Alimentary Pharmacology and Therapeutics
Good clinical outcomes following transjugular intrahepatic portosystemic stent-shunts in Budd–Chiari syndrome D. Tripathi*, R. MacNicholas*, C. Kothari*, L. Sunderraj*, H. Al-Hilou*, B. Rangarajan†, F. Chen‡, K. Mangat†, E. Elias* & S. Olliff†
*Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, UK. † Imaging and Interventional Radiology Department, Queen Elizabeth Hospital Birmingham, Birmingham, UK. ‡ Department of Haematology, Queen Elizabeth Hospital, Birmingham, UK.
Correspondence to: Dr D. Tripathi, Liver Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK. E-mail: [email protected]
Publication data Submitted 10 December 2013 First decision 24 December 2013 Resubmitted 4 January 2014 Accepted 30 January 2014 EV Pub Online 24 February 2014 This article was accepted for publication after full peer-review.
SUMMARY Background There have been encouraging reports on transjugular intrahepatic portosystemic stent-shunt (TIPSS) for Budd–Chiari syndrome (BCS). Long-term data are lacking. Aim To assess long-term outcomes and validate prognostic scores following TIPSS for BCS. Methods A single centre retrospective study. Patients underwent TIPSS using bare or polytertrafluoroethane (PTFE)-covered stents. Results Sixty-seven patients received successful TIPSS between 1996 and 2012 using covered (n = 40) or bare (n = 27) stents. Patients included had a Male: Female ratio of 21:46, and were characterised (mean s.d.) by age 39.9 14.3 years, Model of end stage liver disease (MELD) 16.1 7.0 and Child’s score 8.8 2.0. Seventy-eight percent had haematological risk factors. Presenting symptoms were ascites (n = 61) and variceal bleeding (n = 6). Nine patients underwent hepatic vein dilatation or stenting prior to TIPSS. Mean follow-up was 82 months (range 0.5–184 months). Fifteen percent had post-TIPSS encephalopathy. Two have been transplanted. Primary patency rates (76% vs. 27%, P < 0.001) and shunt re-interventions (22% vs. 100%, P < 0.001) significantly favoured covered stents. Secondary patency was 99%. Six-, 12-, 24-, 60- and 120month survival was 97%, 92%, 87%, 80% and 72% respectively. Six patients had liver related deaths. Two patients developed hepatocellular carcinoma. The BCS TIPS PI independently predicted mortality in the whole cohort, but no prognostic score was a significant predictor of mortality after subgroup validation. Conclusions Long-term outcomes following TIPSS for Budd–Chiari syndrome are very good. PTFE-covered stents have significantly better primary patency. The value of prognostic scores is controversial. TIPSS should be considered as first line therapy in symptomatic patients in whom hepatic vein patency cannot be restored. Aliment Pharmacol Ther 2014; 39: 864–872
864
ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12668
TIPSS for Budd–Chiari syndrome INTRODUCTION Budd–Chiari Syndrome (BCS) is a rare disorder resulting from hepatic venous outflow obstruction and subsequent hepatic impairment. Controlled trials of therapies are lacking, and recommendations are based on case series and expert opinion. In 1999, we reported our outcomes with percutaneous angioplasty of short segment strictures of the hepatic veins and proposed a treatment algorithm 1, 2 (Figure 1). TIPSS was first used for the treatment of BCS in the early 1990s using bare metal stents.3–5 Shunt surgery is now largely replaced by TIPSS, which is less invasive and has the advantage of overcoming intrahepatic outflow obstruction by diverting hepatic and portal blood flow to the supra-caudate inferior vena cava (IVC).6 Shunt insufficiency as high as 60% at 1 year has been reported in uncovered TIPSS.7 In 2006, we presented data (from the period 1984– 2004) showing favourable outcome in BCS with radiological intervention (hepatic vein recanalisation n = 31, TIPSS n = 26 or both procedures n = 4).1 However, there is a lack of data on long-term outcomes following TIPSS. Our primary interventional objective in the management of BCS patients is restoring hepatic vein outflow when possible. We consider TIPSS for symptomatic patients when suitable hepatic veins cannot be recanalised successfully. Covered stents have significantly better patency, with the potential for better outcomes.8, 9 The BCS TIPS PI is a powerful prognostic indicator, and may perform better
Correct underlying prothrombotic risk factors and commence lifelong anticoagulation
Treat complications of portal hypertension. HCC surveillance. Monitor for transformation of underlying myeloproliferative disease
Treat any outflow obstruction that is amenable to angioplasty/stenting
If the patient fails to improve then consider TIPSS
Figure 1 | Algorithm for BCS management.1 Aliment Pharmacol Ther 2014; 39: 864-872 ª 2014 John Wiley & Sons Ltd
than other indices.8 The present study assesses the effect of TIPSS over a 16 year period in a single centre and aims to validate prognostic scores in a large cohort of patients.
