Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage

Background: Rebleeding is an important cause of death and disability in people with aneurysmal subarachnoid haemorrhage. Rebleeding is probably related to the dissolution of the blood clot at the site of the aneurysm rupture by natural fibrinolytic activity. This review is an update of previously published Cochrane Reviews. Objectives: To assess the effects of antifibrinolytic treatment in people with aneurysmal subarachnoid haemorrhage. Search methods: We searched the Cochrane Stroke Group Trials Register (May 2022), CENTRAL (in the Cochrane Library 2021, Issue 1), MEDLINE (December 2012 to May 2022), and Embase (December 2012 to May 2022). In an effort to identify further published, unpublished, and ongoing studies, we searched reference lists and trial registers, performed forward tracking of relevant references, and contacted drug companies (the latter in previous versions of this review). Selection criteria: Randomised trials comparing oral or intravenous antifibrinolytic drugs (tranexamic acid, epsilon amino-caproic acid, or an equivalent) with control in people with subarachnoid haemorrhage of suspected or proven aneurysmal cause. Data collection and analysis: Two review authors (MRG & WJD) independently selected trials for inclusion, and extracted the data for the current update. In total, three review authors (MIB & MRG in the previous update; MRG & WJD in the current update) assessed risk of bias. For the primary outcome, we dichotomised the outcome scales into good and poor outcome, with poor outcome defined as death, vegetative state, or (moderate) severe disability, assessed with either the Glasgow Outcome Scale or the Modified Rankin Scale. We assessed death from any cause, rates of rebleeding, delayed cerebral ischaemia, and hydrocephalus per treatment group. We expressed effects as risk ratios (RR) with 95% confidence intervals (CI). We used random-effects models for all analyses. We assessed the quality of the evidence with GRADE. Main results: We included one new trial in this update, for a total of 11 included trials involving 2717 participants. The risk of bias was low in six studies. Five studies were open label, and we rated them at high risk of performance bias. We also rated one of these studies at high risk for attrition and reporting bias. Five trials reported on poor outcome (death, vegetative state, or (moderate) severe disability), with a pooled risk ratio (RR) of 1.03 (95% confidence interval (CI) 0.94 to 1.13; P = 0.53; 5 trials, 2359 participants; high-quality evidence), which showed no difference between groups. All trials reported on death from all causes, which showed no difference between groups, with a pooled RR of 1.02 (95% CI 0.90 to 1.16; P = 0.77; 11 trials, 2717 participants; high-quality evidence). In trials that combined short-term antifibrinolytic treatment (< 72 hours) with preventative measures for delayed cerebral ischaemia, the RR for poor outcome was 0.98 (95% CI 0.81 to 1.18; P = 0.83; 2 trials, 1318 participants; high-quality evidence). Antifibrinolytic treatment reduced the risk of rebleeding, reported at the end of follow-up (RR 0.65, 95% CI 0.47 to 0.91; P = 0.01; 11 trials, 2717 participants; absolute risk reduction 7%, 95% CI 3 to 12%; moderate-quality evidence), but there was heterogeneity (I² = 59%) between the trials. The pooled RR for delayed cerebral ischaemia was 1.27 (95% CI 1.00 to 1.62; P = 0.05; 7 trials, 2484 participants; moderate-quality evidence). However, this effect was less extreme after the implementation of ischaemia preventative measures and < 72 hours of treatment (RR 1.10, 95% CI 0.83 to 1.46; P = 0.49; 2 trials, 1318 participants; high-quality evidence). Antifibrinolytic treatment showed no effect on the reported rate of hydrocephalus (RR 1.09, 95% CI 0.99 to 1.20; P = 0.09; 6 trials, 1992 participants; high-quality evidence). Authors' conclusions: The current evidence does not support the routine use of antifibrinolytic drugs in the treatment of people with aneurysmal subarachnoid haemorrhage. More specifically, early administration with concomitant treatment strategies to prevent delayed cerebral ischaemia does not improve clinical outcome. There is sufficient evidence from multiple randomised controlled trials to incorporate this conclusion in treatment guidelines

