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The Cochrane Database of Systematic... Aug 2018Epilepsy is a common neurological condition in which abnormal electrical discharges from the brain cause recurrent unprovoked seizures. It is believed that with... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Epilepsy is a common neurological condition in which abnormal electrical discharges from the brain cause recurrent unprovoked seizures. It is believed that with effective drug treatment up to 70% of individuals with active epilepsy have the potential to become seizure-free, and to go into long-term remission shortly after starting drug therapy with a single antiepileptic drug in monotherapy.Worldwide, sodium valproate and phenytoin are commonly used antiepileptic drugs for monotherapy treatment. It is generally believed that phenytoin is more effective for focal onset seizures, and that sodium pvalproate is more effective for generalised onset tonic-clonic seizures (with or without other generalised seizure types). This review is one in a series of Cochrane Reviews investigating pair-wise monotherapy comparisons. This is the latest updated version of the review first published in 2001, and updated in 2013 and 2016.
OBJECTIVES
To review the time to treatment failure, remission and first seizure of sodium valproate compared to phenytoin when used as monotherapy in people with focal onset seizures or generalised tonic-clonic seizures (with or without other generalised seizure types).
SEARCH METHODS
We searched the Cochrane Epilepsy Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform ICTRP on 19 February 2018. We handsearched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field.
SELECTION CRITERIA
Randomised controlled trials (RCTs) comparing monotherapy with either sodium valproate or phenytoin in children or adults with focal onset seizures or generalised onset tonic-clonic seizures DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review. Our primary outcome was time to treatment failure and our secondary outcomes were time to first seizure post-randomisation, time to six-month, and 12-month remission, and incidence of adverse events. We used Cox proportional hazards regression models to obtain trial-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), using the generic inverse variance method to obtain the overall pooled HR and 95% CI.
MAIN RESULTS
We included 11 trials in this review and IPD were available for 669 individuals out of 1119 eligible individuals from five out of 11 trials, 60% of the potential data. Results apply to focal onset seizures (simple, complex and secondary generalised tonic-clonic seizures), and generalised tonic-clonic seizures, but not other generalised seizure types (absence or myoclonus seizure types). For remission outcomes, a HR of less than 1 indicates an advantage for phenytoin, and for first seizure and treatment failure outcomes a HR of less than 1 indicates an advantage for sodium valproate.The main overall results were: time to treatment failure for any reason related to treatment (pooled HR adjusted for seizure type 0.88, 95% CI 0.61 to 1.27; 5 studies; 528 participants; moderate-quality evidence), time to treatment failure due to adverse events (pooled HR adjusted for seizure type 0.77, 95% CI 0.44 to 1.37; 4 studies; 418 participants; moderate-quality evidence), time to treatment failure due to lack of efficacy (pooled HR for all participants 1.16 (95% CI 0.71 to 1.89; 5 studies; 451 participants; moderate-quality evidence). These results suggest that treatment failure for any reason related to treatment and treatment failure due to adverse events may occur earlier on phenytoin compared to sodium valproate, while treatment failure due to lack of efficacy may occur earlier on sodium valproate than phenytoin; however none of these results were statistically significant.Results for time to first seizure (pooled HR adjusted for seizure type 1.08, 95% CI 0.88 to 1.33; 5 studies; 639 participants; low-quality evidence) suggest that first seizure recurrence may occur slightly earlier on sodium valproate compared to phenytoin. There were no clear differences between drugs in terms of time to 12-month remission (pooled HR adjusted for seizure type 1.02, 95% CI 0.81 to 1.28; 4 studies; 514 participants; moderate-quality evidence) and time to six-month remission (pooled HR adjusted for seizure type 1.05, 95% CI 0.86 to 1.27; 5 studies; 639 participants; moderate-quality evidence).Limited information was available regarding adverse events in the trials and we could not make comparisons between the rates of adverse events on sodium valproate and phenytoin. Some adverse events reported with both drugs were drowsiness, rash, dizziness, nausea and gastrointestinal problems. Weight gain was also reported with sodium valproate and gingival hypertrophy/hyperplasia was reported on phenytoin.The methodological quality of the included trials was generally good, however four out of the five trials providing IPD for analysis were of an open-label design, therefore all results were at risk of detection bias. There was also evidence that misclassification of seizure type may have confounded the results of this review, particularly for the outcome 'time to first seizure' and heterogeneity was present in analysis of treatment failure outcomes which could not be explained by subgroup analysis by epilepsy type or by sensitivity analysis for misclassification of seizure type. Therefore, for treatment failure outcomes we judged the quality of the evidence to be moderate to low, for 'time to first seizure' we judged the quality of the evidence to be low, and for remission outcomes we judged the quality of the evidence to be moderate.
AUTHORS' CONCLUSIONS
We have not found evidence that a significant difference exists between valproate and phenytoin for any of the outcomes examined in this review. However detection bias, classification bias and heterogeneity may have impacted on the results of this review. We did not find any outright evidence to support or refute current treatment policies. We recommend that future trials be designed to the highest quality possible with consideration of masking, choice of population, classification of seizure type, duration of follow-up, choice of outcomes and analysis, and presentation of results.
