Calcium antagonists for acute ischemic stroke.

BACKGROUND: The sudden loss of blood supply in ischemic stroke is associated with an increase of calcium ions within neurons. Inhibiting this increase could protect neurons and might reduce neurological impairment, disability, and handicap after stroke. OBJECTIVES: To assess the effects of calcium antagonists for reducing the risk of death or dependency after acute ischemic stroke. We investigated the influence of different drugs, dosages, routes of administration, time intervals after stroke, and trial design on the outcomes. SEARCH METHODS: The evidence is current to 6 February 2018. We searched the Cochrane Stroke Group Trials Register (6 February 2018), Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 2), MEDLINE Ovid (1950 to 6 February 2018), Embase Ovid (1980 to 6 February 2018), and four Chinese databases (6 February 2018): Chinese Biological Medicine Database (CBM-disc), China National Knowledge Infrastructure (CNKI), Chinese Scientific Periodical Database of VIP information, and Wanfang Data. We also searched the following trials registers: ClinicalTrials.gov, EU Clinical Trials Register, Stroke Trials Registry, ISRCTN registry, WHO International Clinical Trials Registry Platform, and Chinese Clinical Trial Registry, and we contacted trialists and researchers. SELECTION CRITERIA: Randomized controlled trials comparing a calcium antagonist versus control in people with acute ischemic stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted data, assessed risk of bias, and applied the GRADE approach to assess the quality of the evidence. We used death or dependency at the end of long-term follow-up (at least three months) in activities of daily living as the primary outcome. We used standard Cochrane methodological procedures. MAIN RESULTS: We included 34 trials involving 7731 participants. All the participants were in the acute stage of ischemic stroke, and their age ranged from 18 to 85 years, with the average age ranging from 52.3 to 74.6 years across different trials. There were more men than women in most trials. Twenty-six trials tested nimodipine, and three trials assessed flunarizine. One trial each used isradipine, nicardipine, PY108-608, fasudil, and lifarizine. More than half of these trials followed participants for at least three months. Calcium antagonists showed no effects on the primary outcome (risk ratio (RR) 1.05; 95% confidence interval (CI) 0.98 to 1.13; 22 trials; 22 studies; 6684 participants; moderate-quality evidence) or on death at the end of follow-up (RR 1.07, 95% CI 0.98 to 1.17; 31 trials; 7483 participants; moderate-quality evidence). Thirteen trials reported adverse events, finding no significant differences between groups. Most trials did not report the allocation process or how they managed missing data, so we considered these at high risk of selection and attrition bias. Most trials reported double-blind methods but did not state who was blinded, and none of the trial protocols were available. AUTHORS' CONCLUSIONS: We found no evidence to support the use of calcium antagonists in people with acute ischemic stroke.

Closure versus medical therapy for preventing recurrent stroke in patients with patent foramen ovale and a history of cryptogenic stroke or transient ischemic attack.