METHODS Study design A retrospective study was performed using prospectively collected data. All patients from 1996 to 2012 attending our Liver Unit and Radiology department who had a TIPSS inserted for BCS were included. Patients were identified via an electronic database and clinical notes were reviewed. Patient characteristics including age, gender, symptoms and signs at presentation were obtained in addition to imaging and laboratory reports. Three prognostic indices for BCS were calculated for each patient (Rotterdam,10 New Clichy,11 BCS TIPS PI8). The presence of haematological malignancy and prothrombotic factors was assessed by a haematologist. Data on all treatments and their complications were obtained including: anti-coagulation use, radiological interventions prior to TIPSS, complications of TIPSS, need for subsequent radiological interventions or liver transplant and length of survival after TIPSS. Patients were followed up at 3–6 monthly clinical intervals, and follow-up was censored at point of death, liver transplantation or loss to follow-up. Method of TIPSS insertion TIPSS was performed by two authors (SO and KM). TIPSS is a nonsurgical means of creating a portosystemic shunt, allowing communication between portal vein and hepatic veins through the hepatic parenchyma. TIPSS was first used for BCS in 1992.3 In most cases, a catheter is passed via the internal jugular to the right hepatic vein under fluoroscopic guidance. A needle is inserted through the catheter to puncture the hepatic parenchyma from a hepatic vein origin or by direct puncture into the liver from the inferior vena cava, creating a tract to link the hepatic vein and usually right portal vein. This tract is kept patent by using an expandable metal stent (Figure 2). During the first part of the study period, uncovered metal stents were used (Memotherm®, Angiomed, Karlsuhe, Germany). From 2003, covered stents were used in preference (Viatorr® W.L. Gore, Flagstaff, AZ, USA). In some cases, additional uncovered stents (Wallstent® Boston Scientific, Natick, MA, USA) were used with covered stents for TIPSS extension into portal vein, hepatic vein or IVC. Anti-coagulation with low molecular weight Heparin or unfractionated Heparin was 865
D. Tripathi et al. (a) Right
(b) Right
(c) Right
(d)
Right
Figure 2 | Venograms showing insertion of TIPSS in a patient with BCS. (a) Cavogram showing contrast in IVC. (b) Puncture into liver showing abnormal collateral veins. (c) Puncture into portal vein branch. (d) Covered TIPSS in position at end of procedure with good shunting of portal blood through the liver.
commenced 6–12 h after TIPSS and then switched to vitamin K antagonist (Warfarin) unless there were local complications such as puncture of the liver capsule, when introduction of Heparin was generally delayed for 12–24 h. INR of 2.5–3.5 was the target level for monitoring Warfarin dose and a target anti-Xa level of 0.5–0.85 IU/mL was used for low molecular weight Heparin. Shunt patency was assessed using annual venography intervention, supplemented by Doppler ultrasound at 6 monthly intervals. Venography was also performed at any time if there was clinical suspicion of shunt insufficiency. Shunt insufficiency was defined as complete occlusion or significant reduction in lumen of shunt or an increase in the portal pressure gradient (PPG) to >12 mmHg.12 Clinical criteria were recurrent ascites, variceal bleeding or other recurrent symptoms of BCS. Primary patency was defined as no shunt insufficiency or re-intervention during TIPSS surveillance.12 Secondary patency was defined as the longest duration of patency with or without shunt insufficiency, i.e. if full patency was re-established after an occlusion or stenosis, then secondary patency is maintained.12
Statistical analysis Data were analysed using the SPSS statistics package (version 15, Chicago, IL, USA), and parametric data expressed as means s.d. Data for survival (overall and transplant free) were analysed using the Kaplan–Meier method and log-rank test. Cox regression analysis was used to identify independent variables predicting mortal866
ity for the whole cohort. All variables with a P < 0.1 following univariate analysis were entered into multivariate analysis. A separate analysis excluding the first 39 patients who were also in a previous study8 was performed for independent validation of the prognostic scores. Chi-squared test (nonparametric data) and Student’s t-test (parametric data) were used to compare unpaired data. Significance was taken at the 5% level.
RESULTS Description of study group In the years 1996–2012, of 104 patients with BCS referred for intervention, 68 patients underwent TIPSS. One of the 68 patients had secondary BCS related to metastatic liver disease and was excluded from analysis. Fifty-six patients had TIPSS as their first intervention, while 12 had previous treatments with interventional radiology or surgery that failed to decompress the hepatic outflow initially or subsequently failed with later significant clinical changes (Figure 3). In these 12 patients, the time from initial intervention to TIPSS ranged from 1 to 132 months. In four cases, two separate attempts at TIPSS creation were necessary. One patient had an initial failed attempt at TIPSS, a surgical shunt which occluded after 2 years and then a successful TIPSS which retains secondary patency 12 years later. One patient not analysed in the series had a single failed attempt at TIPS and subsequently had a surgical meso-caval shunt early in our experience. Covered stents were used at the primary TIPSS procedure in 40 patients. A further eight patients Aliment Pharmacol Ther 2014; 39: 864-872 ª 2014 John Wiley & Sons Ltd
TIPSS for Budd–Chiari syndrome Previous hepatic vein dilatation and/or stent with clinical failure & referral for TIPSS (n = 10/55 in total)
Previous shunt surgery with clinical failure (n = 2)
Referred directly for TIPSS (n = 56)
TIPSS (n = 68*)
Figure 3 | Patients treated with TIPSS for BCS with previous treatments and outcomes (* – one patient with secondary BCS excluded).