Topics: Anticonvulsants; Epilepsies, Partial; Epilepsy, Generalized; Humans; Phenytoin; Randomized Controlled Trials as Topic; Seizures; Treatment Outcome; Valproic Acid
PubMed: 30091458
DOI: 10.1002/14651858.CD001769.pub4 -
The Cochrane Database of Systematic... Aug 2018Acute myeloid leukaemia (AML) is the most common acute leukaemia affecting adults. Most patients diagnosed with AML are at advanced age and present with co-morbidities,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Acute myeloid leukaemia (AML) is the most common acute leukaemia affecting adults. Most patients diagnosed with AML are at advanced age and present with co-morbidities, so that intensive therapy such as stem cell transplantation (SCT) is impossible to provide or is accompanied by high risks for serious adverse events and treatment-related mortality. Especially for these patients, it is necessary to find out whether all-trans retinoic acid (ATRA), an intermediate of vitamin A inducing terminal differentiation of leukaemic cell lines, added to chemotherapy confers increased benefit or harm when compared with the same chemotherapy alone.
OBJECTIVES
This review aims to determine benefits and harms of ATRA in addition to chemotherapy compared to chemotherapy alone for adults with AML (not those with acute promyelocytic leukaemia (non-APL)).
SEARCH METHODS
We searched the Central Register of Controlled Trials (CENTRAL), MEDLINE, study registries and relevant conference proceedings up to July 2018 for randomised controlled trials (RCTs). We also contacted experts for unpublished data.
SELECTION CRITERIA
We included RCTs comparing chemotherapy alone with chemotherapy plus ATRA in patients with all stages of AML. We excluded trials if less than 80% of participants were adults or participants with AML, and if no subgroup data were available. Patients with myelodysplastic syndrome (MDS) were included, if they had a refractory anaemia and more than 20% of blasts.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data and assessed the quality of trials. We contacted study authors to obtain missing information. We used hazard ratios (HR) for overall survival (OS) and disease-free survival (DFS; instead of the pre-planned event-free survival, as this outcome was not reported), and we calculated risk ratios (RR) for the other outcomes quality of life, on-study mortality and adverse events. We presented all measures with 95% confidence intervals (CIs). We assessed the certainty of evidence using GRADE methods.
MAIN RESULTS
Our search resulted in 2192 potentially relevant references, of which we included eight trials with 28 publications assessing 3998 patients. Overall, we judged the potential risk of bias of the eight included trials as moderate. Two of eight trials were published as abstracts only. All the included trials used different chemotherapy schedules and one trial only evaluated the effect of the hypomethylating agent decitabine, a drug know to affect epigenetics, in combination with ATRA.The addition of ATRA to chemotherapy resulted in probably little or no difference in OS compared to chemotherapy only (2985 participants; HR 0.94 (95% confidence interval (CI) 0.87 to 1.02); moderate-certainty evidence). Based on a mortality rate at 24 months of 70% with chemotherapy alone, the mortality rate with chemotherapy plus ATRA was 68% (95% CI 65% to 71%).For DFS, complete response rate (CRR) and on-study mortality there was probably little or no difference between treatment groups (DFS: 1258 participants, HR 0.99, 95% CI 0.87 to 1.12; CRR: 3081 participants, RR 1.02, 95% CI 0.96 to 1.09; on-study mortality: 2839 participants, RR 1.02, 95% CI 0.81 to 1.30, all moderate-certainty evidence).Three trials with 1428 participants reported the adverse events 'infection' and 'cardiac toxicity': There was probably no, or little difference in terms of infection rate between participants receiving ATRA or not (RR 1.05, 95% CI 0.96 to 1.15; moderate-certainty evidence). We are uncertain whether ATRA decreases cardiac toxicity (RR 0.46, 95% CI 0.24 to 0.90; P = 0.02, very low certainty-evidence, however, cardiac toxicity was low).Rates and severity of diarrhoea and nausea/vomiting were assessed in two trials with 337 patients and we are uncertain whether there is a difference between treatment arms (diarrhoea: RR 2.19, 95% CI 1.07 to 4.47; nausea/vomiting: RR 1.46, 95% CI 0.75 to 2.85; both very low-certainty evidence).Quality of life was not reported by any of the included trials.
AUTHORS' CONCLUSIONS
We found no evidence for a difference between participants receiving ATRA in addition to chemotherapy or chemotherapy only for the outcome OS. Regarding DFS, CRR and on-study mortality, there is probably no evidence for a difference between treatment groups. Currently, it seems the risk of adverse events are comparable to chemotherapy only.As quality of life has not been evaluated in any of the included trials, further research is needed to clarify the effect of ATRA on quality of life.
