-
Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data.The Cochrane Database of Systematic... Jun 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 both current first-line treatments carbamazepine and lamotrigine; lamotrigine performed better than all other treatments (aside from levetiracetam), and 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: 28661008
DOI: 10.1002/14651858.CD011412.pub2 -
Carbamazepine versus phenobarbitone monotherapy for epilepsy: an individual participant data review.The Cochrane Database of Systematic... Jul 2015This is an updated version of the original Cochrane review published in Issue 1, 2003, of the Cochrane Database of Systematic Reviews.Epilepsy is a common neurological... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an updated version of the original Cochrane review published in Issue 1, 2003, of the Cochrane Database of Systematic Reviews.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 go into long-term remission shortly after starting drug therapy with a single antiepileptic drug (AED) in monotherapy.Worldwide, carbamazepine (CBZ) and phenobarbitone (PB) are commonly used broad-spectrum antiepileptic drugs, suitable for most epileptic seizure types. Carbamazepine is a current first-line treatment for partial onset seizures in the USA and Europe. Phenobarbitone is no longer considered a first-line treatment because of concerns over associated adverse events, particularly documented behavioural adverse events in children treated with the drug. However, PB is still commonly used in low- and middle-income countries because of its low cost. No consistent differences in efficacy have been found between CBZ and PB in individual trials; however, the confidence intervals generated by these studies are wide, and therefore, synthesising the data of the individual trials may show differences in efficacy.
OBJECTIVES
To review the time to withdrawal, remission, and first seizure of CBZ compared with PB when used as monotherapy in people with partial onset seizures (simple or complex partial and secondarily generalised) or generalised onset tonic-clonic seizures (with or without other generalised seizure types).
SEARCH METHODS
We searched the following databases up to September 2014: the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (2014, Issue 8), MEDLINE (from 1946), Scopus (from 1823), the US National Institutes of Health Ongoing Trials Register (www.clinicaltrials.gov), and the World Health Organization International Clinical Trials Registry platform (WHO ICTRP). We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field.
SELECTION CRITERIA
Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of CBZ monotherapy versus PB monotherapy.
DATA COLLECTION AND ANALYSIS
This was an individual participant data (IPD) review. Our primary outcome was 'Time to withdrawal of allocated treatment', and our secondary outcomes were 'Time to 12-month remission', 'Time to 6-month remission', and 'Time to first seizure postrandomisation'. We used Cox proportional hazards regression models to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), with the generic inverse variance method used to obtain the overall pooled HR and 95% CI.
MAIN RESULTS
Individual participant data were available for 836 participants out of 1455 eligible individuals from 6 out of 13 trials, 57% of the potential data. For remission outcomes, HR > 1 indicated an advantage for PB, and for first seizure and withdrawal outcomes, HR > 1 indicated an advantage for CBZ.The main overall results (pooled HR adjusted for seizure type, 95% CI) were HR 1.50 for time to withdrawal of allocated treatment (95% CI 1.15 to 1.95, P = 0.003); HR 0.93 for time to 12-month remission (95% CI 0.72 to 1.20, P = 0.57); HR 0.99 for time to 6-month remission (95% CI 0.80 to 1.23, P = 0.95); and HR 0.87 for time to first seizure (95% CI 0.72 to 1.06, P = 0.18). Results suggest an advantage for CBZ over PB in terms of time to treatment withdrawal and no statistically significant evidence between the drugs for the other outcomes. We found evidence of a statistically significant interaction between treatment effect and seizure type for time to first seizure recurrence (Chi² test for subgroup differences P = 0.03), where PB was favoured for partial onset seizures (HR 0.76, 95% CI 0.60 to 0.96, P = 0.02) and CBZ was favoured for generalised onset seizures (HR 1.23, 95% CI 0.88 to 1.77, P = 0.27). However, methodological quality of the included studies was variable, with 10 out of the 13 included studies (4 out of 6 studies contributing IPD) judged as high risk of bias for at least 1 methodological aspect, leading to variable individual study results and therefore heterogeneity in the analyses of this review. We conducted sensitivity analyses to examine the impact of poor methodological aspects where possible.