Deaths (n = 17)
with initial bare stents had covered stents placed during follow-up to overcome shunt insufficiency. In two of these, multiple interventions (11 and 15) were required to maintain patency. The mean age at presentation was 39.9 14.2 years. Females outnumbered males by 2.2:1 (n = 46 vs. 21). Presenting symptoms were: ascites (n = 59), abdominal pain (n = 33), variceal bleeding (n = 6) and encephalopathy (n = 6). One patient presented with acute liver failure. All patients were assessed by a haematologist and an underlying haematological predisposition to BCS was discovered in 78% (n = 52) of patients (Table 1). Nine patients had more than one risk factor identified. Liver histology was available in 15 patients, with cirrhosis reported in six patients. Baseline MELD and Child’s scores were 16 7.0 and 8.8 2.0 respectively. Patients were followed up for a mean of 81 months (range 0.5–207 months). Two patients were lost to follow-up. One was of no fixed abode and the other patient repeatedly defaulted clinical appointments. Two patients have been transplanted. Both covered (n = 40) and uncovered (n = 27) stents were used at the index procedure as described above. A comparison of these two groups is provided in Table 2. The follow-up period for bare stents was significantly longer as expected.
TIPSS insertion, complications and anti-coagulation One patient died 4 days after TIPSS from spontaneous bacterial peritonitis and multi-organ failure. Another died at 12 days following multi-organ failure with hepatic encephalopathy. The immediate complications as a Aliment Pharmacol Ther 2014; 39: 864-872 ª 2014 John Wiley & Sons Ltd
Long term survivors (n = 48)
Liver Transplantation (n = 2)
Table 1 | Underlying risk factors predisposing to Budd– Chiari syndrome Risk factor (n) factor for BCS
N
Polycythaemia rubra vera Essential thrombocytosis Myelofibrosis Undefined myeloproliferative disorder JAK2 mutation without evidence of haematological disorder Factor V Leiden Deficiency Paroxysmal nocturnal haemoglobinuria Protein C deficiency Behcet’s disease Oral contraceptive pill & JAK2 positive Oral contraceptive pill and Factor V Leiden deficiency MTHFR homozygote & Essential thrombocytosis PNH and aplastic anaemia Polycythaemia rubra vera and Factor V Leiden deficiency Acute myeloid leukaemia Immune thrombocytopaenic purpura (JAK 2 positive) Anti-phospholipid syndrome and Factor V Leiden deficiency
13 3 2 2 6 7 5 5 2 2 1 1 2 1 1 1 1
result of TIPSS are listed in Table 3. Twenty-one patients (31%) received anti-coagulation with either Heparin or Warfarin prior to TIPSS. One patient developed Heparin induced thrombocytopaenia so was treated with Danaparoid. All of the remaining patients were commenced on lifelong anti-coagulation with Warfarin. One patient with 867
D. Tripathi et al. Table 2 | Baseline characteristics of patients treated with TIPSS for BCS
Age (years) Sex (M/F) Portal vein thrombosis (n) Bilirubin (lmol/L) Albumin (g/L) ALT (U/L) INR Creatinine (lmol/L) Portal pressure pre-TIPSS (mmHg) Portal pressure post-TIPSS (mmHg) Pugh score MELD score Rotterdam BCS index New Clichy PI BCS TIPS PI Follow-up (months)
Bare stents (n = 27)
Covered (n = 40)
39.1 9:18 3 60.2 32.7 65.6 1.7 104.8 36.5
40.5 12:28 1 55.6 34.2 73.4 1.6 89.5 34.9
11.7
37.6 7.0 317.2 0.7 61.1 7.5†
18.8 7.0† 9.4 17 1.4 6.1 4.8 135.2
1.7 8.0 0.6 2.1 1.1 62.3
15.9
76.8 5.9 246.4 0.6 52.4 7.8‡
21.2 6.5‡ 8.4 15.5 1.3 5.3 4.7 45.2
2.0 6.3 0.8 1.9 1.7 37.5*
Mean s.d. unless otherwise stated. * P < 0.05. † n = 22. ‡ n = 39.
Table 3 | Immediate complications and morbidity after TIPSS Complication
n (%)
Procedural Puncture of liver capsule Puncture of intrahepatic bile duct Puncture of right atrium (managed conservatively) Puncture of hepatic artery Liver haematoma on CT Sepsis Abdominal pain Heparin induced thrombocytopaenia Pneumonia Death from spontaneous bacterial peritonitis and multi-organ failure Death from liver failure with encephalopathy Requirement for haemodialysis
17 (25) 10 4 1 1 1 3 2 1 1 1
(5) (3) (2) (2) (2)
1 (2) 6 (9)
Janus kinase 2 (JAK 2) positive myeloproliferative disorder bled spontaneously into a hepatic nodule 9 years after TIPSS insertion while over anti-coagulated with Warfarin. The bleeding settled with correction of coagulation, and Warfarin was recommenced. No further 868
bleeding complications occurred. The liver nodules in this patient behave like hepatic adenomas on Primovist® (Bayer, Levekusen, Germany) enhanced MRI in contrast to the Focal Nodular Hyperplasia like nodules which are more commonly seen in patients with BCS. Six patients had documented hepatic encephalopathy prior to TIPSS. Encephalopathy resolved quickly in three of these and over several weeks in one patient. One patient had persistent encephalopathy and ascites, underwent TIPSS reduction which did not resolve the encephalopathy and ultimately had a liver transplant. The last patient had a marked deterioration of encephalopathy despite medical therapy, and died 12 days after TIPSS insertion. Eight patients developed de novo hepatic encephalopathy following TIPSS. Histology was available for two of these eight patients, and showed cirrhosis in one patient. There was evidence of a coarse nodular liver on imaging in three further patients. All these episodes resolved with medical therapy.