Topics: Adult; Antineoplastic Agents; Decitabine; Diarrhea; Disease Progression; Heart; Humans; Infections; Leukemia, Myeloid, Acute; Nausea; Recurrence; Tretinoin; Vomiting
PubMed: 30080246
DOI: 10.1002/14651858.CD011960.pub2 -
The Cochrane Database of Systematic... May 2018This is an updated version of the Cochrane Review previously published in Issue 3, 2015.The incidence of seizures following supratentorial craniotomy for non-traumatic... (Review)
Review
BACKGROUND
This is an updated version of the Cochrane Review previously published in Issue 3, 2015.The incidence of seizures following supratentorial craniotomy for non-traumatic pathology has been estimated to be between 15% to 20%; however, the risk of experiencing a seizure appears to vary from 3% to 92% over a five-year period. Postoperative seizures can precipitate the development of epilepsy; seizures are most likely to occur within the first month of cranial surgery. The use of antiepileptic drugs (AEDs) administered pre- or postoperatively to prevent seizures following cranial surgery has been investigated in a number of randomised controlled trials (RCTs).
OBJECTIVES
To determine the efficacy and safety of AEDs when used prophylactically in people undergoing craniotomy and to examine which AEDs are most effective.
SEARCH METHODS
For the latest update we searched the following databases on 26 June 2017: Cochrane Epilepsy Group Specialized Register, the CENTRAL, MEDLINE, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP). We did not apply any language restrictions.
SELECTION CRITERIA
We included RCTs of people with no history of epilepsy who were undergoing craniotomy for either therapeutic or diagnostic reasons. We included trials with adequate randomisation methods and concealment; these could either be blinded or unblinded parallel trials. We did not stipulate a minimum treatment period, and we included trials using active drugs or placebo as a control group.
DATA COLLECTION AND ANALYSIS
Three review authors (JW, JG, YD) independently selected trials for inclusion and performed data extraction and risk of bias assessments. We resolved any disagreements through discussion. Outcomes investigated included the number of participants experiencing seizures (early (occurring within first week following craniotomy), and late (occurring after first week following craniotomy)), the number of deaths and the number of people experiencing disability and adverse effects. Due to the heterogeneous nature of the trials, we did not combine data from the included trials in a meta-analysis; we presented the findings of the review in narrative format. Visual comparisons of outcomes are presented in forest plots.
MAIN RESULTS
We included 10 RCTs (N = 1815), which were published between 1983 and 2015. Three trials compared a single AED (phenytoin) with placebo or no treatment. One three-armed trial compared two AEDs (phenytoin, carbamazepine) with no treatment. A second three-armed trial compared phenytoin, phenobarbital with no treatment. Of these five trials comparing AEDs with placebo or no treatment, two trials reported a statistically significant advantage for AED treatment compared to controls for early seizure occurrence; all other comparisons showed no clear or statistically significant differences between AEDs and control treatment. None of the trials that were head-to-head comparisons of AEDs (phenytoin versus sodium valproate, phenytoin versus phenobarbital, levetiracetam versus phenytoin, zonisamide versus phenobarbital) reported any statistically significant differences between treatments for either early or late seizure occurrence.Incidences of death were reported in only five trials. One trial reported statistically significantly fewer deaths in the carbamazepine and no-treatment groups compared with the phenytoin group after 24 months of treatment, but not after six months of treatment. Incidences of adverse effects of treatment were poorly reported; however, three trials did show that significantly more adverse events occurred on phenytoin compared to valproate, placebo, or no treatment. No trials reported any results relating to functional outcomes such as disability.We considered the evidence to be of low quality for all reported outcomes due to methodological issues and variability of comparisons made in the trials.
AUTHORS' CONCLUSIONS
There is limited, low-quality evidence to suggest that AED treatment administered prophylactically is either effective or not effective in the prevention of postcraniotomy (early or late) seizures. The current evidence base is limited due to the different methodologies employed in the trials and inconsistencies in the reporting of outcomes including deaths and adverse events. Further evidence from good-quality, contemporary trials is required in order to assess the clinical effectiveness of prophylactic AED treatment compared to placebo or no treatment, or other AEDs in preventing postcraniotomy seizures in this select group of patients.
Topics: Anticonvulsants; Carbamazepine; Craniotomy; Humans; Isoxazoles; Levetiracetam; Phenobarbital; Phenytoin; Piracetam; Postoperative Complications; Randomized Controlled Trials as Topic; Seizures; Valproic Acid; Zonisamide
PubMed: 29791030
DOI: 10.1002/14651858.CD007286.pub4 -
The Cochrane Database of Systematic... May 2018Despite the high prevalence of apathy in Alzheimer's disease (AD), and its harmful effects, there are currently no therapies proven to treat this symptom. Recently, a... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Despite the high prevalence of apathy in Alzheimer's disease (AD), and its harmful effects, there are currently no therapies proven to treat this symptom. Recently, a number of pharmacological therapies have been investigated as potential treatments for apathy in AD.
OBJECTIVES
Objective 1: To assess the safety and efficacy of pharmacotherapies for the treatment of apathy in Alzheimer's disease (AD).Objective 2: To assess the effect on apathy of pharmacotherapies investigated for other primary outcomes in the treatment of AD.
SEARCH METHODS
We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (ALOIS), MEDLINE, Embase, CINAHL, PsycINFO, LILACS, ClinicalTrials.gov and the World Health Organization (WHO) portal, ICTRP on 17 May 2017.