AUTHORS' CONCLUSIONS
Overall, we found evidence suggestive of an advantage for CBZ in terms of drug effectiveness compared with PB (retention of the drug in terms of seizure control and adverse events) and evidence of an association between treatment effect and seizure type for time to first seizure recurrence (PB favoured for partial seizures and CBZ favoured for generalised seizures). Given the varying quality of studies included in this review and the impact of poor methodological quality on individual study results (and therefore variability (heterogeneity) present in the analysis within this review), we recommend caution when interpreting the results of this review and do not recommend that the results of this review alone should be used in choosing between CBZ and PB. We recommend that future trials should be designed to the highest quality possible with considerations for allocation concealment and masking, choice of population, choice of outcomes and analysis, and presentation of results.
Topics: Adult; Anticonvulsants; Carbamazepine; Child; Epilepsies, Partial; Epilepsy, Generalized; Epilepsy, Tonic-Clonic; Humans; Phenobarbital; Randomized Controlled Trials as Topic
PubMed: 26204241
DOI: 10.1002/14651858.CD001904.pub2 -
The Cochrane Database of Systematic... Jun 2018This is an updated version of the original Cochrane Review published in Issue 11, 2006 of the Cochrane Database of Systematic Reviews.Epilepsy is a common neurological... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an updated version of the original Cochrane Review published in Issue 11, 2006 of the Cochrane Database of Systematic Reviews.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 (AED) in monotherapy.The correct choice of first-line AED for individuals with newly diagnosed seizures is of great importance. It is important that the choice of AEDs for an individual is made using the highest quality evidence regarding the potential benefits and harms of the various treatments.Carbamazepine or lamotrigine are recommended as first-line treatments for new onset focal seizures and as a first- or second-line treatment for generalised tonic-clonic seizures. Performing a synthesis of the evidence from existing trials will increase the precision of the results for outcomes relating to efficacy and tolerability and may assist in informing a choice between the two drugs.
OBJECTIVES
To review the time to treatment failure, remission and first seizure with lamotrigine compared to carbamazepine when used as monotherapy in people with focal onset seizures (simple or complex focal and secondarily generalised) or generalised onset tonic-clonic seizures (with or without other generalised seizure types).
SEARCH METHODS
We conducted the first searches for this review in 1997. For the most recent update, we searched the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), MEDLINE, Clinical Trials.gov and the WHO International Clinical Trials Registry Platform on 26 February 2018, without language restrictions SELECTION CRITERIA: Randomised controlled trials comparing monotherapy with either carbamazepine or lamotrigine 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, 12-month and 24-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 14 trials in this review. Individual participant data were available for 2572 participants out of 3787 eligible individuals from nine out of 14 trials: 68% of the potential data. For remission outcomes, a HR of less than one indicated an advantage for carbamazepine; and for first seizure and treatment failure outcomes, a HR of less than one indicated an advantage for lamotrigine.The main overall results were: time to treatment failure for any reason related to treatment (pooled HR adjusted for seizure type: 0.71, 95% CI 0.62 to 0.82, moderate-quality evidence), time to treatment failure due to adverse events (pooled HR adjusted for seizure type: 0.55 (95% CI 0.45 to 0.66, moderate-quality evidence), time to treatment failure due to lack of efficacy (pooled HR for all participants: 1.03 (95% CI 0.75 to 1.41), moderate-quality evidence) showing a significant advantage for lamotrigine compared to carbamazepine in terms of treatment failure for any reason related to treatment and treatment failure due to adverse events, but no different between drugs for treatment failure due to lack of efficacy.Time to first seizure (pooled HR adjusted for seizure type: 1.26, 95% CI 1.12 to 1.41, high-quality evidence) and time to six-month remission (pooled HR adjusted for seizure type: 0.86, 95% CI 0.76 to 0.97, high-quality evidence), showed a significant advantage for carbamazepine compared to lamotrigine for first seizure and six-month remission. We found no difference between the drugs for time to 12-month remission (pooled HR for all participants 0.91, 95% CI 0.77 to 1.07, high-quality evidence) or time to 24-month remission (HR for all participants 1.00, 95% CI 0.80 to 1.25, high-quality evidence), however only two trials followed up participants for more than one year so evidence is limited.The results of this review are applicable mainly to individuals with focal onset seizures; 88% of included individuals experienced seizures of this type at baseline. Up to 50% of the limited number of individuals classified as experiencing generalised onset seizures at baseline may have had their seizure type misclassified, therefore we recommend caution when interpreting the results of this review for individuals with generalised onset seizures.The most commonly reported adverse events for both of the drugs across all of the included trials were dizziness, fatigue, gastrointestinal disturbances, headache and skin problems. The rate of adverse events was similar across the two drugs.The methodological quality of the included trials was generally good, however there is some evidence that the design choice of masked or open-label treatment may have influenced the treatment failure and withdrawal rates of the trials. Hence, we judged the quality of the evidence for the primary outcome of treatment failure to be moderate for individuals with focal onset seizures and low for individuals with generalised onset seizures. For efficacy outcomes (first seizure, remission), we judged the quality of evidence to be high for individuals with focal onset seizures and moderate for individuals with generalised onset seizures.