Efficacy of TIPSS and need for re-intervention TIPSS was successful in treating ascites or preventing further variceal bleeding in 97% of patients (n = 65). TIPSS dysfunction occurred in 45% (n = 30) of patients, with thrombosis occurring in 10 patients despite anti-coagulation. Radiological intervention to re-establish TIPSS patency included balloon angioplasty and additional stents (n = 15), balloon angioplasty (n = 12) and balloon angioplasty with thrombolysis and additional stents (n = 3). The primary patency rates at 5 years for covered stents was 70% vs. 27% for bare stents (P = 0.001, Figure 4). During follow-up, re-interventions were significantly less for covered TIPSS compared with bare stents (22 vs. 100, P < 0.001). Secondary patency was 99%. One patient with a bare metal stent developed occlusion due to a thrombus during follow-up. Thrombolysis initially achieved patency, followed by stent extension. After a second re-occlusion the patient was asymptomatic for a long period. There was later more extensive thrombosis of the portal system and the patient suffered a fatal variceal bleed 7.9 years after TIPSS. Survival Survival following TIPSS was 97%, 92%, 87%, 80% and 72% at 6, 12, 24, 60 and 120 months respectively (Figure 5). Survival was similar for covered and bare metal stents. During follow-up, 17 (25%) patients died at a median time of 15 months (range 0.1–170 months). The main causes of death were complications of liver disease (n = 6), intracerebral haemorrhage (n = 3), Aliment Pharmacol Ther 2014; 39: 864-872 ª 2014 John Wiley & Sons Ltd
TIPSS for Budd–Chiari syndrome
Proportion free of shunt insufficiency
1.0
0.8 Covered TIPSS 0.6
0.4 Bare TIPSS 0.2
0.0 0
Figure 4 | Kaplan–Meier analysis of primary patency for covered and uncovered stents following TIPSS for BCS (P < 0.05).
6
12
18
24
30
36
42
48
54
60
Time (months) Number at risk Covered TIPSS 40
30
20
14
8
7
Bare TIPSS
13
10
7
6
6
27
1.0
Survival
0.8
0.6
0.4
0.2
Figure 5 | Kaplan–Meier analysis of survival following TIPSS for BCS.
Time (months) Number at risk 67
metastatic breast cancer (n = 1), PNH [cerebral infarction (n = 1) and bleeding (n = 2)], hepatocellular carcinoma (HCC) (n = 1) and other (n = 3). Two patients developed hepatocellular carcinoma, one with lung metastases which proved fatal. The second patient underwent ablation and recent liver transplantation. Three prognostic indices (Rotterdam BCS Index, Revised Clichy PI, BCS TIPS PI) were assessed for their Aliment Pharmacol Ther 2014; 39: 864-872 ª 2014 John Wiley & Sons Ltd
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 10 2 10 8 11 4 12 0
0 6
0.0
59
49
44
35
33
32
30
26
26
22
ability to predict survival following TIPSS (Table 4). Only the BCS TIPS PI independently predicted mortality following multivariate analysis of the whole cohort (HR 1.55, 95% CI 1.21–1.98, P < 0.01). The BCS TIPS PI was significantly higher in those who died compared with survivors (5.80 1.45 vs. 4.40 1.33, P < 0.01). Two of three patients with a BCS TIPS PI >7 died of liver related complications at 0.4 and 6.6 months after TIPSS. 869
D. Tripathi et al. Table 4 | Regression analysis of factors predicting transplant-free survival after TIPSS Univariate analysis* Variable
P
Hazard ratio
95% CI
Sex Child-Pugh score MELD score Presence of myeloproliferative disorder Use of covered stent at index TIPSS Hepatic vein stent prior to TIPSS insertion Revised clichy PI Rotterdam BCS index BCS TIPS PI†
0.63 (0.89) 0.94 (0.95) 0.95 (0.32) 0.10 (0.52) 0.16 0.93 (0.17) 0.67 (0.91) 0.26 (0.84) < 0.01 (0.52)
0.78 (1.17) 0.99 (0.98) 0.99 (0.87) 2.58 (29.77) 0.45 1.10 (0.18) 1.06 (1.03) 1.21 (1.13) 1.55 (1.15)
0.29–2.13 (0.12–11.40) 0.76–1.30 (0.58–1.65) 0.93–1.07 (0.70–1.13) 0.83–7.98 (0.01–831250) 0.15–1.38 0.15–8.40 (0.02–2.02) 0.82–1.35 (0.63 - 1.68) 0.74–3.20 (0.35–3.70) 1.21–1.98 (0.76–1.73)
* Figures in brackets represent results excluding the first 39 patients where applicable. † Significant following multivariate analysis when analysing the whole cohort only (HR 1.55, 95% CI 1.21–1.98, P < 0.01).