SELECTION CRITERIA
Eligible studies were double-blind, randomized, placebo-controlled trials (RCTs) investigating apathy as a primary or secondary outcome in people with AD.
DATA COLLECTION AND ANALYSIS
Three review authors extracted data. We assessed the risks of bias of included studies using Cochrane methods, and the overall quality of evidence for each outcome using GRADE methods. We calculated mean difference (MD), standardized mean difference (SMD) or risk ratio (RR) with 95% confidence intervals on an intention-to-treat basis for all relevant outcome measures.
MAIN RESULTS
We included 21 studies involving a total of 6384 participants in the quantitative analyses. Risk of bias is very low to moderate. All studies reported appropriate methods of randomization and blinding. Most studies reported appropriate methods of allocation concealment. Four studies, three with methylphenidate and one with modafinil, had a primary aim of improving apathy. In these studies, all participants had clinically significant apathy at baseline. Methylphenidate may improve apathy compared to placebo. This finding was present when apathy was assessed using the apathy evaluation scale (AES), which was used by all three studies investigating methylphenidate: MD -4.99, 95% CI -9.55 to -0.43, n = 145, 3 studies, low quality of evidence, but not when assessed with the neuropsychiatric inventory (NPI)-apathy subscale, which was used by two of the three studies investigating methylphenidate: MD -0.08, 95% CI -3.85 to 3.69, n = 85, 2 studies, low quality of evidence. As well as having potential benefits for apathy, methylphenidate probably also slightly improves cognition (MD 1.98, 95% CI 1.06 to 2.91, n = 145, 3 studies, moderate quality of evidence), and probably improves instrumental activities of daily living (MD 2.30, 95% CI 0.74 to 3.86, P = 0.004, n = 60, 1 study, moderate quality of evidence), compared to placebo. There may be no difference between methylphenidate and placebo in the risk of developing an adverse event: RR 1.28, 95% CI 0.67 to 2.42, n = 145, 3 studies, low quality of evidence. There was insufficient evidence from one very small study of modafinil to determine the effect of modafinil on apathy assessed with the FrSBe-apathy subscale: MD 0.27, 95% CI -3.51 to 4.05, n = 22, 1 study, low quality of evidence. In all other included studies, apathy was a secondary outcome and participants were not selected on the basis of clinically significant apathy at baseline. We considered the evidence on apathy from these studies to be indirect and associated with publication bias. There was low or very low quality of evidence on cholinesterase inhibitors (ChEIs) (six studies), ChEI discontinuation (one study), antipsychotics (two studies), antipsychotic discontinuation (one study), antidepressants (two studies), mibampator (one study), valproate (three studies) and semagacestat (one study).
AUTHORS' CONCLUSIONS
Methylphenidate may demonstrate a benefit for apathy and may have slight benefits for cognition and functional performance in people with AD, but this finding is associated with low-quality evidence. Our meta-analysis is limited by the small number of studies within each drug class, risk of bias, publication bias, imprecision and inconsistency between studies. Additional studies should be encouraged targeting people with AD with clinically significant apathy which investigate apathy as a primary outcome measure, and which have a longer duration and a larger sample size. This could increase the quality of evidence for methylphenidate, and may confirm whether or not it is an effective pharmacotherapy for apathy in AD.
Topics: Alanine; Alzheimer Disease; Antidepressive Agents; Apathy; Azepines; Benzhydryl Compounds; Biphenyl Compounds; Central Nervous System Stimulants; Cholinesterase Inhibitors; Humans; Methylphenidate; Modafinil; Randomized Controlled Trials as Topic; Sulfonamides; Valproic Acid
PubMed: 29727467
DOI: 10.1002/14651858.CD012197.pub2 -
The Cochrane Database of Systematic... Apr 2018Chronic antipsychotic drug treatment may cause tardive dyskinesia (TD), a long-term movement disorder. Gamma-aminobutyric acid (GABA) agonist drugs, which have intense... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Chronic antipsychotic drug treatment may cause tardive dyskinesia (TD), a long-term movement disorder. Gamma-aminobutyric acid (GABA) agonist drugs, which have intense sedative properties and may exacerbate psychotic symptoms, have been used to treat TD.
OBJECTIVES
1. Primary objectiveThe primary objective was to determine whether using non-benzodiazepine GABA agonist drugs for at least six weeks was clinically effective for the treatment of antipsychotic-induced TD in people with schizophrenia, schizoaffective disorder or other chronic mental illnesses.2. Secondary objectivesThe secondary objectives were as follows.To examine whether any improvement occurred with short periods of intervention (less than six weeks) and, if this did occur, whether this effect was maintained at longer periods of follow-up.To examine whether there was a differential effect between the various compounds.To test the hypothesis that GABA agonist drugs are most effective for a younger age group (less than 40 years old).
SEARCH METHODS
We searched the Cochrane Schizophrenia Group Trials Register (last searched April 2017), inspected references of all identified studies for further trials, and, when necessary, contacted authors of trials for additional information.