AUTHORS' CONCLUSIONS
Moderate quality evidence indicates that treatment failure for any reason related to treatment or due to adverse events occurs significantly earlier on carbamazepine than lamotrigine, but the results for time to first seizure suggested that carbamazepine may be superior in terms of seizure control. The choice between these first-line treatments must be made with careful consideration. We recommend that future trials should 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: Adult; Anticonvulsants; Carbamazepine; Child; Epilepsies, Partial; Epilepsy, Generalized; Epilepsy, Tonic-Clonic; Humans; Lamotrigine; Randomized Controlled Trials as Topic; Recurrence; Time Factors; Treatment Failure; Triazines; Withholding Treatment
PubMed: 29952431
DOI: 10.1002/14651858.CD001031.pub4 -
Medicine Aug 2020Mycophenolate mofetil (MMF) has been recommended for the treatment of lupus nephritis (LN). Although inter-racial differences exist regarding the appropriate dose and... (Meta-Analysis)
Meta-Analysis
BACKGROUD
Mycophenolate mofetil (MMF) has been recommended for the treatment of lupus nephritis (LN). Although inter-racial differences exist regarding the appropriate dose and efficacy of MMF in patients with LN, no definitive meta-analysis has yet been conducted in Chinese patients. This analysis investigated the efficacy and safety of MMF in Chinese patients with proliferative LN.
METHODS
A systematic literature search was conducted to select randomized controlled trials that reported at least one of the following: complete remission (CR), partial remission, total remission (TR; defined as complete remission + partial remission), relapse rate, serum creatinine, creatinine clearance, end-stage renal disease, death, infections, amenorrhea, leukopenia, alopecia, gastrointestinal symptoms, or liver damage.
RESULTS
Eighteen trials (927 patients) were included; 14 (750 patients) reported CR, partial remission, and TR. Two trials (58 patients) reported relapse rates during maintenance treatment. MMF induction significantly improved CR and TR vs cyclophosphamide (relative risk 1.34, 95% confidence interval: 1.13-1.58; P < .001; relative risk 1.16, 95% confidence interval: 1.02-1.33; P = .03), and was associated with significantly lower risks of infection (P < .001), amenorrhea (P < .001), leukopenia, and alopecia. No significant difference in relapse rate was evident between the MMF and azathioprine groups (P = .66).
CONCLUSION
According to this meta-analysis of 18 trials, MMF is significantly more effective than cyclophosphamide induction, and is associated with reduced incidences of infections, amenorrhea, leukopenia, and alopecia in Chinese patients with proliferative LN.
Topics: Asian People; China; Cyclophosphamide; Enzyme Inhibitors; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Randomized Controlled Trials as Topic
PubMed: 32871981
DOI: 10.1097/MD.0000000000021121 -
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 -
The Cochrane Database of Systematic... Feb 2017This is an updated version of the original Cochrane Review published in Issue 2, 2002 and its subsequent updates in 2010 and 2015.Epilepsy is a common neurological... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an updated version of the original Cochrane Review published in Issue 2, 2002 and its subsequent updates in 2010 and 2015.Epilepsy is a common neurological condition in which recurrent, unprovoked seizures are caused by abnormal electrical discharges from the brain. It is believed that with effective drug treatment, up to 70% of individuals with active epilepsy have the potential to become seizure-free and go into long-term remission shortly after starting drug therapy with a single antiepileptic drug in monotherapy.Worldwide, carbamazepine and phenytoin are commonly-used broad spectrum antiepileptic drugs, suitable for most epileptic seizure types. Carbamazepine is a current first-line treatment for partial onset seizures in the USA and Europe. Phenytoin is no longer considered a first-line treatment due to concerns over adverse events associated with its use, but the drug is still commonly used in low- to middle-income countries because of its low cost. No consistent differences in efficacy have been found between carbamazepine and phenytoin in individual trials, although the confidence intervals generated by these studies are wide. Differences in efficacy may therefore be shown by synthesising the data of the individual trials.
