Deferoxamine in intracerebral hemorrhage: Systematic review and meta-analysis
Clinical neurology and neurosurgery. 2023;227:107634
BACKGROUND Intracerebral hemorrhage (ICH) is a stroke with a high morbidity and mortality rate. Deferoxamine (DFX) is thought to be effective in treating Intracerebral Hemorrhage. In our study, we performed a meta-analysis to evaluate the treatment effects of DFX. METHODS We systematically searched PubMed, Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and Chinese Biomedical Literature Database in Jan 2022 for studies on DFX for ICH patients. Outcome measures included relative hematoma volume, relative edema volume, good neurological functional outcome and adverse events. Odds risk (OR) and weighted mean difference (WMD) were used to evaluate clinical outcomes. RESULTS After searching 636 articles, 4 RCTs, 2 NRCTs, and 1cohort study were included. We found that DFX was effective in hematoma absorption on day 7 after onset, but the difference was not significant on day 14. DFX could suppress edema expansion on days 3, 7, and 14 after onset. DFX did not contribute to better outcomes after 3 and 6 months when used the modified Rankin Scale and the Glasgow Outcome Scale to evaluate neurological prognosis. The pooled results showed no statistically significant difference in Serious adverse events between the experimental and control groups. CONCLUSIONS DFX could limit edema expansion on days 3, 7, and 14 after commencement and facilitate hematoma absorption at week 1 without significantly increasing the risk of adverse events, but it did not improve neurological prognosis.
Patients with intracerebral haemorrhage (n= 7 studies).
Outcome measures included relative haematoma volume, relative oedema volume, good neurological functional outcome and adverse events. DFX was effective in haematoma absorption on day 7 after onset, but the difference was not significant on day 14. DFX could suppress oedema expansion on days 3, 7, and 14 after onset. DFX did not contribute to better outcomes after 3 and 6 months when used the modified Rankin Scale and the Glasgow Outcome Scale to evaluate neurological prognosis. The pooled results showed no statistically significant difference in serious adverse events between the experimental and control groups.
Desmopressin for patients with spontaneous intracerebral haemorrhage taking antiplatelet drugs (DASH): a UK-based, phase 2, randomised, placebo-controlled, multicentre feasibility trial
The Lancet. Neurology. 2023;22(7):557-567
BACKGROUND The risk of death from spontaneous intracerebral haemorrhage is increased for people taking antiplatelet drugs. We aimed to assess the feasibility of randomising patients on antiplatelet drug therapy with spontaneous intracerebral haemorrhage to desmopressin or placebo to reduce the antiplatelet drug effect. METHODS DASH was a phase 2, randomised, placebo-controlled, multicentre feasibility trial. Patients were recruited from ten acute stroke centres in the UK and were eligible if they had an intracerebral haemorrhage with stroke symptom onset within 24 h of randomisation, were aged 18 years or older, and were taking an antiplatelet drug. Participants were randomly assigned (1:1) to a single dose of intravenous desmopressin 20 μg or matching placebo. Treatment allocation was concealed from all staff and patients involved in the trial. The primary outcome was feasibility, which was measured as the number of eligible patients randomised and the proportion of eligible patients approached, and analysis was by intention to treat. The trial was prospectively registered with ISRCTN (reference ISRCTN67038373), and it is closed to recruitment. FINDINGS Between April 1, 2019, and March 31, 2022, 1380 potential participants were screened for eligibility. 176 (13%) participants were potentially eligible, of whom 57 (32%) were approached, and 54 (31%) consented and were subsequently recruited and randomly assigned to receive desmopressin (n=27) or placebo (n=27). The main reason for eligible patients not being recruited was the patient arriving out of hours (74 [61%] of 122 participants). The recruitment rate increased after the enrolment period was extended from 12 h to 24 h, but it was then impaired due to the COVID-19 pandemic. Of the 54 participants included in the analysis (mean age 76·4 years [SD 11·3]), most were male (36 [67%]) and White (50 [93%]). 53 (98%) of 54 participants received all of their allocated treatment (one participant assigned desmopressin only received part of the infusion). No participants were lost to follow-up or withdrew from the trial. Death or dependency on others for daily activities at day 90 (modified Rankin Scale score >4) occurred in six (22%) of 27 participants in the desmopressin group and ten (37%) of 27 participants in the placebo group. Serious adverse events occurred in 12 (44%) participants in the desmopressin group and 13 (48%) participants in the placebo group. The most common adverse events were expansion of the haemorrhagic stroke (four [15%] of 27 participants in the desmopressin group and six [22%] of 27 participants in the placebo group) and pneumonia (one [4%] of 27 participants in the desmopressin group and six [22%] of 27 participants in the placebo group). INTERPRETATION Our results show it is feasible to randomise patients with spontaneous intracerebral haemorrhage who are taking antiplatelet drugs to desmopressin or placebo. Our findings support the need for a definitive trial to determine if desmopressin improves outcomes in patients with intracerebral haemorrhage on antiplatelet drug therapy. FUNDING National Institute for Health Research.