SELECTION CRITERIA
We included randomised controlled trials of non-benzodiazepine GABA agonist drugs in people with antipsychotic-induced TD and schizophrenia or other chronic mental illness.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected and critically appraised studies, extracted and analysed data on an intention-to-treat basis. Where possible and appropriate we calculated risk ratios (RRs) and their 95% confidence intervals (CIs). For continuous data we calculated mean differences (MD). We assumed that people who left early had no improvement. We contacted investigators to obtain missing information. We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE.
MAIN RESULTS
We included 11 studies that randomised 343 people. Overall, the risk of bias in the included studies was unclear, mainly due to poor reporting; allocation concealment was not described, generation of the sequence was not explicit, participants and outcome assessors were not clearly blinded. For some studies we were unsure if data were complete, and data were often poorly or selectively reported.Data from six trials showed that there may be a clinically important improvement in TD symptoms after GABA agonist treatment compared with placebo at six to eight weeks follow-up (6 RCTs, n = 258, RR 0.83, CI 0.74 to 0.92; low-quality evidence). Data from five studies showed no difference between GABA agonist treatment and placebo for deterioration of TD symptoms (5 RCTs, n = 136, RR 1.90, CI 0.70 to 5.16; very low-quality evidence). Studies reporting adverse events found a significant effect favouring placebo compared with baclofen, sodium valproate or progabide for dizziness/confusion (3 RCTs, n = 62 RR 4.54, CI 1.14 to 18.11; very low-quality evidence) and sedation/drowsiness (4 RCTS, n = 144, RR 2.29, CI 1.08 to 4.86; very low-quality evidence). Studies reporting on akathisia (RR 1.05, CI 0.32 to 3.49, 2 RCTs, 80 participants), ataxia (RR 3.25, CI 0.36 to 29.73, 2 RCTs, 95 participants), nausea/vomiting (RR 2.61, CI 0.79 to 8.67, 2 RCTs, 64 participants), loss of muscle tone (RR 3.00, CI 0.15 to 59.89, 1 RCT, 10 participants), seizures (RR 3.00, CI 0.24 to 37.67, 1 RCT, 2 participants), hypotension (RR 3.04, CI 0.33 to 28.31, 2 RCTs, 119 participants) found no significant difference between GABA drug and placebo (very low-quality evidence). Evidence on mental state also showed no effect between treatment groups (6 RCTS, n = 121, RR 2.65, CI 0.71 to 9.86; very low-quality evidence) as did data for leaving the study early (around 10% in both groups, 6 RCTS, n = 218, RR 1.47, CI 0.69 to 3.15; very low-quality evidence). No study reported on social confidence, social inclusion, social networks, or personalised quality of life, a group of outcomes selected as being of particular importance to patients.
AUTHORS' CONCLUSIONS
We are uncertain about the evidence of the effects of baclofen, progabide, sodium valproate or tetrahydroisoxazolopyridinol (THIP) for people with antipsychotic-induced TD. Evidence is inconclusive and unconvincing. The quality of data available for main outcomes ranges from very low to low. Any possible benefits are likely to be outweighed by the adverse effects associated with their use.
Topics: Antipsychotic Agents; Baclofen; Dyskinesia, Drug-Induced; GABA Agonists; Humans; Isoxazoles; Placebos; Randomized Controlled Trials as Topic; Valproic Acid; gamma-Aminobutyric Acid
PubMed: 29663328
DOI: 10.1002/14651858.CD000203.pub4 -
The Cochrane Database of Systematic... Apr 2018Aggressive, agitated or violent behaviour due to psychosis constitutes an emergency psychiatric treatment where fast-acting interventions are required. Risperidone is a... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Aggressive, agitated or violent behaviour due to psychosis constitutes an emergency psychiatric treatment where fast-acting interventions are required. Risperidone is a widely accessible antipsychotic that can be used to manage psychosis-induced aggression or agitation.
OBJECTIVES
To examine whether oral risperidone alone is an effective treatment for psychosis-induced aggression or agitation.
SEARCH METHODS
We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (up to April 2017); this register is compiled by systematic searches of major resources (including AMED, BIOSIS CINAHL, Embase, MEDLINE, PsycINFO, PubMed, and registries of clinical trials) and their monthly updates, handsearches, grey literature, and conference proceedings. There are no language, date, document type, or publication status limitations for inclusion of records into the register.
SELECTION CRITERIA
Randomised controlled trials (RCTs) comparing rapid use of risperidone and other drugs, combinations of drugs or placebo for people exhibiting aggression or agitation (or both) thought to be due to psychosis.
DATA COLLECTION AND ANALYSIS
We independently inspected all citations from searches, identified relevant abstracts, and independently extracted data from all included studies. For binary data we calculated risk ratio (RR) and for continuous data we calculated mean difference (MD), all with 95% confidence intervals (CI) and used a fixed-effect model. We assessed risk of bias for the included studies and used the GRADE approach to produce a 'Summary of findings' tables.