OBJECTIVES
To review the time to withdrawal, six- and 12-month remission, and first seizure with carbamazepine compared to phenytoin, used as monotherapy in people with partial onset seizures (simple partial, complex partial, or secondarily generalised tonic-clonic seizures), or generalised tonic-clonic seizures, with or without other generalised seizure types.
SEARCH METHODS
For the latest update we searched the Cochrane Epilepsy Group's Specialised Register (1st November 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 1st November 2016), MEDLINE (Ovid, 1946 to 1 November 2016), ClinicalTrials.gov (1 November 2016), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP, 1st November 2016). Previously we also searched SCOPUS (1823 to 16th September 2014) as an alternative to Embase, but this is no longer necessary, because randomised and quasi-randomised controlled trials in Embase are now included in CENTRAL. We handsearched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field.
SELECTION CRITERIA
Randomised controlled trials (RCTs) in children or adults with partial onset seizures or generalised onset tonic-clonic seizures, comparing carbamazepine monotherapy versus phenytoin monotherapy.
DATA COLLECTION AND ANALYSIS
This is an individual participant data (IPD) review. Our primary outcome was time to withdrawal of allocated treatment, and our secondary outcomes were time to six-month remission, time to 12-month remission, and time to first seizure post-randomisation. We used Cox proportional hazards regression models to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs) and the generic inverse variance method to obtain the overall pooled HR and 95% CI.
MAIN RESULTS
IPD were available for 595 participants out of 1192 eligible individuals, from four out of 12 trials (i.e. 50% of the potential data). For remission outcomes, HR greater than 1 indicates an advantage for phenytoin; and for first seizure and withdrawal outcomes, HR greater than 1 indicates an advantage for carbamazepine. The methodological quality of the four studies providing IPD was generally good and we rated it at low risk of bias overall in the analyses.The main overall results (pooled HR adjusted for seizure type) were time to withdrawal of allocated treatment: 1.04 (95% CI 0.78 to 1.39; three trials, 546 participants); time to 12-month remission: 1.01 (95% CI 0.78 to 1.31; three trials, 551 participants); time to six-month remission: 1.11 (95% CI 0.89 to 1.37; three trials, 551 participants); and time to first seizure: 0.85 (95% CI 0.70 to 1.04; four trials, 582 participants). The results suggest no overall statistically significant difference between the drugs for these outcomes. There is some evidence of an advantage for phenytoin for individuals with generalised onset seizures for our primary outcome (time to withdrawal of allocated treatment): pooled HR 0.42 (95% CI 0.18 to 0.96; two trials, 118 participants); and a statistical interaction between treatment effect and epilepsy type (partial versus generalised) for this outcome (P = 0.02). However, misclassification of seizure type for up to 48 individuals (32% of those with generalised epilepsy) may have confounded the results of this review. Despite concerns over side effects leading to the withdrawal of phenytoin as a first-line treatment in the USA and Europe, we found no evidence that phenytoin is more likely to be associated with serious side effects than carbamazepine; 26 individuals withdrew from 290 randomised (9%) to carbamazepine due to adverse effects, compared to 12 out of 299 (4%) randomised to phenytoin from four studies conducted in the USA and Europe (risk ratio (RR) 1.42, 95% CI 1.13 to 1.80, P = 0.014). We rated the quality of the evidence as low to moderate according to GRADE criteria, due to imprecision and potential misclassification of seizure type.
