1. Demographic and baseline characteristics
2077 patients were enrolled, of whom 631 received TIPS alone and 1446 received TIPS + E. The demographic and clinical characteristics of these patients are summarized in Table 1. The median age was 52.0 (44.0, 60.0) years, and patients were predominantly men (64.3%); 67.4% of them were viral–related cirrhosis with a median CTP score of 7.0 (6.0, 8.0) and a median MELD score of 10.0 (9.0, 13.0); 67.4% of them had ascites at baseline, while 1.0% had OHE. 74.2% patients received TIPS for secondary prophylaxis, and 90.8% used 8mm–diameter–stents. The median portal pressure gradient was 24.0 (20.0, 27.3) mmHg, while post–TIPS PPG was 8.8 (6.0, 11.0) mmHg. At baseline, missing data consisted of 13 in platelets (PLT) and 7 in hemoglobin (Hb).
Table 1
Demographic and Baseline characteristics of patients underwent TIPS
Characteristics
|
Overall
(n = 2077)
|
TIPS
(n = 631)
|
TIPS + E
(n = 1446)
|
P
|
Age(years)
|
52.0 (44.0, 60.0)
|
53.0 (45.0, 61.0)
|
51.0 (44.0, 60.0)
|
0.03
|
Gender(M/F)
|
1335/742
(64.3%/35.7%)
|
383/248
(60.7%/39.3%)
|
952/494
(65.8%/34.2%)
|
0.03
|
Etiology of cirrhosis
|
|
|
|
0.30
|
Virus
|
1400 (67.4%)
|
440 (69.2%)
|
960 (66.4%)
|
|
Alcoholic
|
124 (6%)
|
33 (5.2%)
|
91(6.3%)
|
|
Others
|
553 (26.6%)
|
158 (25.0%)
|
395 (27.3%)
|
|
PLT (109/L)
|
59.0 (41.0, 87.0)
|
60.0 (40.0, 97.0)
|
58.0 (42.0, 85.0)
|
0.15
|
Hb (g/L)
|
81.0 (70.0, 95.0)
|
81.0 (70.0, 96.0)
|
81.0 (70.0, 95.0)
|
0.24
|
Alb (g/L)
|
33.8 (30.3, 37.4)
|
34.0 (31.0, 37.4)
|
33.6 (30.0, 37.4)
|
0.22
|
TBIL (µmol/L)
|
20.9 (14.4, 30.0)
|
20.0 (13.8, 28.7)
|
21.4 (14.7, 30.4)
|
0.05
|
Cr (µmol/L)
|
73.0 (59.0, 88.0)
|
73.0 (59.0, 89.0)
|
73.0 (59.0, 88.0)
|
0.48
|
INR
|
1.3 (1.2, 1.5)
|
1.3 (1.2, 1.5)
|
1.3 (1.2, 1.5)
|
0.83
|
CTP Score
|
7.0 (6.0, 8.0)
|
7.0 (6.0, 8.0)
|
7.0 (6.0, 8.0)
|
0.42
|
CTP Grade
|
|
|
|
0.68
|
A
|
810 (39.0%)
|
253 (40.1%)
|
557 (38.5%)
|
|
B
|
1061 (51.1%)
|
320 (50.7%)
|
741 (51.2%)
|
|
C
|
206 (9.9%)
|
58 (9.2%)
|
148 (10.2%)
|
|
MELD score
|
10.0 (9.0, 13.0)
|
10.0 (8.0, 13.0)
|
10.0 (9.0, 13.0)
|
0.83
|
Ascites
|
|
|
|
0.84
|
+
|
1399 (67.4%)
|
427 (67.7%)
|
972 (67.2%)
|
|
-
|
678 (32.6%)
|
204 (32.3%)
|
474 (32.8%)
|
|
HE
|
|
|
|
0.77
|
+
|
21 (1.0%)
|
7 (1.1%)
|
14 (1.0%)
|
|
-
|
2056 (99.0%)
|
624 (98.9%)
|
1432 (99.0%)
|
|
PPG, mmHg
|
24.0 (20.0, 27.3)
|
23.5 (19.3, 27.2)
|
24.0 (20.6, 27.9)
|
0.19
|
Stent diameters
|
|
|
|
0.00
|
6mm
|
91 (4.4%)
|
73 (11.6%)
|
18 (1.2%)
|
|
8mm
|
1886 (90.8%)
|
537 (85.1%)
|
1447 (93.3%)
|
|
10mm
|
100 (4.8%)
|
21 (3.3%)
|
79 (5.5%)
|
|
Follow-up time
|
32.5 (19.3, 56.6)
|
29.9 (16.2, 59.5)
|
33.7 (20.5, 54.9)
|
0.05
|
