Meta-Analysis
Copyright ©The Author(s) 2015.
World J Gastroenterol. Mar 14, 2015; 21(10): 3100-3108
Published online Mar 14, 2015. doi: 10.3748/wjg.v21.i10.3100
Table 1 Information of included studies
Ref.YearStudy design and regionsPeriod of enrollmentTarget populationGroupsDefinitions of small varicesn
Andreani et al[11]1990Multi-center RCT from two centers in ParisNov. 1985 to Feb. 1988LC without previous bleeding, but with esophageal varices (small or large)Propranolol vs placeboNon-confluent esophageal varices flattened by insufflation84
Conn et al[16]1991Multi-center double-blinded RCT from three centers in the United States and SpainOct. 1982 to Aug. 1986LC without previous bleeding, but with esophageal varices (small or large)Propranolol vs placeboDiameter: 1-3 mm with Valsalva102
Calés et al[12]1999Multi-center double-blinded RCT from 14 centers in FranceApril 1991 to June 1993LC without varices or small esophageal varicesPropranolol vs placeboDiameter: < 5 mm206
Merkel et al[14]2004Multi-center single-blinded RCT from seven hospitals in ItalyDec. 1996 to April 2000LC with small varicesNadolol vs placeboF1 without red signs according to Beppu et al[27] (small straight varices, minimally elevated on the esophageal mucosal surface)161
Groszmann et al[13]2005Multi-center double-blinded RCT from four hospitals in the United States, Spain, and United KingdomAug. 1993 to March 1999LC with an HVPG of ³ 6 mmHg, and without gastroesophageal varicesTimolol vs placeboNA213
Sarin et al[15]2013Single-center single-blinded RCT in IndiaOct. 2004 to June 2007LC with small varices, without any history of variceal bleedPropranolol vs placeboGrade 1 or 2 according to the classification of Conn[28] or small according to de Franchis et al[29]150
Table 2 Patient characteristics of included studies
Ref.GroupsnAge (yr)Sex (M/F)Etiology (alcohol/viral/other)Child-Pugh score or class A/B/CFollow-up (mo)Lost to follow-upSmall varices, nNo varices, n
Andreani et al[11]Propranolol4355.0 ± 1.327/1633/-/1010/19/13NA6150
Placebo4155.6 ± 1.723/1833/-/810/21/10NA2170
Conn et al[16]Propranolol5154 ± 938/1339/-/12Mean: 8.017.1 ± 10.9NA260
Placebo5154 ± 1135/1641/-/10Mean: 8.316.3 ± 12NA290
Calés et al[12]Propranolol10252.7 ± 10.469/3388/-/246.8 ± 2.1NA416042
Placebo10452.7 ± 11.468/3681/-/236.8 ± 2.0NA326737
Merkel et al[14]Nadolol8356 ± 945/3847/34/26.8 ± 1.636 ± 1811830
Placebo7857 ± 938/4045/28/57.1 ± 1.935 ± 1510780
Groszmann et al[13]Timolol10846 ± 1170/3826/73/95.4 ± 0.7Median: 52.700108
Placebo10544 ± 1156/4925/69/115.4 ± 0.8Median: 57.900105
Sarin et al[15]Propranolol7742 ± 1363/1427/42/87.4 ± 1.925 ± 12.60770
Placebo7344 ± 1357/1626/38/97.7 ± 2.30730
Table 3 Risk of bias for the study
EntryJudgmentSupport for judgment
Andreani (1990)
Random sequence generation (selection bias)Low riskQuote: “the patients in each center were randomly assigned”
Allocation concealment (selection bias)Unclear riskNot described
Blinding of participants and personnel (performance bias)High riskQuote: “these treatments were not administered blindly”
Blinding of outcome assessment (detection bias)Unclear riskNot described
Incomplete outcome data addressed (attrition bias)High riskQuote: “Fourteen patients were lost to follow-up after a period of 4.9 ± 1.9 mo (propranolol=six, sclerosis=six, placebo=two)”
Selective reporting (reporting bias)Low riskBoth potential efficacy and complications were reported. Review authors do not believe that bias will be introduced.
