TIPS improves liver transplantation-free survival in cirrhotic patients with refractory ascites: An updated meta-analysis

Table 1 Characteristics of the included studies

Study characteristics	Lebrec et al[10]	Rössle et al[9]	Ginès et al[8]	Sanyal et al[11]	Salerno et al[12]	Narahara et al[13]
Study design	Single-center, RCT	Multi-center, RCT	Multi-center, RCT	Multi-center, RCT	Multi-center, RCT	Single-center, RCT
Para	TP with albumin infusion (unclear dose) if creatinine clearance < 60 mL/min	LVP with albumin infusion (8 g/L of ascites removed) when clinically indicated	TP with albumin infusion (8 g/L of ascites removed)	TP with albumin infusion (6-8 g/L of ascites removed)	LVP with albumin infusion (8 g/L of ascites removed)	LVP with albumin infusion (6 g/L of ascites removed)
Study population	Cirrhotic patients with refractory ascites	Cirrhotic patients with refractory or recidivant ascites	Cirrhotic patients with refractory ascites	Cirrhotic patients with refractory ascites	Cirrhotic patients with refractory or recidivant ascites	Cirrhotic patients with refractory ascites
Definition of refractory ascites	Adequate diuretic and sodium restriction: body weight loss < 200 g/d in 5 d or > 2 tense ascites in 4 mo.	Definition reported in 1996 by International Ascites Club	Definition reported in 1996 by International Ascites Club	Definition reported in 1996 by International Ascites Club	Definition reported in 1996 by International Ascites Club	Definition reported in 1996 by International Ascites Club
Exclusion criteria	> 70 yr, HE, severe non-hepatic disease, pulmonary hypertension, PVT/HVT, HCC, active bacterial infection, severe alcoholic hepatitis, biliary obstruction, creatinine > 1.7 mg/dL	HE ≥ grade 2, bilirubin > 5 mg/dL, creatinine > 3 mg/dL, PVT, hepatic hydrothorax, advanced cancer, failure paracentesis	< 18 or > 75 yr, bilirubin > 10 mg/dL, INR > 2.5, PLT < 40000/mm3, creatinine > 3 mg/dL, HCC, complete PVT, cardiac or respiratory failure, organic renal failure, bacterial infection, and chronic HE	Bilirubin > 5 mg/dL, INR > 2, heart or renal failure, PVT, active bacterial infection, HE > grade 2, severe alcoholic hepatitis, HCC or incurable cancers, GI bleeding within 6 wk	> 72 yr, HE > grade 2, bilirubin > 6 mg/dL, Child-Pugh > 11, creatinine > 3 mg/dL, PVT, HCC, active bacterial infection, cardiac or pulmonary failure, GI bleeding within 15 d	> 70 yr, HE, HCC or other malignancy, PVT, active infection, severe cardiac or pulmonary disease, organic renal disease
Primary outcomes	Recurrence of ascites	Transplantation-free survival	Transplantation-free survival	Recurrence of ascites and transplantation-free survival	Transplantation-free survival	Overall survival
Secondary outcomes	Overall survival, HE, hemodynamic, liver and renal function	Recurrence of ascites, liver and renal function, HE	Recurrence of ascites, liver and renal function, HE, GI bleeding, HRS	Overall survival, HE, GI bleeding, liver and renal function, quality of life	Recurrence of ascites, HE, GI bleeding, liver and renal function, HRS	Recurrence of ascites, HE
Number of patients screened	NR	155	119	525	137	78
Randomized ratio	1:01	1:01	1:01	1:01	1:01	1:01
Number of patients randomized (total)	25	60	70	109	66	60
Number of participating centers	1	2	4	6	3	1
Mean follow-up time (TIPS/Para)	7.5/12.4	45/44	9.5/10.8	41/38	21/15	27/13

RCT: Randomized controlled trial; NR: Not reported; TIPS: Transjugular intrahepatic portosystemic shunt; Para: Paracentesis; TP: Total paracentesis; LVP: Large-volume paracentesis; HE: Hepatic encephalopathy; PVT: Portal vein thrombosis; HVT: Hepatic vein thrombosis; HCC: Hepatocellular carcinoma; INR: International normalized ratio; PLT: Platelet count; GI: Gastrointestinal; HRS: Hepatorenal syndrome.