There were no liver related deaths in patients with BCS TIPS PI
Good clinical outcomes following transjugular intrahepatic portosystemic stent-shunts in Budd–Chiari syndrome D. Tripathi*, R. MacNicholas*, C. Kothari*, L. Sunderraj*, H. Al-Hilou*, B. Rangarajan†, F. Chen‡, K. Mangat†, E. Elias* & S. Olliff†
*Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, UK. † Imaging and Interventional Radiology Department, Queen Elizabeth Hospital Birmingham, Birmingham, UK. ‡ Department of Haematology, Queen Elizabeth Hospital, Birmingham, UK.
Correspondence to: Dr D. Tripathi, Liver Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK. E-mail: [email protected]
Publication data Submitted 10 December 2013 First decision 24 December 2013 Resubmitted 4 January 2014 Accepted 30 January 2014 EV Pub Online 24 February 2014 This article was accepted for publication after full peer-review.
SUMMARY Background There have been encouraging reports on transjugular intrahepatic portosystemic stent-shunt (TIPSS) for Budd–Chiari syndrome (BCS). Long-term data are lacking. Aim To assess long-term outcomes and validate prognostic scores following TIPSS for BCS. Methods A single centre retrospective study. Patients underwent TIPSS using bare or polytertrafluoroethane (PTFE)-covered stents. Results Sixty-seven patients received successful TIPSS between 1996 and 2012 using covered (n = 40) or bare (n = 27) stents. Patients included had a Male: Female ratio of 21:46, and were characterised (mean s.d.) by age 39.9 14.3 years, Model of end stage liver disease (MELD) 16.1 7.0 and Child’s score 8.8 2.0. Seventy-eight percent had haematological risk factors. Presenting symptoms were ascites (n = 61) and variceal bleeding (n = 6). Nine patients underwent hepatic vein dilatation or stenting prior to TIPSS. Mean follow-up was 82 months (range 0.5–184 months). Fifteen percent had post-TIPSS encephalopathy. Two have been transplanted. Primary patency rates (76% vs. 27%, P < 0.001) and shunt re-interventions (22% vs. 100%, P < 0.001) significantly favoured covered stents. Secondary patency was 99%. Six-, 12-, 24-, 60- and 120month survival was 97%, 92%, 87%, 80% and 72% respectively. Six patients had liver related deaths. Two patients developed hepatocellular carcinoma. The BCS TIPS PI independently predicted mortality in the whole cohort, but no prognostic score was a significant predictor of mortality after subgroup validation. Conclusions Long-term outcomes following TIPSS for Budd–Chiari syndrome are very good. PTFE-covered stents have significantly better primary patency. The value of prognostic scores is controversial. TIPSS should be considered as first line therapy in symptomatic patients in whom hepatic vein patency cannot be restored. Aliment Pharmacol Ther 2014; 39: 864–872
864
ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12668
TIPSS for Budd–Chiari syndrome INTRODUCTION Budd–Chiari Syndrome (BCS) is a rare disorder resulting from hepatic venous outflow obstruction and subsequent hepatic impairment. Controlled trials of therapies are lacking, and recommendations are based on case series and expert opinion. In 1999, we reported our outcomes with percutaneous angioplasty of short segment strictures of the hepatic veins and proposed a treatment algorithm 1, 2 (Figure 1). TIPSS was first used for the treatment of BCS in the early 1990s using bare metal stents.3–5 Shunt surgery is now largely replaced by TIPSS, which is less invasive and has the advantage of overcoming intrahepatic outflow obstruction by diverting hepatic and portal blood flow to the supra-caudate inferior vena cava (IVC).6 Shunt insufficiency as high as 60% at 1 year has been reported in uncovered TIPSS.7 In 2006, we presented data (from the period 1984– 2004) showing favourable outcome in BCS with radiological intervention (hepatic vein recanalisation n = 31, TIPSS n = 26 or both procedures n = 4).1 However, there is a lack of data on long-term outcomes following TIPSS. Our primary interventional objective in the management of BCS patients is restoring hepatic vein outflow when possible. We consider TIPSS for symptomatic patients when suitable hepatic veins cannot be recanalised successfully. Covered stents have significantly better patency, with the potential for better outcomes.8, 9 The BCS TIPS PI is a powerful prognostic indicator, and may perform better
Correct underlying prothrombotic risk factors and commence lifelong anticoagulation
Treat complications of portal hypertension. HCC surveillance. Monitor for transformation of underlying myeloproliferative disease
Treat any outflow obstruction that is amenable to angioplasty/stenting
If the patient fails to improve then consider TIPSS
Figure 1 | Algorithm for BCS management.1 Aliment Pharmacol Ther 2014; 39: 864-872 ª 2014 John Wiley & Sons Ltd
than other indices.8 The present study assesses the effect of TIPSS over a 16 year period in a single centre and aims to validate prognostic scores in a large cohort of patients.