BACKGROUND: The optimal therapy for preventing recurrent stroke in people with cryptogenic stroke and patent foramen ovale (PFO) has not been defined. The choice between medical therapy (antithrombotic treatment with antiplatelet agents or anticoagulants) and transcatheter device closure has been the subject of intense debate over the past several years. Despite the lack of scientific evidence, a substantial number of people undergo transcatheter device closure (TDC) for secondary stroke prevention. OBJECTIVES: To: 1) compare the safety and efficacy of TDC with best medical therapy alone for preventing recurrent stroke (fatal or non-fatal) or transient ischemic attacks (TIAs) in people with PFO and a history of cryptogenic stroke or TIA; 2) identify specific subgroups of people most likely to benefit from closure for secondary prevention; and 3) assess the cost-effectiveness of this strategy, if possible. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (July 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2014), MEDLINE (1950 to July 2014) and EMBASE (1980 to July 2014). In an effort to identify unpublished and ongoing trials we searched seven trials registers and checked reference lists. SELECTION CRITERIA: We included randomized controlled trials (RCTs), irrespective of blinding, publication status, and language, comparing the safety and efficacy of device closure with medical therapy for preventing recurrent stroke or TIA in people with PFO and a history of cryptogenic stroke or TIA. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed quality and risk of bias, and extracted data. The primary outcome measures of this analysis were the composite endpoint of ischemic stroke or TIA events as well as recurrent fatal or non-fatal ischemic stroke. Secondary endpoints included all-cause mortality, serious adverse events (atrial fibrillation, myocardial infarction, bleeding) and procedural success and effective closure. We used the Mantel-Haenszel method to obtain pooled risk ratios (RRs) using the random-effects model regardless of the level of heterogeneity. We pooled data for the primary outcome measure with the generic inverse variance method using the random-effects model, yielding risk estimates as pooled hazard ratio (HR), which accounts for time-to-event outcomes. MAIN RESULTS: We included three RCTs involving a total of 2303 participants: 1150 participants were randomized to receive TDC and 1153 participants were randomized to receive medical therapy. Overall, the risk of bias was regarded as high. The mean follow-up period of all three included trials was less than five years. Baseline characteristics (age, sex, and vascular risk factors) were similar across trials. Intention-to-treat analyses did not show a statistically significant risk reduction in the composite endpoint of recurrent stroke or TIA in the TDC group when compared with medical therapy (RR 0.73, 95% CI 0.45 to 1.17). A time-to-event analysis combining the results of two RCTs also failed to show a significant risk reduction with TDC (HR 0.69, 95% CI 0.43 to 1.13). When assessing stroke prevention alone, TDC still did not show a statistically significant benefit (RR 0.61, 95% CI 0.29 to 1.27) (HR 0.55, 95% CI 0.26 to 1.18). In a sensitivity analysis including the two studies using the Amplatzer PFO occluder, TDC showed a possible protective effect on recurrent stroke compared with medical therapy (HR 0.38, 95% CI 0.14 to 1.02); however, it did not reach statistical significance. Safety analysis found that the overall risks for all-cause mortality and adverse events were similar in both the TDC and medical therapy groups. However, TDC increased the risk of new-onset atrial fibrillation (RR 3.50, 95% CI 1.47 to 8.35) and may be associated with the type of device used. AUTHORS' CONCLUSIONS: The combined data from recent RCTs have shown no statistically significant differences between TDC and medical therapy in the prevention of recurrent ischemic stroke. TDC closure was associated with an increased risk of atrial fibrillation but not with serious adverse events.

Edaravone for acute stroke: Meta-analyses of data from randomized controlled trials.

AIMS: To assess the effectiveness of edaravone for acute stroke including ischemic stroke and intracerebral hemorrhage (ICH). METHODS: We identified randomized controlled trials with comprehensive searches and performed systematic reviews according to the Cochrane methods of systematical reviews. RESULTS: Edaravone can reduce the rate of death or long-term disability significantly for acute ischemic stroke (AIS) (RR = 0.65; 95%CI, 0.48 to 0.89, p = 0.007). However, sensitivity analysis yielded a different result. Edaravone can also improve the short-term neurological impairment of AIS (MD = 7.09; 95%CI, 5.12 to 9.05, p < 0.00001), and ICH (MD = -4.32; 95%CI, -5.35 to -3.29, p < 0.00001). CONCLUSIONS: Edaravone is beneficial in improving neurological impairment resulting from AIS and ICH. However, currently there is no enough convincing evidence that edaravone reduces death or long-term disability for AIS and ICH.

Recent developments of 19-nor-1,25-dihydroxyvitamin D3 analogues.

The vitamin D hormone, 1α,25-dihydroxyvitamin D3 [1,25-(OH)2 D3 ], exerts its hormonal effects predominantly on intestine, bone, and kidney, where it plays a crucial role in calcium and phosphorus homeostasis and bone mineralization. In addition to its classical actions, 1,25(OH)2 D3 exerts pleiotropic effects in a wide variety of target tissues and cell types, often in an autocrine/paracrine fashion. These biological activities of 1,25(OH)2 D3 have suggested a multitude of potential therapeutic applications for the vitamin D hormone in the treatment of hyperproliferative disorders (e.g. cancer and psoriasis), immune dysfunction (autoimmune diseases), and endocrine disorders (e.g. hyperparathyroidism). However, the calcemic effects induced by 1,25(OH)2 D3--hypercalcemia, increased bone resorption, and soft tissue calcification--limit the use of the natural ligand in these clinical applications. Therefore, numerous 1,25(OH)2 D3 analogues have been synthesized with the intent of producing therapeutic agents devoid of hypercalcemic and hyperphosphatemic side effects. To this aim, much attention has been focused on the development of 19-nor-vitamin D3 derivatives that lack the ring-A exocyclic methylene group (C19). In this review, the 19-nor-1,25(OH)2 D3 analogues are classified according to modifications made at the A-ring, the side chain, or both the A-ring and side chain, as well as other positions. The biological activities of these 19-nor-1,25(OH)2 D3 analogues are summarized and their structure-activity relationships and binding features with the vitamin D receptor (VDR) are discussed.