Patients with spontaneous intracerebral haemorrhage taking antiplatelet drugs, enrolled in the DASH feasibility randomised phase 2 trial, in the UK (n= 54)
Single dose of intravenous desmopressin (n= 27).
Matching placebo (n= 27).
The primary outcome was feasibility, which was measured as the number of eligible patients randomised and the proportion of eligible patients approached, and analysis was by intention to treat. 1380 potential participants were screened for eligibility. 176 (13%) participants were potentially eligible, of whom 57 (32%) were approached, and 54 (31%) consented and were subsequently recruited and randomly assigned. The main reason for eligible patients not being recruited was the patient arriving out of hours (74 [61%] of 122 participants). No participants were lost to follow-up or withdrew from the trial. Death or dependency on others for daily activities at day 90 occurred in six (22%) of 27 participants in the desmopressin group and 10 (37%) of 27 participants in the placebo group. Serious adverse events occurred in 12 (44%) participants in the desmopressin group and 13 (48%) participants in the placebo group.
Efficacy and safety of traditional Chinese medicine for intracranial hemorrhage by promoting blood circulation and removing blood stasis: A systematic review and meta-analysis of randomized controlled trials
Frontiers in pharmacology. 2022;13:942657
Background: Although blood-activating Chinese medicine (BACM) has been reported as adjuvant therapy for intracranial hemorrhage (ICH) in China, high-quality evidence is still lacking. Our study aimed to collect the latest high-quality randomized controlled trials (RCTs) and to evaluate the efficacy and safety of BACM for ICH. Methods: RCTs published between January 2015 and March 2022 were searched in databases, including China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), Sino-Med, Wanfang, PubMed, Web of Science, Cochrane Library, and Embase without language restrictions. Eligible RCTs were included and both primary (clinical efficacy evidenced by decreased neurological deficit scores) and secondary outcomes (increased Barthel index, decreased NIHSS, hematoma volume, the volume of cerebral edema, the incidence of side effects, and mortality) were analyzed. The quality of included RCTs was assessed using the Cochrane risk of bias tool. In the meta-analysis, the pooled results were analyzed using Review Manager 5.3 and STATA14.0. Finally, The GRADEpro GDT software (Guideline Development Tool) was used to summarize the results. Sensitivity and subgroup analyses were conducted based on the follow-up time. Results: Fifteen RCTs, involving 1,579 participants, were included for analysis in our study. The pooled outcomes indicated that BACM combined with western medicine treatment (WMT) was superior to WMT alone for patients with ICH, demonstrated by the improvements in efficacy (RR = 1.22 (95% CI, [1.13 to 1.32], p < 0.001), neurological functions (MD(NIHSS) = -2.75, 95% CI [-3.74 to -1.76], p < 0.001), and activities of daily living (MD(Barthel index) = 5.95, 95% CI [3.92 to 7.98], p < 0.001), as well as decreased cerebral hematoma, cerebral edema (MD cerebral hematoma = -2.94, 95% CI [-3.50 to -2.37, p < 0.001 and MD(cerebral edema) = -2.66, 95% CI [-2.95 to -2.37], p < 0.001), side effects and mortality (RR = 0.84 (95% CI [0.60 to 1.19], p = 0.330 and RR = 0.51 (95% CI, [0.16 to 1.65], p = 0.260). In addition, Conioselinum anthriscoides "Chuanxiong" [Apiaceae], Camellia reticulata Lindl. [Theaceae], and Bupleurum sibiricum var. jeholense (Nakai) C.D.Chu [Apiaceae]) were the most frequently used herbs in the treatment of ICH. Recently, there was a trend toward the extensive use of another two herbs, including Rheum palmatum L. [Polygonaceae], Astragalus mongholicus Bunge [Fabaceae]) for ICH. Conclusion: BACM combined with WMT seems to be superior to WMT alone for patients with ICH. Further high-quality RCTs are warranted to confirm the efficacy and safety of BACM.