Aortic dissection masquerading as a code stroke: A single-centre cohort study

Introduction: Data on the incidence of acute aortic dissection in the code stroke population are scarce. We report estimated incidence, clinical manifestations, treatment and outcomes of patients with an acute aortic dissection in a code stroke cohort from a comprehensive stroke centre. Patients and methods: We used data from a single-centre prospective registry of consecutive adult patients who presented to the emergency department between 2015 and 2018 with neurological deficits suggestive of an acute stroke (‘code stroke’). All patients routinely underwent non-contrast computed tomography of the brain and computed tomography-angiography of the aortic arch, cervical and intracranial arteries. Results: Of 2874 code stroke patients, 1563 (54.4%) had acute ischaemia (ischaemic stroke or transient ischaemic attack). Fifteen patients (0.5% of code stroke patients and 0.8% of patients with acute ischaemia) had an acute aortic dissection (all Stanford classification type A). Discerning clinical manifestations were decreased consciousness in 11/15 (73%), pain in 8/15 (53%) and low systolic blood pressure (mean 106 mmHg, SD30). Acute aortic dissection was an incidental finding during computed tomography-angiography in 4/15 (27%). Two out of 15 patients (13%) received intravenous thrombolysis, 9/15 (60%) underwent aortic surgery and 10/15 (67%) died. Of those who survived, 3/5 (60%) had a good functional outcome (modified Rankin Scale 0–2). Discussion and Conclusion: In our comprehensive stroke centre, about 1/200 code stroke patients and 1/125 patients with acute ischaemia had an acute aortic dissection. Multicentre studies are necessary to acquire a more reliable estimate of the incidence of acute aortic dissection in the code stroke population. Given the ramifications of missing this diagnosis, imaging of the entire aortic arch is important in these patients

The association between computed tomography angiography timing and workflow times in patients with acute ischemic stroke

Background: In most hospitals, computed tomography angiography (CTA) is nowadays routinely performed in patients with acute ischemic stroke. However, it is unclear whether CTA is best performed before or after start of intravenous thrombolysis (IVT), since acquisition of CTA before IVT may prolong door-to-needle times, while acquisition after IVT may prolong door-to-groin times in patients undergoing endovascular treatment. Methods: We performed a before-versus-after study (CTA following IVT, period I and CTA prior to IVT, period II), consisting of two periods of one year each. This study is based on a prospective registry of consecutive patients treated with IVT in two collaborating high-volume stroke centers; one primary stroke center and one comprehensive stroke center. The primary outcome was door-to-needle times. Secondary outcomes included door-to-groin times. Quantile regression analyses were performed to evaluate the association between timing of CTA and workflow times, adjusted for prognostic factors. Results: A total of 519 patients received IVT during the study period (246 in period I, 273 in period II). In the adjusted analysis, we found a nonsignificant 1.13 min median difference in door-to-needle times (95% confidence interval: 1.03–3.29). Door-to-groin times was significantly shorter in period II in both unadjusted and adjusted analysis with the latter showing a 19.16 min median difference (95% confidence interval: 3.08–35.24). Conclusions: CTA acquisition prior to start of IVT did not adversely affect door-to-needle times. However, a significantly shorter door-to-groin times was observed in endovascular treatment eligible patients. Performing CTA prior to start of IVT seems the preferred strategy

Direct Intra-arterial thrombectomy in order to Revascularize AIS patients with large vessel occlusion Efficiently in Chinese Tertiary hospitals: A Multicenter randomized clinical Trial (DIRECT-MT)—Protocol

Rationale: Intravenous thrombolysis combined with mechanical thrombectomy (MT) has been proven safe and clinical effective in patients with acute ischemic stroke of anterior circulation large vessel occlusion. However, despite reperfusion, a considerable proportion of patients do not recover. Incidence of symptomatic intracerebral hemorrhage was similar between patients treated with the combination of intravenous thrombolysis and MT, as compared to intravenous thrombolysis alone, suggesting that this complication should be attributed to pre-treatment with intravenous thrombolysis. Conversely, intravenous thrombolysis may be beneficial in patients with small clots occluding intracranial arteries with underlying intracranial atherosclerotic disease, not accessible for MT. Aim: To assess whether direct MT is non-inferior compared to combined intravenous thrombolysis plus MT in patients with AIS due to an anterior circulation large vessel occlusion, and to assess treatment effect modification by presence of intracranial atherosclerotic disease. Sample size: Aim to randomize 636 patients 1:1 to receive direct MT (intervention) or combined intravenous thrombolysis plus MT (control). Design: This is a multicenter, prospective, open label parallel group trial with blinded outcome assessment (PROBE design) assessing non-inferiority of direct MT compared to combined intravenous thrombolysis plus MT. Outcomes: The primary outcome is the score on the modified Rankin Scale assessed blindly at 90 (±14) days. An common odds ratio, adjusted for the prognostic factors (age, NIHSS, collateral score), representing the shift on the 6-category mRS scale measured at three months, estimated with ordinal logistic regression, will be the primary effect parameter. Non-inferiority is established if the lower boundary of the 95% confidence interval does not cross 0.8. Discussion: DIRECT-MT could result in improved therapeutic efficiency and cost reduction in treatment of anterior circulation large vessel occlusion stroke