Recent developments of 2-substituted analogs of 1,25(OH)(2)D(3).

The plethora of biological activities of 1,25(OH)(2)D(3) and its analogs suggests an enormous potential for vitamin D therapy in the treatment of hyperproliferative diseases (cancer, psoriasis), endocrine dysfunction (hyperparathyroidism), immune disorders (autoimmune diseases, transplant rejection), bone disorders (osteoporosis, Paget's bone disease). However, the therapeutic limitation of 1,25(OH)(2)D(3) is its calcemic and phosphatemic activities, since it can cause serious side effects such as hypercalcemia and hyperphosphatemia at super physiological levels. Therefore, numerous efforts have been made to find the new vitamin D analogs, that retain the therapeutically important properties of 1,25(OH)(2)D(3) but with greater selectivity, which allows more effective intervention with fewer toxic side effects. This review will focus on the biological activities of the 2-substituted analogs of 1,25(OH)(2)D(3). They were classified as 2α-, 2ß-, 2,2-disubstituted analogs, and those with modifications in both the A-ring at the 2-position and the side chains. Their structure-activity relationships and binding features with the vitamin D receptor (VDR) were discussed.

Systematic review and meta-analysis of the efficacy of sphingosine-1-phosphate (S1P) receptor agonist FTY720 (fingolimod) in animal models of stroke.

BACKGROUND AND PURPOSE: FTY720 (fingolimod) is a known sphingosine-1-phosphate (S1P) receptor agonist, which has been used in clinical trials for treating multiple sclerosis, renal transplantation, and decreasing reperfusion injury in heart, liver, and kidney. Most of these clinical trials have showed a positive effect. Especially, the trials of MS showed a reduction of relapse rate in FTY720-treated patients. Now, some animal experiments indicated that FTY720 could be a new compound available treatment for stroke patients by exerting neuroprotection via S1P1 mediated antiapoptotic mechanisms. Whether it could be effective in animals is unclear, so we conducted a systematic review to make it clear. METHODS: We conducted a systematic review and meta-analysis of the efficacy of FTY720 in animal models of focal cerebral ischemia by electronic and manual searches of the literature. Data on study quality, FTY720 dose, time of administration, and outcome measured as infarct volume or functional deficit were extracted. Data from all studies were analyzed by means of a standardized mean difference meta-analysis. RESULTS: Of the 19 identified studies, 9 were included. Among all the included studies, 178 animals were calculated for infarct size and 194 animals were assessed of neurological deficits. The methodological quality of the studies ranged from 2 to 10 according to a published 11-item quality scale. Of the nine studies selected, only one reported a negative result of FTY720. The result indicated that FTY720 reduced the infarct volume (SMD = -1.31, 95% CI -1.99 to -0.63) and improve the functional outcome (SMD = -1.61, 95% CI -2.17 to -1.05). CONCLUSIONS: The data we included supporting FTY720 was a candidate drug for stroke, but it should be considered with caution. More good quality experimental studies should be performed to evaluate the safety of FTY720 in the future. Whether FTY720 is effective in aged animals that mimicked human with comorbidities like diabetes and hypertension should also be deliberated.

Posterior versus anterior circulation infarction: how different are the neurological deficits?