A Comparison Between Enteral and Intravenous Nimodipine in Subarachnoid Hemorrhage: A Systematic Review and Network Meta-Analysis
Neurocritical care. 2022
Our objective was to compare the effectiveness of intravenous and enteral nimodipine in preventing poor outcome from delayed cerebral ischemia in patients with subarachnoid hemorrhage. We performed a systematic search and a network meta-analysis using the following databases: PubMed, Scopus, the Cochrane Central Register of Controlled Trials, and Google Scholar. Risk of Bias 2 tool was used to assess risk of bias of included studies. A ranking among methods was performed on the basis of the frequentist analog of the surface under the cumulative ranking curve. Published studies that met the following population, intervention, comparison, outcomes and study (PICOS) criteria were included: patients with subarachnoid hemorrhage aged 15 years or older (P); nimodipine, intravenous and oral formulation (I); placebo or no intervention (C); poor outcome measured at 3 months (defined as death, vegetative state, or severe disability), case fatality at 3 months, delayed cerebral ischemia, delayed ischaemic neurologic deficit, and vasospasm measured with transcranial Doppler or digital subtraction angiography (O); and randomized controlled trials (S). No language or publication date restrictions were applied. Ten studies were finally included, with a total of 1527 randomly assigned patients. Oral and intravenous nimodipine were both effective in preventing poor outcome, delayed cerebral ischemia, and delayed ischaemic neurological deficit. Neither treatment was effective in improving case fatality. Evolving clinical protocols over a 30-year period and the risk of bias of the included studies may limit the strength of our results. Enteral and intravenous nimodipine may have a similar effectiveness in terms of preventing poor outcome, delayed cerebral ischemia, and delayed ischaemic neurological deficit. More research may be needed to fully establish the role of intravenous nimodipine in current clinical practice.
Efficacy of desferrioxamine mesylate in intracerebral hematoma: a systemic review and meta-analysis
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2022;:1-12
BACKGROUND Previous meta-analysis had concluded that desferrioxamine mesylate (DFO) could effectively treat intracerebral hematoma (ICH) in animal models. We hope to confirm that DFO could treat ICH patients effectively through the systemic review and meta-analysis of clinical researches. METHOD Data extraction included hematoma volume (HV), reduction of National Institute of Health Stroke Scale (NIHSS) scores, and relative perihematomal edema (RPHE). The standard mean difference (SMD) and 95% confidence interval (95%CI) were calculated by fixed effects model. I-square (I(2)) statistic was used to test the heterogeneity. All p values were two-side with a significant level at 0.05. RESULTS Five randomized controlled trials were included in the meta-analysis, which included 239 patients. At 7 days after onset, there was significant difference of RPHE development (- 1.87 (- 2.22, - 1.51) (I(2) = 0, p = 0.639)) and significant difference of HV absorption (- 0.71 (- 1.06, 0.36) (I(2) = 17.5%, p = 0.271)) between DFO and control groups. There was significant difference of reduction of NHISS scores (0.25 (0.05, 0.46) (I(2) = 0, p = 0.992)) between DFO and control groups at 30 days after onset. CONCLUSION DFO reduced HV and perihematomal edema in ICH patients at 7 days after onset and improve neurological function at 30 days after onset efficiently and safely. DFO might be a new route of improving treatment of ICH.
