Nonselective beta-blockers in cirrhotic patients with no or small varices: A meta-analysis

Table 1 Information of included studies

Ref.	Year	Study design and regions	Period of enrollment	Target population	Groups	Definitions of small varices	n
Andreani et al[11]	1990	Multi-center RCT from two centers in Paris	Nov. 1985 to Feb. 1988	LC without previous bleeding, but with esophageal varices (small or large)	Propranolol vs placebo	Non-confluent esophageal varices flattened by insufflation	84
Conn et al[16]	1991	Multi-center double-blinded RCT from three centers in the United States and Spain	Oct. 1982 to Aug. 1986	LC without previous bleeding, but with esophageal varices (small or large)	Propranolol vs placebo	Diameter: 1-3 mm with Valsalva	102
Calés et al[12]	1999	Multi-center double-blinded RCT from 14 centers in France	April 1991 to June 1993	LC without varices or small esophageal varices	Propranolol vs placebo	Diameter: < 5 mm	206
Merkel et al[14]	2004	Multi-center single-blinded RCT from seven hospitals in Italy	Dec. 1996 to April 2000	LC with small varices	Nadolol vs placebo	F1 without red signs according to Beppu et al[27] (small straight varices, minimally elevated on the esophageal mucosal surface)	161
Groszmann et al[13]	2005	Multi-center double-blinded RCT from four hospitals in the United States, Spain, and United Kingdom	Aug. 1993 to March 1999	LC with an HVPG of ³ 6 mmHg, and without gastroesophageal varices	Timolol vs placebo	NA	213
Sarin et al[15]	2013	Single-center single-blinded RCT in India	Oct. 2004 to June 2007	LC with small varices, without any history of variceal bleed	Propranolol vs placebo	Grade 1 or 2 according to the classification of Conn[28] or small according to de Franchis et al[29]	150

HVPG: Hepatic venous pressure gradient; LC: Liver cirrhosis; RCT: Randomized controlled trial.

Table 2 Patient characteristics of included studies

Ref.	Groups	n	Age (yr)	Sex (M/F)	Etiology (alcohol/viral/other)	Child-Pugh score or class A/B/C	Follow-up (mo)	Lost to follow-up	Small varices, n	No varices, n
Andreani et al[11]	Propranolol	43	55.0 ± 1.3	27/16	33/-/10	10/19/13	NA	6	15	0
	Placebo	41	55.6 ± 1.7	23/18	33/-/8	10/21/10	NA	2	17	0
Conn et al[16]	Propranolol	51	54 ± 9	38/13	39/-/12	Mean: 8.0	17.1 ± 10.9	NA	26	0
	Placebo	51	54 ± 11	35/16	41/-/10	Mean: 8.3	16.3 ± 12	NA	29	0
Calés et al[12]	Propranolol	102	52.7 ± 10.4	69/33	88/-/24	6.8 ± 2.1	NA	41	60	42
	Placebo	104	52.7 ± 11.4	68/36	81/-/23	6.8 ± 2.0	NA	32	67	37
Merkel et al[14]	Nadolol	83	56 ± 9	45/38	47/34/2	6.8 ± 1.6	36 ± 18	11	83	0
	Placebo	78	57 ± 9	38/40	45/28/5	7.1 ± 1.9	35 ± 15	10	78	0
Groszmann et al[13]	Timolol	108	46 ± 11	70/38	26/73/9	5.4 ± 0.7	Median: 52.7	0	0	108
	Placebo	105	44 ± 11	56/49	25/69/11	5.4 ± 0.8	Median: 57.9	0	0	105
Sarin et al[15]	Propranolol	77	42 ± 13	63/14	27/42/8	7.4 ± 1.9	25 ± 12.6	0	77	0
	Placebo	73	44 ± 13	57/16	26/38/9	7.7 ± 2.3		0	73	0

F: Female; M: Male; NA: Not available. Note: data are expressed as mean ± SD unless otherwise indicated.