Table 2 Characteristics of the patients in the included studies

Patient characteristics	Lebrec et al[10]	Rössle et al[9]	Ginès et al[8]	Sanyal et al[11]	Salerno et al[12]	Narahara et al[13]
Number of randomized patients	12/13	29/31	35/35	52/57	33/33	30/30
Age, yr (mean)	50/52	58/61	59/56	56/52	58/60	58/61
Percentage of refractory ascites (total)	100/100 (100)	58/52 (55)	100/100 (100)	100/100 (100)	72/64 (75)	100/100 (100)
Percentage men (total)	77/66 (72)	72/68 (70)	69/74 (71)	63/70 (66)	72/76 (74)	77/70 (73)
Percentage alcohol-induced cirrhosis (total)	77/83 (80)	83/74 (78)	51/60 (56)	62/58 (60)	45/39 (42)	37/33 (35)
Percentage Child-Pugh class C (total)	31/33 (32)	38/22 (30)	37/43 (26)	NR	79/73 (76)	37/30 (33)
Mean Child-Pugh score	9.3/9.2	9.1/8.7	9.3/9.2	9.2/9.3	9.4/9.4	8.9/8.9
Percentage with HE (total)	15/17 (16)	46/39 (40)	37/40 (39)	NR	27/21 (24)	10/7 (8)
Percentage with previous GI bleeding (total)	NR	NR	34/23 (29)	23/25 (24)	18/21 (20)	NR
Serum bilirubin, mg/dL	2.04 ± 0.5/1.57 ± 0.2	1.8 ± 1.2/1.8 ± 1.0	2.0 ± 0.2/2.4 ± 0.3	1.9 ± 1.2/1.9 ± 1.4	1.7 ± 0.15/1.9 ± 0.24	1.3 ± 0.7/1.4 ± 0.7
Serum albumin, g/dL	3.0 ± 0.1/3.1 ± 0.2	3.5 ± 0.6/3.5 ± 0.4	2.8 ± 0.1/3.0 ± 0.1	2.9 ± 0.4/2.7 ± 0.4	2.9 ± 0.7/2.9 ± 0.8	2.7 ± 0.5/2.7 ± 0.6
Serum creatinine, mg/dL	0.9 ± 0.7/0.9 ± 0.6	1.3 ± 0.4/1.4 ± 0.9	1.4 ± 0.1/1.4 ± 0.1	1.1 ± 0.3/1.0 ± 0.3	1.12 ± 0.06/1.15 ± 0.09	1.03 ± 0.30/1.03 ± 0.35
Serum sodium, mmol/L	130 ± 2/130 ± 2	130 ± 6/131 ± 6	129 ± 1/130 ± 1	NR	133 ± 1/133 ± 1	134 ± 7/133 ± 5

All of the comparisons between groups were not statistically significant (P > 0.05) in any of the included studies. TIPS: Transjugular intrahepatic portosystemic shunt; HE: Hepatic encephalopathy; NR: Not reported; GI: Gastrointestinal.

Table 3 Technical results of the included studies

Technical results	Lebrec et al[10]	Rössle et al[9]	Ginès et al[8]	Sanyal et al[11]	Salerno et al[12]	Narahara et al[13]
Successful stent placement (n/randomized)	10/13 (77)	29/29 (100)	34/35 (97)	49/52 (94)	29/33 (89)	30/30 (100)
PSG change, mmHg	From 20 ± 1 to 14 ± 1	From 24 ± 6 to 10 ± 4	From 19.1 ± 0.8 to 8.7 ± 0.4	From 19.8 ± 4.8 to 8.3 ± 3.6	From 22.5 ± 1.1 to 8.7 ± 0.6	From 20.3 ± 4.6 to 8.5 ± 4.7
Severe TIPS procedure-related complications	1 severe cardiac arrhythmias	None	3 severe hemolytic anemia	NR	1 cerebrovascular embolism	None
TIPS dysfunction	3/10 (30)	13/29 (45)	13/34 (38)	34/49 (70)	12/29 (41)	26/30 (87)
Irreversible stent obstruction	1/10 (10)	2/29 (7)	1/34 (3)	NR	2/29 (7)	2/30 (7)
TIPS-assisted patency, (n/randomized)	6/13 (46)	27/29 (93)	32/35 (91)	> 90%	27/33 (82)	26/30 (86)
Patients crossed over from paracentesis to TIPS	NR	10/31 (32)	3/35 (9)	2/57 (4)	11/33 (33)	6/30 (20)
TIPS patency surveillance	Doppler sonography	Doppler sonography	Hepatic vein catheterization if ascites recurred	Angiography	Doppler sonography	Doppler sonography

Data are expressed as absolute numbers (percentage) or mean ± SD. TIPS: Transjugular intrahepatic portosystemic shunt; PSG: Portosystemic pressure gradient.

