Carvedilol vs endoscopic variceal ligation for primary and secondary prevention of variceal bleeding: Systematic review and meta-analysis

Table 1 Search strategy

Journal database	Search Terms	Articles
CENTRAL	(Cirrhosis OR “esophageal varices” OR “oesophageal varices”) AND (carvedilol) AND (ligation OR “variceal band ligation” OR “endoscopic variceal ligation” OR VBL OR EVL)	20
MEDLINE	(Cirrhosis OR “esophageal varices” OR “oesophageal varices”) AND (carvedilol) AND (ligation or “variceal band ligation” OR “endoscopic variceal ligation” OR VBL OR EVL)	5
EMBASE via Ovid	Cirrhosis AND Carvedilol AND Ligation	3
A manual search of abstracts and citation index from identified paper’s reference list and via https://library.sydney.edu.au/	“portal hypertension”, “cirrhosis”, “carvedilol”, “endoscopic variceal ligation”	54

Table 2 Characteristic of included studies

Ref.	History of variceal bleeding	Treatment groups	Age (mean ± SD, yr)		n	Dosage / method	Follow up(mo)
Tripathi et al[9]	No	Carvedilol		54.2 ± 9.4	77	6.25 mg (starting dose) daily, with target dose of 12.5 mg daily	24
		EVL		54.5 ±11.1	75	Every two weeks until eradication	24
Shah et al[10]	No	Carvedilol		48.3 ± 11.3	82	6.25 mg daily, with target dose of 6.25 mg twice a day	up to 24
		EVL		47.2 ± 13.2	86	Every three weeks until eradication	up to 24
Khan et al[12]	No	Carvedilol		52.1 ± 14.7	125	12.5 mg daily	6
		EVL		54.1±14.3	125	Not mentioned	6
Abd ElRahim et al[11]	No	Carvedilol		51.2 ± 11.0	84	starting dosage of 6.25 mg daily, titrated up every 4 days to reach up to 12.5–50 mg	up to 12
		EVL		50.6 ± 5.9	88	Every two weeks until eradication	up to 12
Smith et al[15]	Yes	Carvedilol		51 ± 10.9	32	6.25 mg daily, with target dose 12.5 of mg daily	29
		EVL		50 ± 13.0	31	Not mentioned	29
Stanley et al[14]	Yes	Carvedilol		51.4 ± 10.8	33	6.25 mg daily, with target dose 12.5 of mg daily	up to 60
		EVL		49.6 ± 12.87	31	Every two weeks until eradication	up to 60
Kumar et al[13]	Yes	Carvedilol		44.1 ± 8.5 (overall)	47	Not mentioned	11.1 - 21.7
		EVL		44.1 ± 8.5 (overall)	56	Not mentioned	11.1 - 21.7

EVL: Endoscopic variceal ligation.

Table 3 Summary of findings for the main comparison

Outcomes	Relative effect	Participants	Quality of the evidence	Comments
	(95%CI)	(studies)	(GRADE)
Variceal bleed in primary prevention (Grade I)	RR 0.38	250	++−−	Benefit for Carvedilol group
	(0.15-0.93)	(1 Study)	low
Variceal bleed in primary prevention (Grade II)	RR 0.92	492	+++−
	(0.42-2.41)	(3 Studies)	moderate
All-cause mortality in primary prevention	RR 1.10	320	++++
	(0.76-1.58)	(2 Studies)	high
Bleeding-related mortality in primary prevention	RR 1.02	320	++++
	(0.34-3.10)	(2 Studies)	high
Side effect of treatment in primary prevention	RR 4.18	276	+++−	Benefit for EVL group
	(2.19-7.95)	(2 Studies)	moderate
Compliance in primary prevention	RR 0.90	122	+++−
	(0.73-1.11)	(2 Studies)	low
Rebleeding events in secondary prevention	RR 1.10	230	++−−
	(0.75-1.61)	(3 Studies)	low
All-cause mortality in secondary prevention	RR 0.51	230	++−−	Benefit for Carvedilol group
	(0.33-0.79)	(3 Studies)	low

GRADE: Grading of Recommendations, Assessment, Development and Evaluation; Patient or population: Portal hypertension or cirrhosis patients; Comparison: Endoscopic variceal ligation; Settings: Secondary or tertiary hospital; Intervention: Carvedilol. 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.