Patient and proxies’ attitudes towards deferred consent in randomised trials of acute treatment for stroke: A qualitative survey

Introduction: Deferral of consent for participation in a clinical study is a relatively novel procedure, in which informed consent is obtained after randomisation and study treatment. Deferred consent can be used in emergency situations, where small therapeutic time windows limit possibilities for patients to provide informed consent. We aimed to investigate patients’ or their proxies’ experiences and opinions regarding deferred consent in acute stroke randomised trials. Patients and methods: For this qualitative study, Dutch Collaboration for New Treatments of Acute Stroke (CONTRAST) trial participants were selected. Study participants were either patients or their proxies who provided consent and were selected with theoretical sampling based on patient characteristics. Semi-structured interviews were conducted face-to-face or by telephone. Themes and subthemes were iteratively defined. Results: Twenty of the 23 interviewed participants (16 patients and 7 proxies) considered deferred consent acceptable. The received study treatment and consent conversation were remembered by 18 participations, although the concept of randomisation and treatment comparison were generally not well understood. Sixteen participants felt capable of overseeing the decision to give deferred consent. Distress in the first days after stroke, lack of understanding and neurological deficits were reasons for feeling incapable of providing consent. Four participants would have preferred a different timing of the consent conversation, of whom two prior to treatment. Conclusion: Our study found that deferred consent was considered acceptable by most study participants who provided consent for acute stroke randomised trials. Though they felt capable, the recall and comprehension of consent were overall limited

Mind the Heart: Electrocardiography-gated cardiac computed tomography-angiography in acute ischaemic stroke—rationale and study design

Rationale: About one-third of ischaemic strokes are caused by cardioembolism, and a substantial proportion of cryptogenic strokes likely also originate from the heart or aortic arch. Early determination of aetiology is important to optimise management. Computed Tomography-angiography of the heart is emerging as an alternative to echocardiography to detect cardio-aortic sources of embolism in stroke patients, but its diagnostic yield in acute ischaemic stroke has not been thoroughly assessed. Hypothesis: We hypothesise that electrocardiography-gated computed tomography-angiography of the heart and aortic arch, acquired in the acute phase in patients with ischaemic stroke, has a higher diagnostic yield than transthoracic echocardiography as a first-line screening method for detection of cardio-aortic sources of embolism. Methods and design: Mind the Heart is a single-centre prospective observational cohort study. We will include consecutive adult patients with acute ischaemic stroke who are potentially eligible for reperfusion therapy. Patients undergo non-electrocardiography-gated computed tomography-angiography of the aortic arch, cervical and intracranial arteries, directly followed by prospective sequential electrocardiography-gated cardiac computed tomography-angiography. Routine work-up for cardioembolism including 12-leads electrocardiography, Holter electrocardiography and transthoracic echocardiography is performed as soon as possible. The primary endpoint is the proportion of patients with a predefined high-risk cardio-aortic source of embolism on computed tomography-angiography versus transthoracic echocardiography in patients who underwent both investigations. Based on an expected 5% additional yield of computed tomography-angiography, a sample size of 450 patients is required. Conclusions: The Mind the Heart study will generate a reliable estimate of the diagnostic yield of echocardiography-gated cardio-aortic computed tomography-angiography performed in the acute phase of ischaemic stroke

Brain atrophy and endovascular treatment effect in acute ischemic stroke: a secondary analysis of the MR CLEAN trial

Background: Brain atrophy is suggested to impair the potential for functional recovery after acute ischemic stroke. We assessed whether the effect of endovascular treatment is modified by brain atrophy in patients with acute ischemic stroke due to large vessel occlusion. Methods: We used data from MR CLEAN, a multicenter trial including patients with acute ischemic stroke due to anterior circulation large vessel occlusion randomized to endovascular treatment plus medical care (intervention) versus medical care alone (control). We segmented total brain volume (TBV) and intracranial volume (ICV) on baseline non-contrast computed tomography (n = 410). Next, we determined the degree of atrophy as the proportion of brain volume in relation to head size (1 − TBV/ICV) × 100%, analyzed as continuous variable and in tertiles. The primary outcome was a shift towards better functional outcome on the modified Rankin Scale expressed as adjusted common odds ratio. Treatment effect modification was tested using an interaction term between brain atrophy (as continuous variable) and treatment allocation. Results: We found that brain atrophy significantly modified the effect of endovascular treatment on functional outcome (P for interaction = 0.04). Endovascular treatment led to larger shifts towards better functional outcome in the higher compared to the lower range of atrophy (adjusted common odds ratio, 1.86 [95% CI: 0.97–3.56] in the lowest tertile vs. 1.97 [95% CI: 1.03–3.74] in the middle tertile vs. 3.15 [95% CI: 1.59–6.24] in the highest tertile). Conclusion: Benefit of endovascular treatment is larger in the higher compared to the lower range of atrophy, demonstrating that advanced atrophy should not be used as an argument to withhold endovascular treatment