Data were presented by median (lower quartile, upper quartile). PLT, platelet; Alb, albumin; TBIL, total bilirubin; INR, international normalized ratio; Hb, hemoglobin; Cr, Creatinine; CTP, Child-Turcotte-Pugh; HE, hepatic encephalopathy; PPG, portal pressure gradient; MELD, model for end-stage liver disease; TIPS, transjugular intrahepatic portosystemic shunt; TIPS + E, transjugular intrahepatic portosystemic shunt plus portosystemic shunt embolization. |
Baseline characteristics were comparable between TIPS and TIPS + E (Table 1). TIPS + E group had younger (P = 0.03), more male patients (P = 0.03), and higher total bilirubin (TBIL) (P = 0.05), than TIPS alone. There were no significant differences in CTP score and levels (P = 0.42, P = 0.68, respectively), MELD score (P = 0.83), portal pressure gradient (P = 0.19) and other variables between the two groups. After TIPS procedure, patients in TIPS + E group had higher post–TIPS PPG (P = 0.01) (Table 2) and longer follow–up time (P = 0.05).
Table 2
Characteristics and outcomes of patients after TIPS.
Characteristics
|
TIPS
(n = 631)
|
TIPS + E
(n = 1446)
|
P
|
Post-TIPS PPG, mmHg
|
8.1 (5.9, 10.4)
|
8.8 (6.5, 11.0)
|
0.01
|
PPG standards
|
|
|
0.11
|
Reach
|
89.7%
|
87.2%
|
|
Not
|
10.3%
|
12.8%
|
|
Outcomes
|
|
|
|
Rebleeding rates
|
123
|
330
|
0.54
|
6 months
|
4.7%
|
5.3%
|
0.49
|
1 year
|
8.5%
|
8.2%
|
0.96
|
2 years
|
14.1%
|
13.7%
|
0.88
|
3 years
|
20.3%
|
18.3%
|
0.51
|
HE rates
|
222
|
480
|
0.20
|
6 months
|
27.4%
|
24.9%
|
0.24
|
1 year
|
31.9%
|
28.7%
|
0.15
|
2 years
|
33.5%
|
31.9%
|
0.16
|
3 years
|
36.1%
|
33.9%
|
0.13
|
Survival
|
458
|
987
|
0.006
|
6 months
|
94.8%
|
97.4%
|
0.07
|
1 year
|
88.6%
|
94.7%
|
0.04
|
2 years
|
72.4%
|
81.0%
|
0.03
|
3 years
|
53.6%
|
60.1%
|
0.004
|
Recompensed survival
|
265
|
621
|
0.04
|
6 months
|
94.9%
|
98.0%
|
0.02
|
1 year
|
88.9%
|
96.1%
|
0.04
|
2 years
|
73.4%
|
83.8%
|
0.02
|
3 years
|
55.1%
|
62.4%
|
0.03
|
Further-Decompensated rates
|
367
|
825
|
0.04
|
6 months
|
22.8%
|
20.6%
|
0.28
|
1 year
|
30.6%
|
26.3%
|
0.05
|
2 years
|
39.6%
|
35.9%
|
0.09
|
3 years
|
50.7%
|
45.9%
|
0.04
|
Post-Further-Decompensated survival
|
597
|
289
|
0.02
|
6 months
|
89.4%
|
90.0%
|
0.11
|
1 year
|
79.8%
|
83.2%
|
0.08
|
2 years
|
59.1%
|
67.2%
|
0.02
|
3 years
|
49.3%
|
51.5%
|
0.04
|
The 6-month, 1-year, 2-year, 3-year cumulative rates were calculated by Cox proportional hazards models. |
2. Clinical Outcomes In Tips And Tips + e Group
2.1. TIPS + E showed no significant reduction in rebleeding compared to TIPS alone
401 (19.3%) patients suffered variceal rebleeding, including 123 (19.5%) in TIPS group and 330 (22.8%) in TIPS + E group, respectively. The 6–months, 1–year, 2–year and 3–year cumulative rebleeding rates were 4.7%, 8.5%, 14.1%, 20.3% in TIPS group, while 5.3%, 8.2%, 13.7%, 18.3% in TIPS + E group, respectively (Fig. 1a, Table 2). There was no significant difference between the two group (P = 0.54, HR = 0.94, 95%CI: 0.76, 1.16).