AUTHORS' CONCLUSIONS
We have not found evidence for a statistically significant difference between carbamazepine and phenytoin for the efficacy outcomes examined in this review, but CIs are wide and we cannot exclude the possibility of important differences. There is no evidence in this review that phenytoin is more strongly associated with serious adverse events than carbamazepine. There is some evidence that people with generalised seizures may be less likely to withdraw early from phenytoin than from carbamazepine, but misclassification of seizure type may have impacted upon our results. We recommend caution when interpreting the results of this review, and do not recommend that our results alone should be used in choosing between carbamazepine and phenytoin. We recommend that future trials should be designed to the highest quality possible, with considerations of allocation concealment and masking, choice of population, choice of outcomes and analysis, and presentation of results.
Topics: Adult; Anticonvulsants; Carbamazepine; Child; Epilepsies, Partial; Epilepsy, Generalized; Humans; Induction Chemotherapy; Phenytoin; Randomized Controlled Trials as Topic; Time Factors; Withholding Treatment
PubMed: 28240353
DOI: 10.1002/14651858.CD001911.pub3 -
Scientific Reports Nov 2022Immune-related cutaneous adverse events (irCAEs) in patients treated with programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint inhibitors may be... (Meta-Analysis)
Meta-Analysis
Immune-related cutaneous adverse events (irCAEs) in patients treated with programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint inhibitors may be associated with better clinical outcomes. However, the extent to which these results can be extrapolated to all tumour types remains unclear. Herein, we conducted a meta-analysis of patients with cancer receiving anti-PD-1/PD-L1 immunotherapy, to determine the cumulative incidence of irCAEs and their association with survival. We systematically searched six databases (PubMed, Embase, Cochrane, CNKI, CSPD, and CQVIP database) for all cohort studies reporting the relationship between irCAEs and patient survival from the time of database construction to 1 November, 2020. The primary outcomes were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), with complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD) as secondary outcomes. Patients with irCAEs exhibited higher ORR, and were more likely to report CR and PR and less likely to develop PD than those who did not experience irCAEs. Moreover, the occurrence of irCAEs was significantly associated with both favourable PFS and OS. Therefore, patients with irCAEs have better survival benefit and a significantly lower risk of tumour progression or death. Hence, the occurrence of irCAEs may be a useful marker for predicting the clinical efficacy of anti-PD-1/PD-L1 immunotherapy.
Topics: Humans; Immune Checkpoint Inhibitors; B7-H1 Antigen; Immunotherapy; Progression-Free Survival; Databases, Factual
PubMed: 36414662
DOI: 10.1038/s41598-022-24286-3 -
Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome.The Cochrane Database of Systematic... Oct 2014Idiopathic membranous nephropathy (IMN) is the most common form of nephrotic syndrome in adults. The disease shows a benign or indolent course in the majority of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Idiopathic membranous nephropathy (IMN) is the most common form of nephrotic syndrome in adults. The disease shows a benign or indolent course in the majority of patients, with a rate of spontaneous complete or partial remission of nephrotic syndrome as high as 30% or more. Despite this, 30% to 40% of patients progress toward end-stage kidney disease (ESKD) within five to 15 years. The efficacy and safety of immunosuppression for IMN with nephrotic syndrome are still controversial. This is an update of a Cochrane review first published in 2004.
OBJECTIVES
The aim of this review was to evaluate the safety and efficacy of immunosuppressive treatments for adult patients with IMN and nephrotic syndrome. Moreover it was attempted to identify the best therapeutic regimen, when to start immunosuppression and whether the above therapies should be given to all adult patients at high risk of progression to ESKD or only restricted to those with impaired kidney function.
SEARCH METHODS
We searched Cochrane Renal Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Chinese databases, reference lists of articles, and clinical trial registries to June 2014. We also contacted principal investigators of some of the studies for additional information.
SELECTION CRITERIA
Randomised controlled trials (RCTs) investigating the effects of immunosuppression in adults with IMN and nephrotic syndrome.
DATA COLLECTION AND ANALYSIS
Study selection, data extraction, quality assessment, and data synthesis were performed using the Cochrane-recommended methods. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes.