Cilostazol for Aneurysmal Subarachnoid Hemorrhage: An Updated Systematic Review and Meta-Analysis
Cerebrovascular Diseases (Basel, Switzerland). 2022;51(2):138-148
BACKGROUND AND PURPOSE Delayed cerebral ischemia is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). Cilostazol, a selective inhibitor of phosphodiesterase 3, was reported to reduce cerebral vasospasm and improve outcomes. We aimed to conduct an updated systematic review and meta-analysis of the efﬁcacy and safety of cilostazol in aSAH. METHODS We systematically searched PubMed, Embase, MEDLINE, and the Cochrane Library for articles published in English with the latest publishing time in August 2020. Articles reporting favorable outcome as the primary outcome and reporting severe angiographic vasospasm (aVS), symptomatic vasospasm (sVS), new cerebral infarction, or mortality as the secondary outcome were included in this review. Furthermore, we examined whether clinical outcomes were associated with the dosage of cilostazol (300 mg/day vs. 100-200 mg/day). RESULTS Data from 405 patients in 4 randomized controlled trials (RCTs) and 461 patients in 4 observational studies (OSs) were included. In RCT studies, cilostazol was associated with significant favorable outcomes at discharge or 1 month (risk ratio [RR] 1.41, 95% confidence interval [CI] 1.01-1.97, p = 0.04) or 3 or 6 months (RR 1.16, 95% CI 1.05-1.28, p = 0.002). However, in OSs, no significant difference was indicated in favorable outcomes at discharge or 1 month (RR 1.22, 95% CI 0.94-1.60, p = 0.14) nor 3 or 6 months (RR 1.29, 95% CI 0.92-1.81, p = 0.14). The analyses found that cilostazol significantly reduced the incidences of severe aVS (RCT: RR 0.64, 95% CI 0.41-1.01, p = 0.05; OS: RR 0.61, 95% CI 0.43-0.88, p = 0.007), sVS (RCT: RR 0.46, 95% CI 0.31-0.70, p = 0.0002; OS: RR 0.38, 95% CI 0.21-0.68, p = 0.001), and new cerebral infarction (RCT: RR 0.40, 95% CI 0.24-0.67, p = 0.0005; OS: RR 0.38, 95% CI 0.23-0.64, p = 0.0002). However, no significant difference in mortality (RCT: RR 0.86, 95% CI 0.23-3.21, p = 0.82; OS: RR 0.16, 95% CI 0.02-1.24, p = 0.08) was found. In 3 OSs which reported different doses of cilostazol (300 mg/day vs. 100-200 mg/day) for aSAH, the 300-mg/day cilostazol groups showed decreased delayed cerebral infarction (RR 0.27, 95% CI 0.09-0.81, p = 0.02) but no significant difference in shunt-dependent hydrocephalus (RR 0.92, 95% CI 0.33-2.60, p = 0.88) or functional outcomes (RR 1.14, 95% CI 0.74-1.75, p = 0.56) compared with the 100-200 mg/day cilostazol groups. CONCLUSIONS The meta-analyses suggest the credible efficacy and safety of cilostazol in treating aSAH. Furthermore, 300-mg/day cilostazol treatment appeared to be more effective than 100-200 mg/day treatment.
Clinical efficacy of Intraventricular rt-PA (Actilyse) in the outcome of patients with spontaneous intraventricular hemorrhage
Turkish neurosurgery. 2022
AIM: Intraventricular injection of a thrombolytic agent appears to be effective in the lysis of intraventricular hematoma, and improves the final clinical outcome. In this study, we evaluated the effectiveness of intraventricular injection of rt-PA (Actilyse) in patients with spontaneous intraventricular hemorrhage (IVH) who had undergone external ventricular drainage (EVD). MATERIAL AND METHODS This randomized clinical trial recruited 60 patients with spontaneous IVH who had undergone EVD due to the signs of hydrocephalus. The patients were randomly divided into two groups, including a group receiving intraventricular injection of rt-PA and the other normal saline. RESULTS Both groups receiving rt-PA Actilyse (n = 28) or placebo (n = 32) were male by majority (58.33%). We found no difference in the prevalence of meningitis and brain infection (35.7% vs. 37.5%, P = 0.665). Changes in hematoma volume at the end of the fourth day compared to the first day after EVD differed significantly between the two groups (P = 0.004). The majority (64.29%) showed a decrease in the rt-PA group, but in the placebo group, the majority (53.13%) remained constant. As a result, changes in the rt-PA group were significantly higher than those in the placebo group. Improvements in the level of consciousness (GCS) at the end of the fourth day compared to the first day after EVD implantation was 1.07 units in the Actilyse group and -1.91 in the placebo group. As shown, the fourth day showed significant differences between the two groups (P 0.001). Improvements in the Glasgow Coma Scale (GCS) were observed at the end of the period. CONCLUSION It can be concluded that intraventricular injection of rt-PA (Actilyse) can effectively reduce the volume of hematoma and improve the level of consciousness (GCS) during treatment. Intraventricular injection of 2-mg rt-PA is safe for patients and does not cause any acute complications such as cerebral hematoma expansion.