MAIN RESULTS
The review now contains data from nine trials (total n = 582) reporting on five comparisons. Due to risk of bias, small size of trials, indirectness of outcome measures and a paucity of investigated and reported 'pragmatic' outcomes, evidence was graded as very-low quality. None of the included studies provided useable data on our primary outcome 'tranquillisation or asleep' by 30 minutes, repeated need for tranquillisation or any economic outcomes. Data were available for our other main outcomes of agitation or aggression, needing restraint, and incidence of adverse effects.Risperidone versus haloperidol (up to 24 hours follow-up)For the outcome, specific behaviour - agitation, no clear difference was found between risperidone and haloperidol in terms of efficacy, measured as at least 50% reduction in the Positive and Negative Syndrome Scale - Psychotic Agitation Sub-score (PANSS-PAS) (RR 1.04, 95% CI 0.86 to 1.26; participants = 124; studies = 1; very low-quality evidence) and no effect was observed for need to use restraints (RR 2.00, 95% CI 0.43 to 9.21; participants = 28; studies = 1; very low-quality evidence). Incidence of adverse effects was similar between treatment groups (RR 0.94, 95% CI 0.54 to 1.66; participants = 124; studies = 1; very low-quality evidence).Risperidone versus olanzapineOne small trial (n = 29) reported useable data for the comparison risperidone versus olanzapine. No effect was observed for agitation measured as PANSS-PAS endpoint score at two hours (MD 2.50, 95% CI -2.46 to 7.46; very low-quality evidence); need to use restraints at four days (RR 1.43, 95% CI 0.39 to 5.28; very-low quality evidence); specific movement disorders measured as Behavioural Activity Rating Scale (BARS) endpoint score at four days (MD 0.20, 95% CI -0.43 to 0.83; very low-quality evidence).Risperidone versus quetiapineOne trial reported (n = 40) useable data for the comparison risperidone versus quetiapine. Aggression was measured using the Modified Overt Aggression Scale (MOAS) endpoint score at two weeks. A clear difference, favouring quetiapine was observed (MD 1.80, 95% CI 0.20 to 3.40; very-low quality evidence). No evidence of a difference between treatment groups could be observed for incidence of akathisia after 24 hours (RR 1.67, 95% CI 0.46 to 6.06; very low-quality evidence). Two participants allocated to risperidone and one allocated to quetiapine experienced myocardial ischaemia during the trial.Risperidone versus risperidone + oxcarbazepineOne trial (n = 68) measured agitation using the Positive and Negative Syndrome Scale - Excited Component.(PANSS-EC) endpoint score and found a clear difference, favouring the combination treatment at one week (MD 2.70, 95% CI 0.42 to 4.98; very low-quality evidence), but no effect was observed for global state using Clinical Global Impression - Improvement (CGI-I) endpoint score at one week (MD -0.20, 95% CI -0.61 to 0.21; very-low quality evidence). Incidence of extrapyramidal symptoms after 24 hours was similar between treatment groups (RR 1.59, 95% CI 0.49 to 5.14; very-low quality evidence).Risperidone versus risperidone + valproic acidTwo trials compared risperidone with a combination of risperidone plus valproic acid. No clear differences between the treatment groups were observed for aggression (MOAS endpoint score at three days: MD 1.07, 95% CI -0.20 to 2.34; participants = 54; studies = 1; very low-quality evidence) or incidence of akathisia after 24 hours: RR 0.75, 95% CI 0.28 to 2.03; participants = 122; studies = 2; very low-quality evidence).
AUTHORS' CONCLUSIONS
Overall, results for the main outcomes show no real effect for risperidone. The only data available for use in this review are from nine under-sampled trials and the evidence available is of very low quality. This casts uncertainty on the role of risperidone in rapid tranquillisation for people with psychosis-induced aggression. High-quality pragmatic RCTs are feasible and are needed before clear recommendations can be drawn on the use of risperidone for psychosis-induced aggression or agitation.
Topics: Administration, Oral; Aggression; Antipsychotic Agents; Carbamazepine; Humans; Oxcarbazepine; Psychomotor Agitation; Psychotic Disorders; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Tranquilizing Agents; Valproic Acid
PubMed: 29634083
DOI: 10.1002/14651858.CD009412.pub2 -
Neurology Mar 2018To systematically review evidence regarding ataxia treatment.
Comprehensive systematic review summary: Treatment of cerebellar motor dysfunction and ataxia: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.
OBJECTIVE
To systematically review evidence regarding ataxia treatment.
METHODS
A comprehensive systematic review was performed according to American Academy of Neurology methodology.
CONCLUSIONS
For patients with episodic ataxia type 2, 4-aminopyridine 15 mg/d probably reduces ataxia attack frequency over 3 months (1 Class I study). For patients with ataxia of mixed etiology, riluzole probably improves ataxia signs at 8 weeks (1 Class I study). For patients with Friedreich ataxia or spinocerebellar ataxia (SCA), riluzole probably improves ataxia signs at 12 months (1 Class I study). For patients with SCA type 3, valproic acid 1,200 mg/d possibly improves ataxia at 12 weeks. For patients with spinocerebellar degeneration, thyrotropin-releasing hormone possibly improves some ataxia signs over 10 to 14 days (1 Class II study). For patients with SCA type 3 who are ambulatory, lithium probably does not improve signs of ataxia over 48 weeks (1 Class I study). For patients with Friedreich ataxia, deferiprone possibly worsens ataxia signs over 6 months (1 Class II study). Data are insufficient to support or refute the use of numerous agents. For nonpharmacologic options, in patients with degenerative ataxias, 4-week inpatient rehabilitation probably improves ataxia and function (1 Class I study); transcranial magnetic stimulation possibly improves cerebellar motor signs at 21 days (1 Class II study). For patients with multiple sclerosis-associated ataxia, the addition of pressure splints possibly has no additional benefit compared with neuromuscular rehabilitation alone (1 Class II study). Data are insufficient to support or refute use of stochastic whole-body vibration therapy (1 Class III study).