METHODS Study design A retrospective study was performed using prospectively collected data. All patients from 1996 to 2012 attending our Liver Unit and Radiology department who had a TIPSS inserted for BCS were included. Patients were identified via an electronic database and clinical notes were reviewed. Patient characteristics including age, gender, symptoms and signs at presentation were obtained in addition to imaging and laboratory reports. Three prognostic indices for BCS were calculated for each patient (Rotterdam,10 New Clichy,11 BCS TIPS PI8). The presence of haematological malignancy and prothrombotic factors was assessed by a haematologist. Data on all treatments and their complications were obtained including: anti-coagulation use, radiological interventions prior to TIPSS, complications of TIPSS, need for subsequent radiological interventions or liver transplant and length of survival after TIPSS. Patients were followed up at 3–6 monthly clinical intervals, and follow-up was censored at point of death, liver transplantation or loss to follow-up. Method of TIPSS insertion TIPSS was performed by two authors (SO and KM). TIPSS is a nonsurgical means of creating a portosystemic shunt, allowing communication between portal vein and hepatic veins through the hepatic parenchyma. TIPSS was first used for BCS in 1992.3 In most cases, a catheter is passed via the internal jugular to the right hepatic vein under fluoroscopic guidance. A needle is inserted through the catheter to puncture the hepatic parenchyma from a hepatic vein origin or by direct puncture into the liver from the inferior vena cava, creating a tract to link the hepatic vein and usually right portal vein. This tract is kept patent by using an expandable metal stent (Figure 2). During the first part of the study period, uncovered metal stents were used (Memotherm®, Angiomed, Karlsuhe, Germany). From 2003, covered stents were used in preference (Viatorr® W.L. Gore, Flagstaff, AZ, USA). In some cases, additional uncovered stents (Wallstent® Boston Scientific, Natick, MA, USA) were used with covered stents for TIPSS extension into portal vein, hepatic vein or IVC. Anti-coagulation with low molecular weight Heparin or unfractionated Heparin was 865
D. Tripathi et al. (a) Right
(b) Right
(c) Right
(d)
Right
Figure 2 | Venograms showing insertion of TIPSS in a patient with BCS. (a) Cavogram showing contrast in IVC. (b) Puncture into liver showing abnormal collateral veins. (c) Puncture into portal vein branch. (d) Covered TIPSS in position at end of procedure with good shunting of portal blood through the liver.
commenced 6–12 h after TIPSS and then switched to vitamin K antagonist (Warfarin) unless there were local complications such as puncture of the liver capsule, when introduction of Heparin was generally delayed for 12–24 h. INR of 2.5–3.5 was the target level for monitoring Warfarin dose and a target anti-Xa level of 0.5–0.85 IU/mL was used for low molecular weight Heparin. Shunt patency was assessed using annual venography intervention, supplemented by Doppler ultrasound at 6 monthly intervals. Venography was also performed at any time if there was clinical suspicion of shunt insufficiency. Shunt insufficiency was defined as complete occlusion or significant reduction in lumen of shunt or an increase in the portal pressure gradient (PPG) to >12 mmHg.12 Clinical criteria were recurrent ascites, variceal bleeding or other recurrent symptoms of BCS. Primary patency was defined as no shunt insufficiency or re-intervention during TIPSS surveillance.12 Secondary patency was defined as the longest duration of patency with or without shunt insufficiency, i.e. if full patency was re-established after an occlusion or stenosis, then secondary patency is maintained.12
Statistical analysis Data were analysed using the SPSS statistics package (version 15, Chicago, IL, USA), and parametric data expressed as means s.d. Data for survival (overall and transplant free) were analysed using the Kaplan–Meier method and log-rank test. Cox regression analysis was used to identify independent variables predicting mortal866
ity for the whole cohort. All variables with a P < 0.1 following univariate analysis were entered into multivariate analysis. A separate analysis excluding the first 39 patients who were also in a previous study8 was performed for independent validation of the prognostic scores. Chi-squared test (nonparametric data) and Student’s t-test (parametric data) were used to compare unpaired data. Significance was taken at the 5% level.
RESULTS Description of study group In the years 1996–2012, of 104 patients with BCS referred for intervention, 68 patients underwent TIPSS. One of the 68 patients had secondary BCS related to metastatic liver disease and was excluded from analysis. Fifty-six patients had TIPSS as their first intervention, while 12 had previous treatments with interventional radiology or surgery that failed to decompress the hepatic outflow initially or subsequently failed with later significant clinical changes (Figure 3). In these 12 patients, the time from initial intervention to TIPSS ranged from 1 to 132 months. In four cases, two separate attempts at TIPSS creation were necessary. One patient had an initial failed attempt at TIPSS, a surgical shunt which occluded after 2 years and then a successful TIPSS which retains secondary patency 12 years later. One patient not analysed in the series had a single failed attempt at TIPS and subsequently had a surgical meso-caval shunt early in our experience. Covered stents were used at the primary TIPSS procedure in 40 patients. A further eight patients Aliment Pharmacol Ther 2014; 39: 864-872 ª 2014 John Wiley & Sons Ltd
TIPSS for Budd–Chiari syndrome Previous hepatic vein dilatation and/or stent with clinical failure & referral for TIPSS (n = 10/55 in total)
Previous shunt surgery with clinical failure (n = 2)
Referred directly for TIPSS (n = 56)
TIPSS (n = 68*)
Figure 3 | Patients treated with TIPSS for BCS with previous treatments and outcomes (* – one patient with secondary BCS excluded).