Cardiac thrombi detected by CT in patients with acute ischemic stroke: A substudy of Mind the Heart

Background: Cardiac thrombi are a major risk factor for ischemic stroke, but are rarely diagnosed in the acute phase. We examined characteristics and functional outcome of patients with ischemic stroke and a concomitant cardiac thrombus detected on cardiac CT performed in the acute phase. Patients and Methods: We used data from “Mind the Heart,” a prospective cohort study in which consecutive adult patients with acute ischemic stroke underwent prospective ECG-gated cardiac CT during their acute stroke imaging protocol. We compared characteristics, functional outcome (modified Rankin scale) and stroke recurrence rate at 90 days of patients with a cardiac thrombus on CT (defined as filling defect <100 Hounsfield Units) to those without a cardiac thrombus. Results: Among 452 included patients, cardiac CT detected 41 thrombi in 38 (8%) patients. Thrombi were most often located in the left atrial appendage (31/38 [82%]). Patients with a cardiac thrombus more frequently had intracranial occlusions in multiple vascular territories (5% vs 0.5%, p = 0.04) and a higher baseline NIHSS score (17 [IQR 6–22] vs 5 [IQR 2–3], p < 0.001) compared to patients without a cardiac thrombus. In 13/38 (34%) patients with a cardiac thrombus, no atrial fibrillation was detected. A cardiac thrombus was associated with worse functional outcome (adjusted common odds ratio 3.18 95%CI 1.68–6.00). Recurrence rate was not significantly different (8% vs 4%, aOR 1.50 (0.39–5.82). Discussion and Conclusion: Cardiac CT detected a cardiac thrombus in one in every 12 patients with acute ischemic stroke, and these patients had more severe deficits, multivessel occlusions, and a worse functional outcome

Admission blood pressure and clinical outcomes in patients with acute ischaemic stroke treated with intravenous alteplase and endovascular treatment versus endovascular treatment alone: A MR CLEAN-NO IV substudy

Introduction: High systolic blood pressure (SBP) is associated with poor functional outcome. We analysed whether the association of SBP with outcomes after endovascular treatment (EVT) is modified by prior intravenous thrombolysis (IVT). Patients and methods: This was a post-hoc analysis of MR CLEAN-NO IV, a randomised trial of IVT with alteplase followed by EVT versus EVT alone, within 4.5 h from stroke onset. SBP was recorded on hospital admission. The primary outcome was 90-day modified Rankin Scale (mRS) score and secondary outcomes included symptomatic intracranial haemorrhage (sICH) and successful reperfusion (eTICI 2b-3), analysed with (ordinal) logistic regression. Estimates were calculated per 10 mmHg change in SBP. We assessed whether IVT modified the associations of SBP with these outcomes using multiplicative interaction terms. Results: Of 539 randomised patients, 266 received IVT. The association of SBP with mRS score was J-shaped, with an inflection point at 150 mmHg. Using 150 mmHg as a reference point, SBPs higher than 150 mmHg were associated with poor functional outcome (acOR: 1.23, 95% CI: 1.09–1.38), but lower SBPs were not (acOR: 1.14, 95% CI: 0.99–1.30). Higher SBP was not associated with the risk of sICH (aOR: 1.09, 95% CI: 0.93–1.27) nor with the probability of successful reperfusion (aOR: 1.00, 95% CI: 0.91–1.10). Our main result was that we found no effect modification by IVT (p-values for interaction, mRS = 0.94; sICH = 0.26; successful reperfusion = 0.58). Discussion and conclusion: There was no effect modification of IVT with SBP for any of the clinical outcomes. Therefore, the level of SBP (if ⩽185/110 mmHg) should not guide IVT decisions in patients otherwise eligible for both IVT and EVT within the 4.5-h time window. Trial registration: ISRCTN80619088, https://www.isrctn.com/ISRCTN80619088