Conn (1991)
Random sequence generation (selection bias)Low riskQuote: “the patients were randomly selected”
Allocation concealment (selection bias)Low riskQuote: “using a sealed envelope technique and computer-generated randomization”
Blinding of participants and personnel (performance bias)Low riskQuote: “double-blinded”, “The placebo and the propranolol tablets were identical in appearance”
Blinding of outcome assessment (detection bias)Low riskQuote: “double-blinded”, “the patients were examined on each visit by a nurse and the postdoctoral fellow assigned to the study”
Incomplete outcome data addressed (attrition bias)Unclear riskNot described
Selective reporting (reporting bias)Low riskBoth potential efficacy and complications were reported. Review authors do not believe that bias will be introduced
Cales (1999)
Random sequence generation (selection bias)Low riskQuote: “patients were randomized”
Allocation concealment (selection bias)Low riskQuote: “by the opaque sealed envelope method”
Blinding of participants and personnel (performance bias)Low riskQuote: “double-blinded”, “Patients and physicians were unaware of the treatment”
Blinding of outcome assessment (detection bias)Low riskQuote: “double-blinded”, “Patients and physicians were unaware of the treatment”
Incomplete outcome data addressed (attrition bias)High riskQuote: “In the propranolol group, 41 patients were lost to follow-up, compared with 32 in the placebo group”
Selective reporting (reporting bias)Low riskBoth potential efficacy and complications were reported. Review authors do not believe that bias will be introduced
Merkel (2004)
Random sequence generation (selection bias)Low riskQuote: “A total of 83 patients were randomized to”
Allocation concealment (selection bias)Low riskQuote: “Randomization was generated by tables of random numbers, stratified by participating centers, prepared at the University of Padua, and administered by opaque sealed and consecutively numbered envelopes containing randomization”
Blinding of participants and personnel (performance bias)Low riskQuote: “The single-blind study design was chosen”
Blinding of outcome assessment (detection bias)High riskQuote: “The single-blind study design was chosen”
Incomplete outcome data addressed (attrition bias)High riskQuote: “11 patients randomized to nadolol and 10 patients randomized to placebo were lost to follow-up”
Selective reporting (reporting bias)Low riskBoth potential efficacy and complications were reported. Review authors do not believe that bias will be introduced
Groszmann (2005)
Random sequence generation (selection bias)Low riskQuote: “patients were randomly assigned”
Allocation concealment (selection bias)Low riskQuote: “The randomization code was generated by computer for each participating center”
Blinding of participants and personnel (performance bias)Low riskQuote: “The study was an investigator-initiated, randomized, double-blind, placebo-controlled, clinical trial conducted at four sites”
Blinding of outcome assessment (detection bias)Low riskQuote: “double-blinded”, “To maintain study blinding, the patient’s heart rate was measured by the study nurse and not by the investigators”
Incomplete outcome data addressed (attrition bias)Low riskQuote: “The remaining 277 were excluded for the following reasons: …6 were lost to follow-up…” Patients who were lost to follow-up were excluded from the final analysis
Selective reporting (reporting bias)Low riskBoth potential efficacy and complications were reported. Review authors do not believe that bias will be introduced
Sarin (2012)
Random sequence generation (selection bias)Low riskQuote: “Patients were randomly assigned”
Allocation concealment (selection bias)Low riskQuote: “All randomizations were done by computer-generated random numbers”
Blinding of participants and personnel (performance bias)Low riskQuote: “single-blind”
Blinding of outcome assessment (detection bias)High riskQuote: “single-blind”
Incomplete outcome data addressed (attrition bias)Low riskQuote: “Another 14 patients were excluded because they dropped out before the completion of 6 months of study” Patients who were lost to follow-up were excluded from the final analysis
Selective reporting (reporting bias)Low riskBoth potential efficacy and complications were reported. Review authors do not believe that bias will be introduced
Table 4 Results of subgroup analyses
CategoryStudies,Patients,OR (95%CI)HeterogeneitySubgroup difference
nn
Development of large varices
No varices22922.43 (0.44-13.55)I² = 71%I² = 0%
P = 0.31P = 0.06P = 0.51
Small varices34441.07 (0.19-6.18)I² = 93%
P = 0.94P < 0.01
First bleeding
No varices12130.38 (0.07-1.99)NAI² = 0%
P = 0.25P = 0.64
Small varices43980.64 (0.15-2.79)I² = 47%
P = 0.55P = 0.13
Death
No varices12130.61 (0.26-1.43)NAI² = 0
P = 0.26P = 0.84
Small varices23110.68 (0.37-1.26)I² = 0%
P = 0.22P = 0.39
Adverse events
No varices12131.94 (1.11-3.38)NAI² = 37.1%
P = 0.02P = 0.21
Small varices23115.75 (1.17-28.29)I² = 15%
P = 0.03P = 0.28
Table 5 Results of sensitivity analyses
OutcomesStudies,Patients,OR (95%CI)Heterogeneity
nn
Development of large varices35691.95 (0.73-5.24)I² = 74%
P = 0.18P = 0.02
First bleeding46240.96 (0.37-2.54)I² = 0%
P = 0.94P = 0.42
Death35690.79 (0.43-1.43)I² = 0%
P = 0.43P = 0.65
Adverse events35692.68 (1.33-5.43)I² = 24%
P = 0.01P = 0.27