Chlorpromazine versus metiapine for schizophrenia

Morteza Zare; Azam Bazrafshan

doi:10.1002/14651858.CD011655.pub2

Klorpromazin nasuprot metiapinu u liječenju šizofrenije

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Referencias

References to studies included in this review

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otras referencias

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Additional references

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Kramer 1975

Methods	Allocation: randomly assigned by block ‐ no further description. Blindness: double ‐ identical capsules. Duration: 4 weeks. Design: parallel. Country: USA. Setting: hospital.
Participants	Diagnosis: acute schizophrenia (presence of clinical symptoms according to BPRS). n = 90. Age: range 18 to 54 years, mean ˜ 33 years. Sex: 70 men, 20 women. History: newly admitted to hospital. Excluded: history of brain, cardiovascular, hepatic or renal disorders; history of alcoholism or drug addiction; mental retardation; history or clinical evidence of glaucoma.
Interventions	1. Metiapine: range 25 mg/day to 600 mg/day, mean 219 mg/day. n = 30.* 2. Chlorpromazine: range 50 mg/day to 1200 mg/day, mean 427 mg/day. n = 30. 3. Combination of butabarbital + atropine: between butabarbital sodium 225 mg/day + atropine sulphate 0.26 mg/day and butabarbital sodium 180 mg/day + atropine sulphate 2.04 mg/day. Mean butabarbital sodium 78 mg/day + atropine sulphate 1.17 mg/day. n = 30.
Outcomes	Global state: clinical improvement (CGI), nurse's evaluation (change score NOSIE). Adverse effects: movement disorders, hepatic problems, 'severe reactions', cardiovascular problems. Leaving the study early. Unable to use: Mental state: BPRS (no SD).
Notes	* Only 5 of the metiapine participants, 1 of chlorpromazine participants and 1 of the butabarbital + atropine participants received maximal dosage.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "recently hospitalized schizophrenics who were randomized into three groups." "Patients were assigned in blocks of six, with two patients being assigned to each of the three groups."
Allocation concealment (selection bias)	Unclear risk	No information provided.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "a four‐week double‐blind study."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Missing data were addressed in the study. Full‐analysis‐set, used to assess efficacy measures. All‐participants‐treated‐set, used to assess safety measures.
Selective reporting (reporting bias)	Unclear risk	All expected outcomes reported, some means and SDs omitted.
Other bias	Unclear risk	Metiapine supplied by Merrell‐National Laboratories. No source of funding reported.

Simpson 1973

Methods	Allocation: randomised ‐ table of random numbers. Blindness: double. Duration: 28 weeks (4 weeks' placebo control, 8 weeks' intervention for each metiapine or chlorpromazine treatment, 4 weeks' placebo control, 8 weeks' cross‐over period, and 4 weeks' drying out period). Setting: inpatient. Design: cross‐over. Country: USA. Setting: hospital.
Participants	Diagnosis: schizophrenia (unclear means of diagnosis). n = 10*. Age: range 29 to 57 years. Sex: all men. History: "chronic", hospitalised > 1 year, majority "uncooperative", "withdrawn."
Interventions	1. Metiapine: capsule, range 100 mg/day to 600 mg/day. n = 5. 2. Chlorpromazine: capsule, range 100 mg/day to ‐600 mg/day. n = 5.
Outcomes	Global state: 'symptomatic', mean change score (GAS). Adverse effects: severe reactions, movement disorders (use of anti‐parkinsonism medications "or other remedial medications," cardiovascular (ECG abnormalities), ophthalmological. Leaving the study early. Unable to use: Global state: CGI (no mean, n or SD, no data before cross‐over). Mental state: BPRS (no mean, n or SD, no data before cross‐over). Adverse effects: abnormal laboratory findings, central nervous system symptoms, autonomic system symptoms, "miscellaneous" of unclear meaning (percentages did not round to complete people), handwriting tests (no data before cross‐over).
Notes	* Only 10 participants entered treatment: "One patient did not meet symptom criteria at end of baseline period was dropped" ‐ no more information.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Subjects were assigned to treatment on random number."
Allocation concealment (selection bias)	Unclear risk	No information provided.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The study was conducted under double blind condition."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "the patients and the physician or nurse conducting outcome assessment were unaware of the treatment each patient received."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Premature termination of treatment was not required by any subjects." Full‐analysis‐set, used to assess safety measures.
Selective reporting (reporting bias)	Unclear risk	All expected outcomes reported, some means and SDs omitted.
Other bias	Unclear risk	Metiapine supplied by Merrell‐National Laboratories. Chlorpromazine supplied by SKF.