Table 3 Risk of bias for the study

Entry	Judgment	Support for judgment
Andreani (1990)
Random sequence generation (selection bias)	Low risk	Quote: “the patients in each center were randomly assigned”
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding of participants and personnel (performance bias)	High risk	Quote: “these treatments were not administered blindly”
Blinding of outcome assessment (detection bias)	Unclear risk	Not described
Incomplete outcome data addressed (attrition bias)	High risk	Quote: “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 risk	Both potential efficacy and complications were reported. Review authors do not believe that bias will be introduced.
Conn (1991)
Random sequence generation (selection bias)	Low risk	Quote: “the patients were randomly selected”
Allocation concealment (selection bias)	Low risk	Quote: “using a sealed envelope technique and computer-generated randomization”
Blinding of participants and personnel (performance bias)	Low risk	Quote: “double-blinded”, “The placebo and the propranolol tablets were identical in appearance”
Blinding of outcome assessment (detection bias)	Low risk	Quote: “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 risk	Not described
Selective reporting (reporting bias)	Low risk	Both potential efficacy and complications were reported. Review authors do not believe that bias will be introduced
Cales (1999)
Random sequence generation (selection bias)	Low risk	Quote: “patients were randomized”
Allocation concealment (selection bias)	Low risk	Quote: “by the opaque sealed envelope method”
Blinding of participants and personnel (performance bias)	Low risk	Quote: “double-blinded”, “Patients and physicians were unaware of the treatment”
Blinding of outcome assessment (detection bias)	Low risk	Quote: “double-blinded”, “Patients and physicians were unaware of the treatment”
Incomplete outcome data addressed (attrition bias)	High risk	Quote: “In the propranolol group, 41 patients were lost to follow-up, compared with 32 in the placebo group”
Selective reporting (reporting bias)	Low risk	Both potential efficacy and complications were reported. Review authors do not believe that bias will be introduced
Merkel (2004)
Random sequence generation (selection bias)	Low risk	Quote: “A total of 83 patients were randomized to”
Allocation concealment (selection bias)	Low risk	Quote: “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 risk	Quote: “The single-blind study design was chosen”
Blinding of outcome assessment (detection bias)	High risk	Quote: “The single-blind study design was chosen”
Incomplete outcome data addressed (attrition bias)	High risk	Quote: “11 patients randomized to nadolol and 10 patients randomized to placebo were lost to follow-up”
Selective reporting (reporting bias)	Low risk	Both potential efficacy and complications were reported. Review authors do not believe that bias will be introduced
Groszmann (2005)
Random sequence generation (selection bias)	Low risk	Quote: “patients were randomly assigned”
Allocation concealment (selection bias)	Low risk	Quote: “The randomization code was generated by computer for each participating center”
Blinding of participants and personnel (performance bias)	Low risk	Quote: “The study was an investigator-initiated, randomized, double-blind, placebo-controlled, clinical trial conducted at four sites”
Blinding of outcome assessment (detection bias)	Low risk	Quote: “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 risk	Quote: “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 risk	Both potential efficacy and complications were reported. Review authors do not believe that bias will be introduced
Sarin (2012)
Random sequence generation (selection bias)	Low risk	Quote: “Patients were randomly assigned”
Allocation concealment (selection bias)	Low risk	Quote: “All randomizations were done by computer-generated random numbers”
Blinding of participants and personnel (performance bias)	Low risk	Quote: “single-blind”
Blinding of outcome assessment (detection bias)	High risk	Quote: “single-blind”
Incomplete outcome data addressed (attrition bias)	Low risk	Quote: “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 risk	Both potential efficacy and complications were reported. Review authors do not believe that bias will be introduced

Table 4 Results of subgroup analyses

Category	Studies,	Patients,	OR (95%CI)	Heterogeneity	Subgroup difference
	n	n
Development of large varices
No varices	2	292	2.43 (0.44-13.55)	I² = 71%	I² = 0%
			P = 0.31	P = 0.06	P = 0.51
Small varices	3	444	1.07 (0.19-6.18)	I² = 93%
			P = 0.94	P < 0.01
First bleeding
No varices	1	213	0.38 (0.07-1.99)	NA	I² = 0%
			P = 0.25		P = 0.64
Small varices	4	398	0.64 (0.15-2.79)	I² = 47%
			P = 0.55	P = 0.13
Death
No varices	1	213	0.61 (0.26-1.43)	NA	I² = 0
			P = 0.26		P = 0.84
Small varices	2	311	0.68 (0.37-1.26)	I² = 0%
			P = 0.22	P = 0.39
Adverse events
No varices	1	213	1.94 (1.11-3.38)	NA	I² = 37.1%
			P = 0.02		P = 0.21
Small varices	2	311	5.75 (1.17-28.29)	I² = 15%
			P = 0.03	P = 0.28

NA: Not assessed; OR: Odds ratio.

Table 5 Results of sensitivity analyses

Outcomes	Studies,	Patients,	OR (95%CI)	Heterogeneity
	n	n
Development of large varices	3	569	1.95 (0.73-5.24)	I² = 74%
			P = 0.18	P = 0.02
First bleeding	4	624	0.96 (0.37-2.54)	I² = 0%
			P = 0.94	P = 0.42
Death	3	569	0.79 (0.43-1.43)	I² = 0%
			P = 0.43	P = 0.65
Adverse events	3	569	2.68 (1.33-5.43)	I² = 24%
			P = 0.01	P = 0.27

OR: Odds ratio.