BACKGROUND AND PURPOSE: Distinguishing between symptoms of posterior circulation infarction (PCI) and anterior circulation infarction (ACI) can be challenging. This study evaluated the frequency of symptoms/signs in the 2 vascular territories to determine the diagnostic value of particular symptoms/signs for PCI. METHODS: Neurological deficits were reviewed and compared from 1174 consecutive patients with a diagnosis of PCI or ACI confirmed by magnetic resonance imaging in the Chengdu Stroke Registry. The diagnostic value of specific symptoms/signs for PCI was determined by measuring their sensitivity, specificity, positive predictive value (PPV), and the OR. RESULTS: Homolateral hemiplegia (PCI, 53.6% versus ACI, 74.9%; P<0.001), central facial/lingual palsy (PCI, 40.7% versus ACI, 62.2%; P<0.001), and hemisensory deficits (PCI, 36.4% versus ACI, 34.2%; P=0.479) were the 3 most common symptoms/signs in PCI and ACI. The signs with the highest predictive values favoring a diagnosis of PCI were Horner's syndrome (4.0% versus 0%; P<0.001; PPV=100.0%; OR=4.00), crossed sensory deficits (3.0% versus 0%; P<0.001; PPV=100.0%; OR=3.98), quadrantanopia (1.3% versus 0%; P<0.001; PPV=100.0%; OR=3.93), oculomotor nerve palsy (4.0% versus 0%; P<0.001; PPV=100.0%; OR=4.00), and crossed motor deficits (4.0% versus 0.1%; P<0.001; PPV=92.3%; OR=36.04); however, all had a very low sensitivity, ranging from 1.3% to 4.0%. CONCLUSIONS: This study indicates that the symptoms/signs considered typical of PCI occur far less often than was expected. Inaccurate localization would occur commonly if clinicians relied on the clinical neurological deficits alone to differentiate PCI from ACI. Neuroimaging is vital to ensure accurate localization of cerebral infarction.

Calcium antagonists for acute ischemic stroke.

BACKGROUND: The sudden loss of blood supply in ischemic stroke is associated with the increase of calcium ions within neurons. Inhibiting this increase could protect neurons and hence might reduce neurological impairment, disability and handicap after stroke. OBJECTIVES: To determine whether calcium antagonists reduce the risk of death or dependency after acute ischemic stroke. To investigate the influence of different drugs, dosages, routes of administration, time intervals after stroke and trial design on the risk of a primary outcome. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (January 2012), MEDLINE (1950 to December 2011), EMBASE (1980 to December 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2011 issue 4) and four Chinese databases (December 2011): Chinese Biological Medicine Database (CBM-disc), China National Knowledge Infrastructure (CNKI), Chinese scientific periodical database of VIP information and Wanfang Data. We also contacted trialists and researchers. SELECTION CRITERIA: All truly randomized trials comparing a calcium antagonist with control in patients with acute ischemic stroke. DATA COLLECTION AND ANALYSIS: Two authors assessed all trials and extracted the data. We used death or dependency at the end of long-term follow-up (at least three months) in activities of daily living as the primary outcome. Analyses were, if possible, intention-to-treat. MAIN RESULTS: We included 34 trials including 7731 patients. There was no effect of calcium antagonists on the primary outcome (risk ratio (RR) 1.05; 95% confidence interval (CI) 0.98 to 1.13), or on death at the end of follow-up (RR 1.07, 95% CI 0.98 to 1.17). Comparisons of different doses of nimodipine suggested that the highest doses were associated with poorer outcome. AUTHORS' CONCLUSIONS: No evidence is available using calcium antagonists in patients with acute ischemic stroke is effective.

Ozagrel for acute ischemic stroke: a meta-analysis of data from randomized controlled trials.

BACKGROUND: In patients with acute ischemic stroke (AIS), platelets are activated in the acute phase, releasing neurotoxic, and thrombogenic eicosanoids, which may reduce the brain blood flow and cause brain damage. Sodium ozagrel (ozagrel), a thromboxane A2 synthase inhibitor, is one of the most studied drugs which may reduce the risk of neurological impairment and reduce the volume of brain damage. We systematically reviewed all published randomized controlled trials (RCTs) comparing ozagrel with control among patients with AIS. METHODS: We searched seven databases, using the Cochrane Stroke Group search strategy and the terms of ozagrel and stroke. Two independent investigators evaluated trial quality using the Cochrane Collaboration's risk of bias tool and extracted the data from each study. Pooled analyses for the outcomes of combined death or disability and improvement of neurological impairment were calculated. RESULTS: The effect of ozagrel on the reduction of death for AIS at the end of follow-up was relative risk (RR) = 0·67 (95% CI: 0·11 to 4·04, P = 0·67). The effect evaluated by Modified Edinburgh-Scandinavian Stroke Scale (MESSS) at the end of treatment was mean difference (MD) = -4·17 (95% CI, -4·95 to -3·40; P<0·00001). The most severe adverse events of ozagrel were digestive hemorrhage and hemorrhagic stroke; however, there was no significant difference between the two groups. The subgroup analysis of different dose showed that 80 and 160 mg ozagrel per day might both increase the improvement of the neurological impairment. DISCUSSION: During scheduled treatment, ozagrel is effective for the improvement of neurological impairment for AIS patients. However, the evidence of ozagrel to reduce the long-term death or disability is limited and quality of these trials is insufficent hence, large-sample and high quality RCTs are warrented to confirm the efficacy of ozagrel for acute ischemic stroke.