Topics: Ataxia; Cerebellar Diseases; Humans
PubMed: 29440566
DOI: 10.1212/WNL.0000000000005055 -
British Journal of Clinical Pharmacology May 2018Population pharmacokinetics is an essential tool that helps guide individualized dosing regimens. The aims of this systematic review are to provide knowledge concerning...
AIMS
Population pharmacokinetics is an essential tool that helps guide individualized dosing regimens. The aims of this systematic review are to provide knowledge concerning population pharmacokinetics of valproic acid (VPA) and to identify factors influencing VPA pharmacokinetic variability.
METHODS
PubMed and Embase databases were systematically searched from inception to June, 2017. Relevant articles from reference lists were also included. All population pharmacokinetic studies of VPA conducted in humans and that employed a nonlinear mixed effect modelling approach were included in this review.
RESULTS
Twenty-six studies were included in this review. Most studies characterized VPA pharmacokinetics as a one-compartment model. Three studies reported a two-compartment model. Body weight, dose and age were significant predictors for VPA volume of distribution (V ). The estimated V for one-compartment models ranged from 8.4 to 23.3 l. For two-compartment models, peripheral volumes of distribution ranged from 4.08 to 42.1 l. Frequently reported significant predictors for VPA clearance (CL ) included body weight, VPA dose, concomitant medications, gender and age. The estimated CL ranged from 0.206 to 1.154 l h and the inter-individual variability ranged from 13.40 to 35.90%. Two studies reported population pharmacokinetics/pharmacodynamics of VPA in patients with epilepsy. Seventeen studies evaluated the performance of their final models.
CONCLUSIONS
Significant predictors influencing VPA pharmacokinetics as well as model methodologies are highlighted in this review. For clinical application, CL could be predicted using body weight, VPA dose, concomitant medications, gender or age. For future research, there is a knowledge gap regarding population pharmacokinetics/pharmacodynamics of VPA in a population other than epileptic patients.
Topics: Anticonvulsants; Humans; Models, Biological; Valproic Acid
PubMed: 29328514
DOI: 10.1111/bcp.13510 -
Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data.The Cochrane Database of Systematic... Dec 2017Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer-term... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer-term remission from seizures, and most achieve that remission shortly after starting antiepileptic drug treatment. Most people with epilepsy are treated with a single antiepileptic drug (monotherapy) and current guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom for adults and children recommend carbamazepine or lamotrigine as first-line treatment for partial onset seizures and sodium valproate for generalised onset seizures; however a range of other antiepileptic drug (AED) treatments are available, and evidence is needed regarding their comparative effectiveness in order to inform treatment choices.
OBJECTIVES
To compare the time to withdrawal of allocated treatment, remission and first seizure of 10 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide) currently used as monotherapy in children and adults with partial onset seizures (simple partial, complex partial or secondary generalised) or generalised tonic-clonic seizures with or without other generalised seizure types (absence, myoclonus).
SEARCH METHODS
We searched the following databases: Cochrane Epilepsy's Specialised Register, CENTRAL, MEDLINE and SCOPUS, and two clinical trials registers. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. The date of the most recent search was 27 July 2016.
SELECTION CRITERIA
We included randomised controlled trials of a monotherapy design in adults or children with partial onset seizures or generalised onset tonic-clonic seizures (with or without other generalised seizure types).
DATA COLLECTION AND ANALYSIS
This was an individual participant data (IPD) review and network meta-analysis. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary outcomes were 'time to achieve 12-month remission', 'time to achieve six-month remission', 'time to first seizure post-randomisation', and 'occurrence of adverse events'. We presented all time-to-event outcomes as Cox proportional hazard ratios (HRs) with 95% confidence intervals (CIs). We performed pairwise meta-analysis of head-to-head comparisons between drugs within trials to obtain 'direct' treatment effect estimates and we performed frequentist network meta-analysis to combine direct evidence with indirect evidence across the treatment network of 10 drugs. We investigated inconsistency between direct estimates and network meta-analysis via node splitting. Due to variability in methods and detail of reporting adverse events, we have not performed an analysis. We have provided a narrative summary of the most commonly reported adverse events.