Deaths (n = 17)
with initial bare stents had covered stents placed during follow-up to overcome shunt insufficiency. In two of these, multiple interventions (11 and 15) were required to maintain patency. The mean age at presentation was 39.9 14.2 years. Females outnumbered males by 2.2:1 (n = 46 vs. 21). Presenting symptoms were: ascites (n = 59), abdominal pain (n = 33), variceal bleeding (n = 6) and encephalopathy (n = 6). One patient presented with acute liver failure. All patients were assessed by a haematologist and an underlying haematological predisposition to BCS was discovered in 78% (n = 52) of patients (Table 1). Nine patients had more than one risk factor identified. Liver histology was available in 15 patients, with cirrhosis reported in six patients. Baseline MELD and Child’s scores were 16 7.0 and 8.8 2.0 respectively. Patients were followed up for a mean of 81 months (range 0.5–207 months). Two patients were lost to follow-up. One was of no fixed abode and the other patient repeatedly defaulted clinical appointments. Two patients have been transplanted. Both covered (n = 40) and uncovered (n = 27) stents were used at the index procedure as described above. A comparison of these two groups is provided in Table 2. The follow-up period for bare stents was significantly longer as expected.
TIPSS insertion, complications and anti-coagulation One patient died 4 days after TIPSS from spontaneous bacterial peritonitis and multi-organ failure. Another died at 12 days following multi-organ failure with hepatic encephalopathy. The immediate complications as a Aliment Pharmacol Ther 2014; 39: 864-872 ª 2014 John Wiley & Sons Ltd
Long term survivors (n = 48)
Liver Transplantation (n = 2)
Table 1 | Underlying risk factors predisposing to Budd– Chiari syndrome Risk factor (n) factor for BCS
N
Polycythaemia rubra vera Essential thrombocytosis Myelofibrosis Undefined myeloproliferative disorder JAK2 mutation without evidence of haematological disorder Factor V Leiden Deficiency Paroxysmal nocturnal haemoglobinuria Protein C deficiency Behcet’s disease Oral contraceptive pill & JAK2 positive Oral contraceptive pill and Factor V Leiden deficiency MTHFR homozygote & Essential thrombocytosis PNH and aplastic anaemia Polycythaemia rubra vera and Factor V Leiden deficiency Acute myeloid leukaemia Immune thrombocytopaenic purpura (JAK 2 positive) Anti-phospholipid syndrome and Factor V Leiden deficiency
13 3 2 2 6 7 5 5 2 2 1 1 2 1 1 1 1
result of TIPSS are listed in Table 3. Twenty-one patients (31%) received anti-coagulation with either Heparin or Warfarin prior to TIPSS. One patient developed Heparin induced thrombocytopaenia so was treated with Danaparoid. All of the remaining patients were commenced on lifelong anti-coagulation with Warfarin. One patient with 867
D. Tripathi et al. Table 2 | Baseline characteristics of patients treated with TIPSS for BCS
Age (years) Sex (M/F) Portal vein thrombosis (n) Bilirubin (lmol/L) Albumin (g/L) ALT (U/L) INR Creatinine (lmol/L) Portal pressure pre-TIPSS (mmHg) Portal pressure post-TIPSS (mmHg) Pugh score MELD score Rotterdam BCS index New Clichy PI BCS TIPS PI Follow-up (months)
Bare stents (n = 27)
Covered (n = 40)
39.1 9:18 3 60.2 32.7 65.6 1.7 104.8 36.5
40.5 12:28 1 55.6 34.2 73.4 1.6 89.5 34.9
11.7
37.6 7.0 317.2 0.7 61.1 7.5†
18.8 7.0† 9.4 17 1.4 6.1 4.8 135.2
1.7 8.0 0.6 2.1 1.1 62.3
15.9
76.8 5.9 246.4 0.6 52.4 7.8‡
21.2 6.5‡ 8.4 15.5 1.3 5.3 4.7 45.2
2.0 6.3 0.8 1.9 1.7 37.5*
Mean s.d. unless otherwise stated. * P < 0.05. † n = 22. ‡ n = 39.
Table 3 | Immediate complications and morbidity after TIPSS Complication
n (%)
Procedural Puncture of liver capsule Puncture of intrahepatic bile duct Puncture of right atrium (managed conservatively) Puncture of hepatic artery Liver haematoma on CT Sepsis Abdominal pain Heparin induced thrombocytopaenia Pneumonia Death from spontaneous bacterial peritonitis and multi-organ failure Death from liver failure with encephalopathy Requirement for haemodialysis
17 (25) 10 4 1 1 1 3 2 1 1 1
(5) (3) (2) (2) (2)
1 (2) 6 (9)
Janus kinase 2 (JAK 2) positive myeloproliferative disorder bled spontaneously into a hepatic nodule 9 years after TIPSS insertion while over anti-coagulated with Warfarin. The bleeding settled with correction of coagulation, and Warfarin was recommenced. No further 868
bleeding complications occurred. The liver nodules in this patient behave like hepatic adenomas on Primovist® (Bayer, Levekusen, Germany) enhanced MRI in contrast to the Focal Nodular Hyperplasia like nodules which are more commonly seen in patients with BCS. Six patients had documented hepatic encephalopathy prior to TIPSS. Encephalopathy resolved quickly in three of these and over several weeks in one patient. One patient had persistent encephalopathy and ascites, underwent TIPSS reduction which did not resolve the encephalopathy and ultimately had a liver transplant. The last patient had a marked deterioration of encephalopathy despite medical therapy, and died 12 days after TIPSS insertion. Eight patients developed de novo hepatic encephalopathy following TIPSS. Histology was available for two of these eight patients, and showed cirrhosis in one patient. There was evidence of a coarse nodular liver on imaging in three further patients. All these episodes resolved with medical therapy.