Efficacy and safety of human urinary kallidinogenase injection for acute ischemic stroke: a systematic review.

OBJECTIVE: To assess the efficacy and safety of human urinary kallidinogenase injection (HUK) in treating patients with acute ischemic stroke. METHODS: We searched the Chinese Stroke Trials Register, the Cochrane Stroke Group Trials Register, CENTRAL, Medline, EMBASE, the China Biological Medicine Database(CBM), and the China National Knowledge Infrastructure (CNKI), which were all last searched October 2010. Randomized controlled trials (RCTs) about HUK for patients with acute ischemic stroke were included. The quality of each trial was assessed using the Cochrane Reviewers' Handbook 5.0.2. RESULTS: Twenty-four trials involving 2433 patients were included. Only two trials reported death or dependence at the end of three months follow up. In those trials, HUK reduced death or dependency comparing to the control group (relative ratio (RR) = 0.69, 95% CI 0.55 to 0.86). Twenty trials (2117 patients) reported the proportion of patients with marked neurological improvement after treatment. Meta analysis showed the HUK-treated group had more neurological improvement than did the control group (RR = 1.56, 95% CI 1.44 to 1.70). Fifteen trials reported adverse events, of which transient hypotension was most common (1.5%-5.1%). Non-fatal intracerebral hemorrhage was detected in seven patients, but the difference between the treatment and control groups was not significant (RR = 1.82, 95% CI 0.34 to 9.61). Deaths occurred in both the HUK group (0.4%) and the control group (1.1%), with no significant difference for this outcome (RR = 0.6, 95% CI 0.09 to 3.92). No trial assessed quality of life. CONCLUSIONS: Available evidence suggests that HUK injection reduces neurological impairment after acute ischemic stroke and improves long-term outcomes, though a few patients suffered from transient hypotension. Further high-quality, large scale randomized trials are needed to confirm these results.

Assessment of methodological quality and outcome measures of acute stroke randomized controlled trials in China in recent 15 years.

BACKGROUND: Randomized controlled trials (RCTs) are the most important evidence to guide clinical practice in the treatment of acute stroke. This study aims to evaluate the changes of quantity and methodological quality of acute stroke RCTs in Mainland China published in recent 15 years. METHOD: We included un-confounded RCTs on acute stroke from eight databases published in Chinese or English from 1996 to 2010. General characteristics, design methodology, and outcome measures of studies were assessed. RESULTS: Totally, 9061 RCTs were identified. The number of acute stroke RCTs had increased by years, the total of trials published in 2010 was 20 times of that published in 1996. Three thousand four hundred eighty-eight trials (38.5%) used western drugs in the treatment, 3026 (33.4%) trials used traditional Chinese medicine (TCM), and 1933 (22.0%) trials used physical therapy. Ischemic stroke was the most common research subject among all trials (65.1%, 5,989). There were 541 (6.0%) RCTs using adequate randomization methods, 34 (0.4%) RCTs using adequate allocation concealment, and 195 (2.2%) using adequate blinding methods. Thirty-three (0.4%) RCTs adopted both adequate randomization methods and allocation concealment. Only 23 (0.3%) trials used all three methods of adequate randomization methods, allocation concealment, and blinding. During the 15 years, only the number of trials using adequate randomized methods and reporting adverse events had significantly increased (both P < 0.001). As for these RCTs, only the number of trials using adequate blinding method in pharmaceutical intervention was statistical differences compared with that of nondrug intervention trials (P = 0.043). Outcomes were assessed blindly in 72 trials. Death was reported by 14.2% of trials, impairment by 85.1%, disability by 22.5%, and handicap or quality of life by 0.4%. 99.7% trials reported positive results. Larger trials were more likely to use adequate randomized methods, allocation concealment and blinding methods, as well as to measure disability. Only 14 large-sample high-quality RCTs were found. CONCLUSION: During 15 years, the number of acute stroke RCTs has increased dramatically, but the quality of trials improves slowly. Most acute stroke trials used inadequate outcome measures in terms of their content, reliability, validity, blinding assessment.