Pre-hospital delays (patients delay, late referral, late arrival of ambulance, being transferred between hospitals or arriving at the hospital outside of office hours) were associated with treatment delay. In-hospital factors (patients with complications, procedure before definitive treatment, slow work-up, type of treatment) were less associated with treatment delay. CONCLUSIONS The pathway from onset to definitive treatment of a patients with aSAH consists of multiple stages with multiple influencing factors. This review provides the first comprehensive understanding of extent and factors associated with time to treatment of aSAH. There is an opportunity to target modifiable factors to reduce time to treatment but further research considering more factors are needed.
Therapeutic Variation in Lowering Blood Pressure: Effects on Intracranial Pressure in Acute Intracerebral Haemorrhage
High blood pressure & cardiovascular prevention : the official journal of the Italian Society of Hypertension. 2021
INTRODUCTION Intracerebral haemorrhage (ICH) is associated with high morbidity and mortality. Blood pressure (BP) control is one of the main management strategies in acute ICH. Limited data currently exist regarding intracranial pressure (ICP) in acute ICH. The relationship between BP lowering and ICP is yet to be fully elucidated. METHODS We conducted a systematic review to investigate the effects of BP lowering on ICP in acute ICH. The study protocol was registered on PROSPERO (CRD42019134470). RESULTS Following PRISMA guidelines, MEDLINE, EMBASE and CENTRAL were searched for studies on ICH with BP and ICP or surrogate measures. 1096 articles were identified after duplicates were removed; 18 studies meeting the inclusion criteria. Dihydropyridine calcium channel blockers (CCBs) were the most common agent used to lower BP, but had a varying effect on ICP. Other BP-lowering agents used also had a varying effect on ICP. DISCUSSION AND CONCLUSION Further work, including large observational or randomized interventional studies, is needed to develop a better understanding of the effect of BP lowering on ICP in acute ICH, which will assist the development of more effective management strategies. TRIAL REGISTRATION The study protocol was registered on PROSPERO (CRD42019134470) on 29/05/2019.
Neuroimaging Markers of Cerebral Small Vessel Disease on Hemorrhagic Transformation and Functional Outcome After Intravenous Thrombolysis in Patients With Acute Ischemic Stroke: A Systematic Review and Meta-Analysis
Frontiers in aging neuroscience. 2021;13:692942
Objective: The aim of this study was to perform a systematic review and meta-analysis to assess whether cerebral small vessel disease (CSVD) on neuroimaging of patients with acute ischemic stroke (AIS) treated with intravenous thrombolysis (IVT) is associated with an increased risk of hemorrhagic transformation (HT), symptomatic intracranial hemorrhage (sICH), and poor functional outcome (PFO). Methods: A thorough search of several databases was carried out to identify relevant studies up to December 2020. We included studies of patients with AIS and neuroimaging markers of CSVD treated with IVT. The primary outcome was HT, and the secondary outcomes were sICH and 3-month PFO. The quality of the studies involved was evaluated using the Newcastle-Ottawa Scale (NOS). The meta-analysis with the fixed effects model was performed. Results: Twenty-four eligible studies (n = 9,419) were pooled in the meta-analysis. All included studies were regarded as high quality with the NOS scores of at least 6 points. The meta-analysis revealed associations between the presence of CSVD and HT, sICH, and the 3-month PFO after IVT. Compared with no CSVD, the presence of CSVD was associated with an increased risk of HT (OR: 1.81, 95% CI: 1.52-2.16), sICH (OR: 2.42, 95% CI: 1.76-3.33), and 3-month PFO (OR: 2.15, 95% CI: 1.89-2.44). For patients with AIS complicated with CSVD, compared with a CSVD score of 0-1, a CSVD score of 2-4 was associated with an increased risk of HT (OR: 3.10, 95% CI: 1.67-5.77), sICH (OR: 2.86, 95% CI: 1.26-6.49), and 3-month PFO (OR: 4.58, 95% CI: 2.97-7.06). Conclusion: Patients with AIS complicated with neuroimaging markers of CSVD are at increased risk of HT and 3-month PFO after IVT. However, it is still necessary to clarify the exact role of CSVD in the occurrence, development, and prognosis of AIS. Systematic Review Registration: www.ClinicalTrials.gov, identifier CRD4202123 3900.