Efficacy of TIPSS and need for re-intervention TIPSS was successful in treating ascites or preventing further variceal bleeding in 97% of patients (n = 65). TIPSS dysfunction occurred in 45% (n = 30) of patients, with thrombosis occurring in 10 patients despite anti-coagulation. Radiological intervention to re-establish TIPSS patency included balloon angioplasty and additional stents (n = 15), balloon angioplasty (n = 12) and balloon angioplasty with thrombolysis and additional stents (n = 3). The primary patency rates at 5 years for covered stents was 70% vs. 27% for bare stents (P = 0.001, Figure 4). During follow-up, re-interventions were significantly less for covered TIPSS compared with bare stents (22 vs. 100, P < 0.001). Secondary patency was 99%. One patient with a bare metal stent developed occlusion due to a thrombus during follow-up. Thrombolysis initially achieved patency, followed by stent extension. After a second re-occlusion the patient was asymptomatic for a long period. There was later more extensive thrombosis of the portal system and the patient suffered a fatal variceal bleed 7.9 years after TIPSS. Survival Survival following TIPSS was 97%, 92%, 87%, 80% and 72% at 6, 12, 24, 60 and 120 months respectively (Figure 5). Survival was similar for covered and bare metal stents. During follow-up, 17 (25%) patients died at a median time of 15 months (range 0.1–170 months). The main causes of death were complications of liver disease (n = 6), intracerebral haemorrhage (n = 3), Aliment Pharmacol Ther 2014; 39: 864-872 ª 2014 John Wiley & Sons Ltd
TIPSS for Budd–Chiari syndrome
Proportion free of shunt insufficiency
1.0
0.8 Covered TIPSS 0.6
0.4 Bare TIPSS 0.2
0.0 0
Figure 4 | Kaplan–Meier analysis of primary patency for covered and uncovered stents following TIPSS for BCS (P < 0.05).
6
12
18
24
30
36
42
48
54
60
Time (months) Number at risk Covered TIPSS 40
30
20
14
8
7
Bare TIPSS
13
10
7
6
6
27
1.0
Survival
0.8
0.6
0.4
0.2
Figure 5 | Kaplan–Meier analysis of survival following TIPSS for BCS.
Time (months) Number at risk 67
metastatic breast cancer (n = 1), PNH [cerebral infarction (n = 1) and bleeding (n = 2)], hepatocellular carcinoma (HCC) (n = 1) and other (n = 3). Two patients developed hepatocellular carcinoma, one with lung metastases which proved fatal. The second patient underwent ablation and recent liver transplantation. Three prognostic indices (Rotterdam BCS Index, Revised Clichy PI, BCS TIPS PI) were assessed for their Aliment Pharmacol Ther 2014; 39: 864-872 ª 2014 John Wiley & Sons Ltd
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 10 2 10 8 11 4 12 0
0 6
0.0
59
49
44
35
33
32
30
26
26
22
ability to predict survival following TIPSS (Table 4). Only the BCS TIPS PI independently predicted mortality following multivariate analysis of the whole cohort (HR 1.55, 95% CI 1.21–1.98, P < 0.01). The BCS TIPS PI was significantly higher in those who died compared with survivors (5.80 1.45 vs. 4.40 1.33, P < 0.01). Two of three patients with a BCS TIPS PI >7 died of liver related complications at 0.4 and 6.6 months after TIPSS. 869
D. Tripathi et al. Table 4 | Regression analysis of factors predicting transplant-free survival after TIPSS Univariate analysis* Variable
P
Hazard ratio
95% CI
Sex Child-Pugh score MELD score Presence of myeloproliferative disorder Use of covered stent at index TIPSS Hepatic vein stent prior to TIPSS insertion Revised clichy PI Rotterdam BCS index BCS TIPS PI†
0.63 (0.89) 0.94 (0.95) 0.95 (0.32) 0.10 (0.52) 0.16 0.93 (0.17) 0.67 (0.91) 0.26 (0.84) < 0.01 (0.52)
0.78 (1.17) 0.99 (0.98) 0.99 (0.87) 2.58 (29.77) 0.45 1.10 (0.18) 1.06 (1.03) 1.21 (1.13) 1.55 (1.15)
0.29–2.13 (0.12–11.40) 0.76–1.30 (0.58–1.65) 0.93–1.07 (0.70–1.13) 0.83–7.98 (0.01–831250) 0.15–1.38 0.15–8.40 (0.02–2.02) 0.82–1.35 (0.63 - 1.68) 0.74–3.20 (0.35–3.70) 1.21–1.98 (0.76–1.73)
* Figures in brackets represent results excluding the first 39 patients where applicable. † Significant following multivariate analysis when analysing the whole cohort only (HR 1.55, 95% CI 1.21–1.98, P < 0.01).
There were no liver related deaths in patients with BCS TIPS PI