MAIN RESULTS
Thirty nine studies with 1825 patients were included, 36 of these could be included in our meta-analyses. The data from two studies could not be extracted and one study was terminated due to poor accrual. Immunosuppression significantly reduced all-cause mortality or risk of ESKD ((15 studies, 791 patients): RR 0.58 (95% CI 0.36 to 0.95, P = 0.03) and risk of ESKD ((15 studies, 791 patients): RR 0.55, 95% CI 0.31 to 0.95, P = 0.03), increased complete or partial remission ((16 studies, 864 patients): RR 1.31, 95% CI 1.01 to 1.70, P = 0.04), and decreased proteinuria ((9 studies,(393 patients): MD -0.95 g/24 h, 95% CI -1.81 to -0.09, P = 0.03) at the end of follow-up (range 6 to 120 months). However this regimen was associated with more discontinuations or hospitalisations ((16 studies, 880 studies): RR 5.35, 95% CI 2.19 to 13.02), P = 0.0002). Combined corticosteroids and alkylating agents significantly reduced death or risk of ESKD ((8 studies, 448 patients): RR 0.44, 95% CI 0.26 to 0.75, P = 0.002) and ESKD ((8 studies, 448 patients): RR 0.45, 95% CI 0.25 to 0.81, P = 0.008), increased complete or partial remission ((7 studies, 422 patients): RR 1.46, 95% CI 1.13 to 1.89, P = 0.004) and complete remission ((7 studies, 422 patients): RR 2.32, 95% CI 1.61 to 3.32, P < 0.00001), and decreased proteinuria ((6 studies, 279 patients): MD -1.25 g/24 h, 95% CI -1.93 to -0.57, P = 0.0003) at the end of follow-up (range 9 to 120 months). In a population with an assumed risk of death or ESKD of 181/1000 patients, this regimen would be expected to reduce the number of patients experiencing death or ESKD to 80/1000 patients (range 47 to 136). In a population with an assumed complete or partial remission of 408/1000 patients, this regimen would be expected to increase the number of patients experiencing complete or partial remission to 596/1000 patients (range 462 to 772). However this combined regimen was associated with a significantly higher risk of discontinuation or hospitalisation due to adverse effects ((4 studies, 303 patients): RR 4.20, 95% CI 1.15 to 15.32, P = 0.03). Whether this combined therapy should be indicated in all adult patients at high risk of progression to ESKD or only restricted to those with deteriorating kidney function still remained unclear. Cyclophosphamide was safer than chlorambucil ((3 studies, 147 patients): RR 0.48, 95% CI 0.26 to 0.90, P = 0.02). There was no clear evidence to support the use of either corticosteroid or alkylating agent monotherapy. Cyclosporine and mycophenolate mofetil failed to show superiority over alkylating agents. Tacrolimus and adrenocorticotropic hormone significantly reduced proteinuria. The numbers of corresponding studies related to tacrolimus, mycophenolate mofetil, adrenocorticotropic hormone, azathioprine, mizoribine, and Tripterygium wilfordii are still too sparse to draw final conclusions.
AUTHORS' CONCLUSIONS
In this update, a combined alkylating agent and corticosteroid regimen had short- and long-term benefits on adult IMN with nephrotic syndrome. Among alkylating agents, cyclophosphamide was safer than chlorambucil. This regimen was significantly associated with more withdrawals or hospitalisations. It should be emphasised that the number of included studies with high-quality design was relatively small and most of included studies did not have adequate follow-up and enough power to assess the prespecified definite endpoints. Although a six-month course of alternating monthly cycles of corticosteroids and cyclophosphamide was recommended by the KDIGO Clinical Practice Guideline 2012 as the initial therapy for adult IMN with nephrotic syndrome, clinicians should inform their patients of the lack of high-quality evidence for these benefits as well as the well-recognised adverse effects of this therapy. Cyclosporine or tacrolimus was recommended by the KDIGO Clinical Practice Guideline 2012 as the alternative regimen for adult IMN with nephrotic syndrome; however, there was no evidence that calcineurin inhibitors could alter the combined outcome of death or ESKD.