MAIN RESULTS
IPD was provided for at least one outcome of this review for 12,391 out of a total of 17,961 eligible participants (69% of total data) from 36 out of the 77 eligible trials (47% of total trials). We could not include IPD from the remaining 41 trials in analysis for a variety of reasons, such as being unable to contact an author or sponsor to request data, data being lost or no longer available, cost and resources required to prepare data being prohibitive, or local authority or country-specific restrictions.We were able to calculate direct treatment effect estimates for between half and two thirds of comparisons across the outcomes of the review, however for many of the comparisons, data were contributed by only a single trial or by a small number of participants, so confidence intervals of estimates were wide.Network meta-analysis showed that for the primary outcome 'Time to withdrawal of allocated treatment,' for individuals with partial seizures; levetiracetam performed (statistically) significantly better than current first-line treatment carbamazepine and other current first-line treatment lamotrigine performed better than all other treatments (aside from levetiracetam); carbamazepine performed significantly better than gabapentin and phenobarbitone (high-quality evidence). For individuals with generalised onset seizures, first-line treatment sodium valproate performed significantly better than carbamazepine, topiramate and phenobarbitone (moderate- to high-quality evidence). Furthermore, for both partial and generalised onset seizures, the earliest licenced treatment, phenobarbitone seems to perform worse than all other treatments (moderate- to high-quality evidence).Network meta-analysis also showed that for secondary outcomes 'Time to 12-month remission of seizures' and 'Time to six-month remission of seizures,' few notable differences were shown for either partial or generalised seizure types (moderate- to high-quality evidence). For secondary outcome 'Time to first seizure,' for individuals with partial seizures; phenobarbitone performed significantly better than both current first-line treatments carbamazepine and lamotrigine; carbamazepine performed significantly better than sodium valproate, gabapentin and lamotrigine. Phenytoin also performed significantly better than lamotrigine (high-quality evidence). In general, the earliest licenced treatments (phenytoin and phenobarbitone) performed better than the other treatments for both seizure types (moderate- to high-quality evidence).Generally, direct evidence and network meta-analysis estimates (direct plus indirect evidence) were numerically similar and consistent with confidence intervals of effect sizes overlapping.The most commonly reported adverse events across all drugs were drowsiness/fatigue, headache or migraine, gastrointestinal disturbances, dizziness/faintness and rash or skin disorders.
AUTHORS' CONCLUSIONS
Overall, the high-quality evidence provided by this review supports current guidance (e.g. NICE) that carbamazepine and lamotrigine are suitable first-line treatments for individuals with partial onset seizures and also demonstrates that levetiracetam may be a suitable alternative. High-quality evidence from this review also supports the use of sodium valproate as the first-line treatment for individuals with generalised tonic-clonic seizures (with or without other generalised seizure types) and also demonstrates that lamotrigine and levetiracetam would be suitable alternatives to either of these first-line treatments, particularly for those of childbearing potential, for whom sodium valproate may not be an appropriate treatment option due to teratogenicity.
Topics: Adult; Amines; Anticonvulsants; Carbamazepine; Child; Cyclohexanecarboxylic Acids; Epilepsies, Partial; Epilepsy; Epilepsy, Generalized; Fructose; Gabapentin; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Network Meta-Analysis; Oxcarbazepine; Phenobarbital; Phenytoin; Piracetam; Remission Induction; Topiramate; Triazines; Valproic Acid; Zonisamide; gamma-Aminobutyric Acid
PubMed: 29243813
DOI: 10.1002/14651858.CD011412.pub3 -
Jornal de Pediatria 2017This systematic review of national or regional guidelines published in English aimed to better understand variance in pre-hospital and emergency department treatment of...
OBJECTIVE
This systematic review of national or regional guidelines published in English aimed to better understand variance in pre-hospital and emergency department treatment of status epilepticus.
SOURCES
Systematic search of national or regional guidelines (January 2000 to February 2017) contained within PubMed and Google Scholar databases, and article reference lists. The search keywords were status epilepticus, prolonged seizure, treatment, and guideline.
SUMMARY OF FINDINGS
356 articles were retrieved and 13 were selected according to the inclusion criteria. In all six pre-hospital guidelines, the preferred route of medication administration was to use alternatives to the intravenous route: all recommended buccal and intranasal midazolam; three also recommended intramuscular midazolam, and five recommended using rectal diazepam. All 11 emergency department guidelines described three phases in therapy. Intravenous medication, by phase, was indicated as such: initial phase - ten/11 guidelines recommended lorazepam, and eight/11 recommended diazepam; second phase - most (ten/11) guidelines recommended phenytoin, but other options were phenobarbital (nine/11), valproic acid (six/11), and either fosphenytoin or levetiracetam (each four/11); third phase - four/11 guidelines included the choice of repeating second phase therapy, whereas the other guidelines recommended using a variety of intravenous anesthetic agents (thiopental, midazolam, propofol, and pentobarbital).
CONCLUSIONS
All of the guidelines share a similar framework for management of status epilepticus. The choice in route of administration and drug type varied across guidelines. Hence, the adoption of a particular guideline should take account of local practice options in health service delivery.
Topics: Anticonvulsants; Child; Clinical Protocols; Emergency Service, Hospital; Humans; Status Epilepticus
PubMed: 28941387
DOI: 10.1016/j.jped.2017.08.004