Safety and efficacy of intravenous thrombolysis in acute ischemic stroke patients with a history of intracranial hemorrhage: A systematic review and meta-analysis
Clinical neurology and neurosurgery. 2022;215:107205
Acute ischemic stroke (AIS) is a fatal and debilitating condition killing 2.7 million people each year worldwide. The most commonly used treatment modality for AIS is intravenous thrombolysis (IVT) with alteplase which is indicated for those presenting within 4.5 h of onset. Due to a lack of reliable evidence on harm or benefit, the 2019 American Heart Association/American Stroke Association (AHA/ASA) guidelines consider a history of previous intracranial hemorrhage (ICH) as potentially harmful and no longer an absolute contraindication for IVT in patients with AIS, and the U.S. Food and Drug Administration (FDA) removed chronic ICH as a specific contraindication for IVT from the label in 2015. Despite a shift in guidelines, physicians frequently face the dilemmatic choice whether to administer IVT in this subset of patients due to the risk of symptomatic intracranial hemorrhage (SICH). The benefit of IVT in such patients has not been thoroughly investigated, and there are only a few studies on the subject in the literature to date. We conducted the present meta-analysis in an aim to provide solid evidence on the efficacy and safety of IVT for treating AIS in patients with a history of remote ICH. Our meta-analysis found that IVT improves functional outcomes in AIS patients with prior remote ICH without increasing SICH or all-cause mortality. These findings may contribute to the decision-making process for IVT administration in AIS patients.
Cilostazol Administration for Subarachnoid Hemorrhage: A Meta-analysis of Randomized Controlled Trials
Clinical Neuropharmacology. 2022;45(5):111-116
INTRODUCTION The efficacy of cilostazol administration to treat subarachnoid hemorrhage remains controversial. We conduct a systematic review and meta-analysis to explore the influence of cilostazol administration on treatment efficacy for subarachnoid hemorrhage. METHODS We have searched PubMed, Embase, Web of science, EBSCO, and Cochrane Library databases through July 2020 for randomized controlled trials assessing the effect of cilostazol administration in patients with subarachnoid hemorrhage. This meta-analysis is performed using the random-effect model. RESULTS Four randomized controlled trials involving 405 patients were included in the meta-analysis. Overall, compared with control group for subarachnoid hemorrhage, cilostazol intervention can significantly reduce symptomatic vasospasm (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.21-0.60; P = 0.0001) and cerebral infarction (OR, 0.40; 95% CI, 0.22-0.73; P = 0.003) and improve no or mild angiographic vasospasm (OR, 2.01; 95% CI, 1.19-3.42; P = 0.01) and an mRS score of 2 or less (OR, 2.70; 95% CI, 1.09-6.71; P = 0.03), but revealed no obvious influence on severe angiographic vasospasm (OR, 0.53; 95% CI, 0.27-1.02; P = 0.06). There were no increase in adverse events (OR, 1.17; 95% CI, 0.54-2.52; P = 0.69), hemorrhagic events (OR, 0.62; 95% CI, 0.06-6.27; P = 0.69), and cardiac events (OR, 2.14; 95% CI, 0.44-10.27; P = 0.34) after the cilostazol intervention than control intervention. CONCLUSIONS Cilostazol treatment may be effective to treat subarachnoid hemorrhage in the terms of symptomatic vasospasm, cerebral infarction, no or mild angiographic vasospasm, and an mRS score of 2 or less.
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.