Steinbook 1975

Methods	Allocation: randomised. Blindness: double ‐ identical capsules. Duration: 6 weeks. Design: parallel. Country: USA. Setting: hospital.
Participants	Diagnosis: acute schizophrenia (diagnosed by clinical symptoms). n = 60. Age: 21 to 60 years. Sex: 19 men, 41 women. History: newly admitted to hospital.
Interventions	1. Chlorpromazine: range 150 mg/day to 900 mg/day, mean 627 mg/day. n = 30.* 2. Metiapine: range 75 mg/day to 450 mg/day, mean 287 mg/day. n = 30.*
Outcomes	Global state: clinical improvement (CGI). Adverse effects: movement disorders, central nervous system, cardiovascular, 'severe reaction', hepatic. Service utilisation: staying in hospital. Unable to use: Mental state: BPRS (no SD).
Notes	* 9 of metiapine participants and 11 of chlorpromazine participants were treated with maximum dosage.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Sixty patients were randomly assigned to metiapine or chlorpromazine."
Allocation concealment (selection bias)	Unclear risk	No information provided.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "in a double blind manner."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing data or excluded participants from the study were reported. Full‐analysis‐set used to assess safety measures.
Selective reporting (reporting bias)	Unclear risk	All expected outcomes reported, some means and SDs omitted.
Other bias	Unclear risk	No source of funding reported.

BPRS: Brief Psychiatric Rating Scale;

CGI: Clinical Global Impression;

ECG: electrocardiogram;