Topics: Adrenal Cortex Hormones; Adult; Alkylating Agents; Cyclosporine; Drug Therapy, Combination; Glomerulonephritis, Membranous; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Nephrotic Syndrome; Proteinuria; Randomized Controlled Trials as Topic
PubMed: 25318831
DOI: 10.1002/14651858.CD004293.pub3 -
Medicine Jul 2021The objective of this meta-analysis was to compare the efficacy and safety of tacrolimus (TAC) monotherapy versus cyclophosphamide (CTX)-corticosteroid combination... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The objective of this meta-analysis was to compare the efficacy and safety of tacrolimus (TAC) monotherapy versus cyclophosphamide (CTX)-corticosteroid combination therapy in idiopathic membranous nephropathy (IMN) patients.
METHODS
Databases including the PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases were searched from inception to October 20, 2020. Eligible studies comparing TAC monotherapy and CTX-corticosteroid combination therapy in IMN patients were included. Data were analyzed using Review Manager Version 5.3.
RESULTS
Nine studies were included in the meta-analysis. One randomized controlled trial and eight cohort studies involving 442 patients were identified. Compared with CTX-corticosteroid combination therapy for IMN, TAC monotherapy had higher complete remission (CR) at month 6 (odds ratio [OR] 2.18, 95% confidence interval [CI] 1.35-3.50, P < .01). The 2 therapeutic regimens had similar partial remission (OR 0.69, 95% CI 0.45-1.04, P = .08), total remission (OR 1.38, 95% CI 0.85-2.23, P = 0.19) at month 6, and similar CR (OR 1.64, 95% CI 0.84-3.19, P = .15), partial remission (OR 0.71, 95% CI 0.37-1.38, P = 0.31), and total remission (OR 1.29, 95% CI 0.55-3.01, P = .56) after 1 year. The relapse rate of the TAC group was higher than that of the CTX group, but the difference was not statistically significant (OR 1.85, 95% CI 0.75-4.53, P = .18). There was no difference between the 2 therapeutic regimens concerning glucose intolerance (OR 1.15, 95% CI 0.61-2.14, P = .67), acute renal failure (OR 1.14, 95% CI 0.39-3.33, P = .81), or tremors (OR 4.39, 95% CI 0.75-25.67, P = .10). Incidences of gastrointestinal symptoms (OR 0.29, 95% CI 0.10-0.79, P = .02), infection (OR 0.18, 95% CI 0.08-0.39, P < 0.01), leukopenia (OR 0.14, 95% CI 0.04-0.51, P < .01), and abnormal aminotransferase (OR 0.31, 95% CI 0.13-0.77, P = .01) in the TAC group were all lower than those in the CTX group. Subgroup analysis showed that there was no significant difference between the TAC group and the CTX combined with corticosteroid 0.8 to 1 mg/kg/day group concerning CR at month 6 (P > .05). There was no significant difference between the TAC group and the CTX combined with corticosteroid 0.5 mg/kg/day group concerning abnormal aminotransferase (P > .05).
CONCLUSION
TAC monotherapy is comparable to CTX-corticosteroid combination therapy for renal remission in IMN patients. TAC monotherapy had a higher CR in the early stage and had fewer drug-related adverse effects. The relapse rate of TAC monotherapy was higher than that of CTX-corticosteroid combination therapy, but the difference was not significant.
Topics: Adrenal Cortex Hormones; Cyclophosphamide; Drug Therapy, Combination; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Remission Induction; Tacrolimus
PubMed: 34260552
DOI: 10.1097/MD.0000000000026628 -
Carbamazepine versus phenobarbitone monotherapy for epilepsy: an individual participant data review.The Cochrane Database of Systematic... Dec 2016This is an updated version of the original Cochrane Review, first published in Issue 1, 2003 and updated in 2015. This review is one in a series of Cochrane Reviews... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an updated version of the original Cochrane Review, first published in Issue 1, 2003 and updated in 2015. This review is one in a series of Cochrane Reviews investigating pair-wise monotherapy comparisons.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 go into long-term remission shortly after starting drug therapy with a single antiepileptic drug in monotherapy.Worldwide, carbamazepine and phenobarbitone are commonly used broad-spectrum antiepileptic drugs, suitable for most epileptic seizure types. Carbamazepine is a current first-line treatment for partial onset seizures, and is used in the USA and Europe. Phenobarbitone is no longer considered a first-line treatment because of concerns over associated adverse events, particularly documented behavioural adverse events in children treated with the drug. However, phenobarbitone is still commonly used in low- and middle-income countries because of its low cost. No consistent differences in efficacy have been found between carbamazepine and phenobarbitone in individual trials; however, the confidence intervals generated by these studies are wide, and therefore, synthesising the data of the individual trials may show differences in efficacy.