Table 4 Risk of bias assessment of the included studies

Risk of bias	Lebrec et al[10]	Rössle et al[9]	Ginés et al[8]	Sanyal et al[11]	Salerno et al[12]	Narahara et al[13]
Generation of random allocation sequence (risk)	NR (unclear)	NR (unclear)	NR (unclear)	NR (unclear)	NR (unclear)	NR (unclear)
Concealment of allocation sequence (risk)	Sealed opaque envelopes (low)	NR (unclear)	Sealed opaque envelopes (low)	Sealed opaque envelopes (low)	Sealed opaque envelopes (low)	Sealed opaque envelopes (low)
Blinding of participants and personnel (risk)	Unblinded (high)	Unblinded (high)	Unblinded (high)	Unblinded (high)	Unblinded (high)	Unblinded (high)
Blinding of outcome assessment (risk)	Unblinded (high)	Unblinded (high)	Unblinded (high)	Unblinded (high)	Unblinded (high)	Unblinded (high)
Incomplete outcome data (risk)	Intention-to-treat analysis, description of drop-outs (low)	Intention-to-treat analysis, description of drop-outs (low)	Intention-to-treat analysis, description of drop-outs (low)	Intention-to-treat analysis, description of drop-outs (low)	Intention-to-treat analysis, description of drop-outs (low)	Intention-to-treat analysis, description of drop-outs (low)
Selective outcome reporting (risk)	All of the outcomes in the methods section were reported in the results section (low)	All of the outcomes in the methods section were reported in the results section (low)	All of the outcomes in the methods section were reported in the results section (low)	All of the outcomes in the methods section were reported in the results section (low)	All of the outcomes in the methods section were reported in the results section (low)	All of the outcomes in the methods section were reported in the results section (low)

NR: Not reported.

Table 5 Results of each study and pooled estimations of recurrence of ascites, hepatic encephalopathy, severe hepatic encephalopathy, gastrointestinal bleeding and hepatorenal syndrome by sensitivity analysis

Ref.	Liver-transplantation			Liver-disease-related mortality			Non-liver-disease-related mortality			Recurrence ascites			HE			Severe HE			Hepatorenal syndrome
	TIPS	Para	OR (95%CI)	TIPS	Para	OR (95%CI)	TIPS	Para	OR (95%CI)	TIPS	Para	OR (95%CI)	TIPS	Para	OR (95%CI)	TIPS	Para	OR (95%CI)	TIPS	Para	OR (95%CI)
Lebrec et al[10]	0/13	1/12	0.28 (0.01-7.67)	41438	4/12	1.71 (0.34-8.68)	3/13	0/12	8.33 (0.39-180.36)	10/13	11/12	0.30 (0.03-3.41)	3/13	0/12	8.33 (0.39-180.36)	2/13	0/12	5.43 (0.24-125.59)	-	-	-
Rössle et al[9]	0	2/31	0.52 (0.04-6.04)	10/29	20/31	0.29 (0.10-0.84)	5/29	3/31	1.94 (0.42-8.99)	14/29	26/31	0.18 (0.05-0.60)	6/29	3/31	2.43 (0.55-10.82)	-	-	-	-	-	-
Ginés et al[8]	7/35	7/35	1.00 (0.31-3.23)	-	-	-	-	-	-	17/35	29/35	0.20 (0.06-0.59)	27/35	23/35	1.76 (0.61-5.05)	21/35	12/35	2.88 (1.09-7.60)	3/35	11/35	0.20 (0.05-0.81)
Sanyal et al[11]	16/52	17/57	1.05 (0.46-2.37)	13/52	13/57	1.13 (0.47-2.72)	5/52	6/57	0.90 (0.26-3.16)	22/52	48/57	0.14 (0.06-0.34)	22/52	13/57	2.48 (1.08-5.68)	15/52	10/57	1.91 (0.77-4.73)	-	-	-
Salerno et al[12]	4/33	4/33	1.00 (0.23-4.39)	10/33	16/33	0.46 (0.17-1.27)	3/33	4/33	0.72 (0.15-3.53)	13/33	32/33	0.02 (0.00-0.17)	20/33	13/33	2.37 (0.88-6.35)	14/33	10/33	1.69 (0.61-4.67)	3/33	5/33	0.56 (0.12-2.56)
Narahara et al[13]	0/30	0/30	-	8/30	13/30	0.48 (0.16-1.41)	9/30	8/30	1.18 (0.38-3.63)	22/30	27/30	0.31 (0.07-1.29)	20/30	5/30	10.00 (2.94-34.01)	-	-	-	-	-	-
Total	28/192	31/198	0.94 (0.53-1.67)	47/157	66/163	0.62 (0.39-0.98)a	25/157	21/163	1.27 (0.68-2.38)	98/192	173/198	0.15 (0.09-0.24)b	98/192	57/198	2.95 (1.87-4.66)b	52/133	32/137	2.18 (1.27-3.76)b	6/68	16/68	0.32 (0.12-0.86)a
Subgroup without the study by Lebrec et al, 1996	28/179	30/186	0.98 (0.54-1.77)	41/144	62/151	0.56 (0.34-0.91)a	22/144	21/151	1.11 (0.57-2.14)	88/179	162/186	0.14 (0.08-0.24)b	95/179	57/186	2.86 (1.80-4.54)b	50/120	32/125	2.10 (1.21-3.67)b	-	-	-

^aP < 0.05,

^bP < 0.01; No significant heterogeneity was observed among these meta-analyses (I² = 0%-31%). All of these meta-analyses were performed under the fixed-effect model. TIPS: Transjugular intrahepatic portosystemic shunt; Para: Paracentesis; HE: Hepatic encephalopathy.