GAS: Global Assessment of Psychiatric Symptoms

n: number of participants

NOSIE: Nurse's Observation Scale for Inpatient Evaluation

SD: standard deviation

Data and analyses

Open in table viewer

Comparison 1. CHLORPROMAZINE versus METIAPINE (all data short term)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Global state: 1. Clinically important improvement (CGI, high = poor)) Show forest plot	2	120	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.84, 1.47]
Open in figure viewer Analysis 1.1 Comparison 1 CHLORPROMAZINE versus METIAPINE (all data short term), Outcome 1 Global state: 1. Clinically important improvement (CGI, high = poor)).
2 Global state: 2a. Overall: remaining symptomatic Show forest plot	1	10	Risk Difference (M‐H, Random, 95% CI)	0.0 [‐0.31, 0.31]
Open in figure viewer Analysis 1.2 Comparison 1 CHLORPROMAZINE versus METIAPINE (all data short term), Outcome 2 Global state: 2a. Overall: remaining symptomatic.
3 Global state: 2b. Overall: mean endpoint score (NOSIE, high = poor) Show forest plot	1	60	Mean Difference (IV, Random, 95% CI)	0.20 [‐3.49, 3.89]
Open in figure viewer Analysis 1.3 Comparison 1 CHLORPROMAZINE versus METIAPINE (all data short term), Outcome 3 Global state: 2b. Overall: mean endpoint score (NOSIE, high = poor).
4 Adverse effects: 1. General: "severe reactions" Show forest plot	3	140	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.41, 1.49]
Open in figure viewer Analysis 1.4 Comparison 1 CHLORPROMAZINE versus METIAPINE (all data short term), Outcome 4 Adverse effects: 1. General: "severe reactions".
5 Adverse effects: 2a. Specific: central nervous system ‐ drowsiness Show forest plot	1	60	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.15, 6.64]
Open in figure viewer Analysis 1.5 Comparison 1 CHLORPROMAZINE versus METIAPINE (all data short term), Outcome 5 Adverse effects: 2a. Specific: central nervous system ‐ drowsiness.
6 Adverse effects: 2b. Specific: hepatic ‐ abnormal liver function test Show forest plot	2	120	Risk Ratio (M‐H, Random, 95% CI)	1.35 [0.17, 10.75]
Open in figure viewer Analysis 1.6 Comparison 1 CHLORPROMAZINE versus METIAPINE (all data short term), Outcome 6 Adverse effects: 2b. Specific: hepatic ‐ abnormal liver function test.
7 Adverse effects: 2c. Specific: movement disorders Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.7 Comparison 1 CHLORPROMAZINE versus METIAPINE (all data short term), Outcome 7 Adverse effects: 2c. Specific: movement disorders.
7.1 Akathisia	1	60	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.32, 3.10]
7.2 Dystonic symptoms	1	60	Risk Ratio (M‐H, Random, 95% CI)	5.0 [0.25, 99.95]
7.3 Parkinsonism	2	70	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.46, 2.03]
7.4 Rigidity	1	60	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.23, 1.69]
7.5 Tremor	1	60	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.87]
7.6 Use of anti‐parkinson or other remedial medication	1	10	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.73, 2.06]
8 Adverse effects: 2d. Specific: others Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.8 Comparison 1 CHLORPROMAZINE versus METIAPINE (all data short term), Outcome 8 Adverse effects: 2d. Specific: others.
8.1 Autonomic ‐ blurred vision	1	60	Risk Ratio (M‐H, Random, 95% CI)	5.0 [0.25, 99.95]
8.2 Cardiovascular (heart) problem	3	130	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.09, 3.08]
8.3 Ophthalmological ‐ "eye changes"	1	10	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
9 Leaving the study Show forest plot	2	70	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.87]
Open in figure viewer Analysis 1.9 Comparison 1 CHLORPROMAZINE versus METIAPINE (all data short term), Outcome 9 Leaving the study.
10 Service utilisation: staying in hospital Show forest plot	1	60	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.74, 1.48]
Open in figure viewer Analysis 1.10 Comparison 1 CHLORPROMAZINE versus METIAPINE (all data short term), Outcome 10 Service utilisation: staying in hospital.

Figure 1

Chlorpromazine ‐ structure.

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Figure 2

Metiapine structure.

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Figure 3

Study flow diagram.

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Figure 4

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 5

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1 CHLORPROMAZINE versus METIAPINE (all data short term), Outcome 1 Global state: 1. Clinically important improvement (CGI, high = poor)).

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Analysis 1.2

Comparison 1 CHLORPROMAZINE versus METIAPINE (all data short term), Outcome 2 Global state: 2a. Overall: remaining symptomatic.

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Analysis 1.3

Comparison 1 CHLORPROMAZINE versus METIAPINE (all data short term), Outcome 3 Global state: 2b. Overall: mean endpoint score (NOSIE, high = poor).

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Analysis 1.4

Comparison 1 CHLORPROMAZINE versus METIAPINE (all data short term), Outcome 4 Adverse effects: 1. General: "severe reactions".

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Analysis 1.5

Comparison 1 CHLORPROMAZINE versus METIAPINE (all data short term), Outcome 5 Adverse effects: 2a. Specific: central nervous system ‐ drowsiness.

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Analysis 1.6

Comparison 1 CHLORPROMAZINE versus METIAPINE (all data short term), Outcome 6 Adverse effects: 2b. Specific: hepatic ‐ abnormal liver function test.

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Analysis 1.7

Comparison 1 CHLORPROMAZINE versus METIAPINE (all data short term), Outcome 7 Adverse effects: 2c. Specific: movement disorders.

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Analysis 1.8

Comparison 1 CHLORPROMAZINE versus METIAPINE (all data short term), Outcome 8 Adverse effects: 2d. Specific: others.