OBJECTIVES
To review the time to withdrawal, remission, and first seizure of carbamazepine compared with phenobarbitone when used as monotherapy in people with partial onset seizures (simple or complex partial and secondarily generalised) or generalised onset tonic-clonic seizures (with or without other generalised seizure types).
SEARCH METHODS
For the latest update, we searched the following databases on 18 August 2016: the Cochrane Epilepsy Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid, from 1946), the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov), and the World Health Organization International Clinical Trials Registry Platform (ICTRP). Previously we also searched SCOPUS (from 1823) as an alternative to Embase, but this is no longer necessary, because randomised controlled trials (RCTs) and quasi-RCTs in Embase are now included in CENTRAL. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field.
SELECTION CRITERIA
RCTs in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of carbamazepine monotherapy versus phenobarbitone monotherapy.
DATA COLLECTION AND ANALYSIS
This was an individual participant data (IPD) review. 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 'adverse events'. We used Cox proportional hazards regression models to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), with the generic inverse variance method used to obtain the overall pooled HR and 95% CI.
MAIN RESULTS
IPD were available for 836 participants out of 1455 eligible individuals from six out of 13 trials; 57% of the potential data. For remission outcomes, HR > 1 indicated an advantage for phenobarbitone, and for first seizure and withdrawal outcomes, HR > 1 indicated an advantage for carbamazepine.The main overall results (pooled HR adjusted for seizure type, 95% CI) were HR 1.50 for time to withdrawal of allocated treatment (95% CI 1.15 to 1.95; P = 0.003); HR 0.93 for time to achieve 12-month remission (95% CI 0.72 to 1.20; P = 0.57); HR 0.99 for time to achieve six-month remission (95% CI 0.80 to 1.23; P = 0.95); and HR 0.87 for time to first seizure (95% CI 0.72 to 1.06; P = 0.18). Results suggest an advantage for carbamazepine over phenobarbitone in terms of time to treatment withdrawal and no statistically significant evidence between the drugs for the other outcomes. We found evidence of a statistically significant interaction between treatment effect and seizure type for time to first seizure recurrence (Chi² test for subgroup differences P = 0.03), where phenobarbitone was favoured for partial onset seizures (HR 0.76, 95% CI 0.60 to 0.96; P = 0.02) and carbamazepine was favoured for generalised onset seizures (HR 1.23, 95% CI 0.88 to 1.77; P = 0.27). We found no evidence of an interaction between treatment effect and seizure type for the other outcomes. However, methodological quality of the included studies was variable, with 10 out of the 13 included studies (4 out of 6 studies contributing IPD) judged at high risk of bias for at least one methodological aspect, leading to variable individual study results, and therefore, heterogeneity in the analyses of this review. We conducted sensitivity analyses to examine the impact of poor methodological aspects, where possible.
AUTHORS' CONCLUSIONS
Overall, we found evidence suggestive of an advantage for carbamazepine in terms of drug effectiveness compared with phenobarbitone (retention of the drug in terms of seizure control and adverse events) and evidence suggestive of an association between treatment effect and seizure type for time to first seizure recurrence (phenobarbitone favoured for partial seizures and carbamazepine favoured for generalised seizures). However, this evidence was judged to be of low quality due to poor methodological quality and the potential impact on individual study results (and therefore variability (heterogeneity) present in the analysis within this review), we encourage caution when interpreting the results of this review and do not advocate that the results of this review alone should be used in choosing between carbamazepine and phenobarbitone. We recommend that future trials should be designed to the highest quality possible with considerations for allocation concealment and masking, choice of population, choice of outcomes and analysis, and presentation of results.
Topics: Adult; Anticonvulsants; Carbamazepine; Child; Epilepsies, Partial; Epilepsy, Generalized; Epilepsy, Tonic-Clonic; Humans; Phenobarbital; Randomized Controlled Trials as Topic; Remission Induction; Seizures
PubMed: 27976799
DOI: 10.1002/14651858.CD001904.pub3