Tranexamic Acid in Intracerebral Hemorrhage: A Meta-Analysis
The International journal of neuroscience. 2021;:1-12
Background ：Tranexamic acid（TA） is an antifibrinolytic agent, which has shown an effect on reducing blood loss in many diseases. Tranexamic acid might be beneficial for intracerebral hemorrhage（ICH）. However, whether TA can treatment of intracerebral hemorrhage is still controversial.Objective: Evidence-based medicine was used to evaluate the efficacy and safety of tranexamic acid in patients with intracerebral hemorrhage.Methods: Pubmed (MEDLINE), Embase, and Cochrane Library were searched from January 2001 to October 2020 for randomized controlled trials (RCTs),cohort studies, and retrospective case series .The Jadad scale and RevMan software version 5.3 were used for literature quality assessment and meta-analysis.Results: In total, 4 randomized controlled trials and 1 retrospective case series with 2808 participants were included in the meta-analysis. Compared with control intervention in intracerebral hemorrhage, tranexamic acid could significantly reduce growth of hemorrhagic mass (odds ratio (OR) =0.81; 95% confidence interval（CI）=0.68 to 0.99; p = 0.04) and Modified Rankin Scale score(MRS) at 90 days at 0-3 (OR =1.20; 95% CI =1.00 to 1.43; p = 0.05), mortality by day 90 (OR= 1.03; 95% CI= 0.85-1.25; p = 0.77) and major thromboembolic events (OR= 1.14; 95% CI= 0.73-1.77; p = 0.58) .Conclusions:Treatment with tranexamic acid could reduce hematoma expansion in intracerebral hemorrhage,and the treatment was safe with no increase in thromboembolic complications. But showed no notable impact on good functional outcomes and mortality.
The Function of Tranexamic Acid to Prevent Hematoma Expansion After Intracerebral Hemorrhage: A Systematic Review and Meta-Analysis From Randomized Controlled Trials
Frontiers in neurology. 2021;12:710568
Objectives: The clinical results caused by spontaneous intracerebral hemorrhage (ICH) are disastrous to most patient. As tranexamic acid (TXA) has been proved to decrease the influence of ICH, we conducted this research to explore the function of TXA for the prognosis of ICH compared with placebo. Methods: We searched MEDLINE, Embase, Cochrane Library, and Clinicaltrials.gov for randomized controlled trials (RCTs) that were performed to evaluate TXA vs. placebo for ICH up to February 2021. The data were assessed by Review Manager 5.3 software. The risk ratio (RR) and mean difference were analyzed using dichotomous outcomes and continuous outcomes, respectively, with a fixed effect model. Results: We collected 2,479 patients from four RCTs. Then, we took the change of hematoma volume, modified Rankin Scale (mRS), and adverse events as evaluation standard of the treatment for ICH. Through statistical analysis, we found that there is no obvious hematoma expansion effect after the application of TXA (RR = 1.05), and we proceeded the quantitative analysis of percentage change in hematoma volume from baseline, indicating that TXA could inhibit the expansion of hematoma volume (RR = -2.02) compared with placebo. However, according to the outcomes of mRS (0-1, RR = 1.04; 0-2, RR = 0.96), TXA cannot improve neurological functional prognosis. As for the security outcomes-mortality (RR = 1.02), thromboembolic events (RR = 0.99), neurological deterioration (RR = 0.92), infection (RR = 0.86), and craniotomy (RR = 0.41), there seems exist no statistical difference between TXA and placebo. Conclusions: TXA has an advantage in the aspect of preventing hematoma expansion compared with placebo for ICH, but cannot illustrate the efficacy of TXA in improving neurological functional prognosis, which still needs more researches with large sample sizes. Moreover, for safety, we did not find obvious statistical difference between TXA and placebo.
Tranexamic acid in non-traumatic intracranial bleeding: a systematic review and meta-analysis
Scientific reports. 2021;11(1):15275
Non-traumatic intracranial bleeding (NTIB), comprising subarachnoid hemorrhage (SAH) and intra-cranial bleeding (ICH) is a significant public health concern. Tranexamic acid (TXA) is a promising treatment with benefits yet to be fully demonstrated. We conducted a systematic review and meta-analysis on the impact of TXA on mortality in NTIB. We searched the PubMed, Cochrane Library, Google Scholar and ScienceDirect databases for studies reporting mortality data following the use of TXA in NTIB for comparisons with a control group. We computed random-effect meta-analysis on estimates of risk and sensitivity analyses. We computed meta-regression to examine the putative effects of the severity of NTIB, sociodemographic data (age, sex), and publication date. Among potentially 10,008 articles, we included 15 studies representing a total of 4883 patients: 2455 receiving TXA and 2428 controls; 1110 died (23%) during the follow-up. The meta-analysis demonstrated a potential of 22% decrease in mortality for patients treated by TXA (RR = 0.78, 95%CI 0.58-0.98, p = 0.002). Meta-regression did not demonstrate any influence of the severity of NTIB, age, sex, length of treatment or date of publication. Sensitivity analyses confirmed benefits of TXA on mortality. TXA appears to be a therapeutic option to reduce non-traumatic intracranial bleeding mortality, particularly in patients with SAH.