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Analysis 1.9

Comparison 1 CHLORPROMAZINE versus METIAPINE (all data short term), Outcome 9 Leaving the study.

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Analysis 1.10

Comparison 1 CHLORPROMAZINE versus METIAPINE (all data short term), Outcome 10 Service utilisation: staying in hospital.

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Table 2. Suggestions for design of future study

Methods	Allocation: randomised, with sequence generation and concealment of allocation clearly described. Blindness: double, tested. Duration: ≥ 12 months beyond end of intervention. Raters: independent.
Participants	Diagnosis: people with schizophrenia ‐ however diagnosed.* Age: any. Sex: both. History: any. n = 300.**
Interventions	1. Metiapine: about 200 mg/day. n = 150. 2. Chlorpromazine: about 400 mg/day. n = 150.
Outcomes	Global state ‐ relapse, clinically important change. Mental state ‐ general ‐ clinically important change in mental state, mean change in negative symptoms. Adverse effects ‐ incidence of serious adverse events/effects, clinically important extrapyramidal symptoms. Leaving the study early ‐ for any reason. Cost of care. Service outcomes: admitted, number of admissions, length of hospitalisation, discharge, contacts with psychiatric services. Compliance with drugs. Economic evaluations: cost‐effectiveness, cost‐benefit.
Notes	* This could be diagnosed by clinical decision. If funds were permitting all participants could be screened using operational criteria, otherwise a random sample should suffice. ** Size of study with sufficient power to highlight about a 10% difference between groups for primary outcome.
n: number of participants.

Table 2. Suggestions for design of future study

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Summary of findings for the main comparison. Chlorpromazine versus metiapine for schizophrenia

Chlorpromazine versus metiapine for schizophrenia
Patient or population: people with schizophrenia Settings: hospital Intervention: chlorpromazine Comparison: metiapine
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Chlorpromazine	Metiapine
Global state: clinically important improvement Clinical Global Impression Follow‐up: mean 5 weeks	600 per 1000	684 per 1000 (522 to 894)	RR 1.11 (0.84 to 1.47)	120 (2 studies)	⊕⊝⊝⊝ Very low^1,2,3	1 trial reported CGI at 4 weeks, and 1 trial reported CGI at 6 weeks' follow‐up, both indicated no significant difference between the 2 drugs.
Mental state: clinically important improvement	No studies reported this outcome.
Adverse effects. Specific: movement disorders ‐ parkinsonism Follow‐up: 8 weeks	168 per 1000	144 per 1000 (89 to 233)	RR 0.97 (0.46 to 2.03)	70 (2 studies)	⊕⊝⊝⊝ Very low^1,2,3	‐
Service use: readmission due to relapse	No studies reported on these outcomes.
Satisfaction of participant or care provider with treatment
Behaviour: aggressive or violent behaviour
Cost of care
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Risk of bias: serious (downgraded by 1 level): study had unclear risk of other biases as supported by a pharmaceutical company for drug supply. ² Risk of bias: serious (downgraded by 1 level): studies had unclear risk of bias for allocation concealment and blinding outcome assessment. ³ Imprecision: serious (downgraded by 1 level): total sample size was very small.

Summary of findings for the main comparison. Chlorpromazine versus metiapine for schizophrenia

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Table 1. The Cochrane Reviews/protocols relevant to chlorpromazine for people with schizophrenia

Review title	Reference
Acetophenazine versus chlorpromazine for schizophrenia.	Bazrafshan 2015
Chlorpromazine dose for people with schizophrenia.	Liu 2009
Cessation of medication for people with schizophrenia already stable on chlorpromazine.	Almerie 2007
Chlorpromazine versus atypical antipsychotic drugs for schizophrenia.	Saha 2013
Chlorpromazine versus clotiapine for schizophrenia.	Mazhari 2015