2.2. TIPS + E had a trend towards decreasing HE rates compared to TIPS alone
702 (34.4%) patients occurred HE after receiving TIPS procedure, including 222 (35.2%) in TIPS group and 480 (33.2%) in TIPS + E group, respectively. The 6–months, 1–year, 2–year and 3–year cumulative HE rates were 27.4%, 31.9%, 33.5%, 36.1% in TIPS group, comparing 24.9%, 28.7%, 31.9%, 33.9% in TIPS + E group, respectively (Fig. 1b, Table 2). There was no significant difference between the two group (P = 0.20, HR = 0.90, 95%CI: 0.77, 1.06).
2.3. Tips + e Significantly Improved Survival Compared To Tips Alone
During follow–up, there were 1445 (69.6%) surviving patients, including 458 (72.5%) in TIPS group and 987 (68.3%) in the TIPS + E group, respectively. The 6–months, 1–year, 2–year, and 3–year cumulative survival rates were 94.8%, 88.6%, 72.4%, and 53.6% in the TIPS group, while 97.4%, 94.7%, 81.0%, and 60.1% in the TIPS + E group, respectively (Fig. 1c, Table 2). There was a significant difference between the two groups (P = 0.006, HR = 0.86, 95%CI: 0.76, 0.96).
2.4. Tips + e Significantly Improved Prognosis Compared To Tips Alone
According to our definition, 886 (42.7%) patients achieved re-compensation after the TIPS procedure, including 265 (42.0%) in the TIPS group and 621 (42.9%) in TIPS + E group, respectively. The 6–months, 1–year, 2–year, and 3–year cumulative R–survival rates were 94.9%, 88.9%, 73.4%, and 55.1% in the TIPS group, while 98.0%, 96.1%, 83.8%, and 62.4% in the TIPS + E group, respectively (Fig. 1d, Table 2). There was a significant difference between the two groups (P = 0.04, HR = 0.86, 95%CI: 0.74, 1.00).
Furthermore, 1192 patients suffered recurrence, including 367 in TIPS and 825 in TIPS + E, respectively. The 6–months, 1–year, 2–year, and 3–year cumulative further–decompensated rates were 22.8%, 30.6%, 39.6%, and 50.7% in the TIPS group, while 20.6%, 26.3%, 35.9%, and 45.9% in the TIPS + E group, respectively (Fig. 1e, Table 2). There was significant difference between the two groups (P = 0.04, HR = 0.88, 95%CI: 0.77, 1.00). Among these, 955 patients suffered variceal bleeding or HE after TIPS and 69 of them died during this recurrence. Thus, 886 PFD-patients consist of 289 in TIPS and 597 in TIPS + E, with median survival time 35.9 and 41.27, respectively. The 1–year, 2–year, and 3–year cumulative PFD–survival rates were 89.4%, 79.8%, 59.1%, and 49.3% in the TIPS group, while 90.0%, 83.2%, 67.2%, and 51.5% in the TIPS + E group, respectively (Fig. 1f, Table 2). There was a significant difference between the two groups (P = 0.02, HR = 0.81, 95%CI: 0.68, 0.98).
3. Subgroup analysis on clinical outcomes of TIPS + E by Cox proportional hazards regression models
We attempted to explore the risk factors and clinical–benefited patients of TIPS + E. Baseline data and PPG–related indexes, were pooled in univariate and multivariate analysis in a Cox proportional hazards regression model (Fig. 2 and Supplementary table 1–6). Multivariable analysis in TIPS + E group showed sex (0/1), Hb, PPG standard (0/1) and post–TIPS PPG were independent risk factors for rebleeding; Age, HE (0/1), Hb, Cr, INR and CTP score for HE; Sex (0/1), Age, TBIL, CTP score and PPG for further–decompensated rates. Interestingly, Cr, Alb, PPG, and Ascites (0/1) were all independent risk factors for survival (other variables: PPG%, Age, Sex), recompensated survival (INR, Age, Sex), and PFD–survival (PPG%).