Chlorpromazine versus metiapine for schizophrenia.	This review
Chlorpromazine versus penfluridol for schizophrenia.	Khalili 2015
Chlorpromazine versus piperacetazine for schizophrenia.	Eslami 2015
Chlorpromazine versus placebo for schizophrenia.	Adams 2014
Chlorpromazine for psychosis induced aggression or agitation.	Ahmed 2010
Haloperidol versus chlorpromazine for schizophrenia.	Leucht 2008
*

Table 1. The Cochrane Reviews/protocols relevant to chlorpromazine for people with schizophrenia

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Comparison 1. CHLORPROMAZINE versus METIAPINE (all data short term)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Global state: 1. Clinically important improvement (CGI, high = poor)) Show forest plot	2	120	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.84, 1.47]

2 Global state: 2a. Overall: remaining symptomatic Show forest plot	1	10	Risk Difference (M‐H, Random, 95% CI)	0.0 [‐0.31, 0.31]

3 Global state: 2b. Overall: mean endpoint score (NOSIE, high = poor) Show forest plot	1	60	Mean Difference (IV, Random, 95% CI)	0.20 [‐3.49, 3.89]

4 Adverse effects: 1. General: "severe reactions" Show forest plot	3	140	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.41, 1.49]

5 Adverse effects: 2a. Specific: central nervous system ‐ drowsiness Show forest plot	1	60	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.15, 6.64]

6 Adverse effects: 2b. Specific: hepatic ‐ abnormal liver function test Show forest plot	2	120	Risk Ratio (M‐H, Random, 95% CI)	1.35 [0.17, 10.75]

7 Adverse effects: 2c. Specific: movement disorders Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

7.1 Akathisia	1	60	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.32, 3.10]
7.2 Dystonic symptoms	1	60	Risk Ratio (M‐H, Random, 95% CI)	5.0 [0.25, 99.95]
7.3 Parkinsonism	2	70	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.46, 2.03]
7.4 Rigidity	1	60	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.23, 1.69]
7.5 Tremor	1	60	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.87]
7.6 Use of anti‐parkinson or other remedial medication	1	10	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.73, 2.06]
8 Adverse effects: 2d. Specific: others Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

8.1 Autonomic ‐ blurred vision	1	60	Risk Ratio (M‐H, Random, 95% CI)	5.0 [0.25, 99.95]
8.2 Cardiovascular (heart) problem	3	130	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.09, 3.08]
8.3 Ophthalmological ‐ "eye changes"	1	10	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
9 Leaving the study Show forest plot	2	70	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.87]

10 Service utilisation: staying in hospital Show forest plot	1	60	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.74, 1.48]

Comparison 1. CHLORPROMAZINE versus METIAPINE (all data short term)

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Referencias

References to studies included in this review

Kramer 1975 {published data only}

Simpson 1973 {published data only}

Steinbook 1975 {published data only}

Additional references

Adams 2014

Ahmed 2010

Almerie 2007

Altman 1996

Bazrafshan 2015

Bland 1997

Boissel 1999

Carpenter 1994

Crow 1980

Deeks 2000

Deeks 2011

Dickenson 2013

Divine 1992

Dold 2012

Donner 2002

Egger 1997

Elbourne 2002

Elis 2013

Eslami 2015

Furukawa 2006

Gallant 1970

Gibson 1973

Grozier 1973

Gulliford 1999

Guy 1976

Higgins 2003

Higgins 2011a

Higgins 2011b

Higgins 2011c

Honigfeld 1965

Hutton 2009

Kay 1986

Ketteler 1970

Khalili 2015

Leon 2006

Leucht 2005a

Leucht 2005b

Leucht 2008

Liu 2009

Marshall 2000

Mazhari 2015

Moher 2001

Overall 1962

RevMan 2014 [Computer program]

Saha 2013

Schünemann 2011

Sterne 2011

Tardy 2011

Tardy 2014a

Tardy 2014b

Trikalinos 2004

Ukoumunne 1999

WHO 2001

WHO 2011

Xia 2009

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Data and analyses

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