Abstract
Background
Bleeding from gastric fundal varices (IGVI/GOV2) represents a major problem due to a high incidence of rebleeding and death with standard of care therapy (endoscopic obliteration with tissue adhesives plus pharmacological therapy). TIPS is recommended as a rescue therapy. Pre-emptive “early” TIPS (pTIPS) significantly improves control of bleeding and survival in high-risk patients bleeding from esophageal varices.
Aim and methods
The present randomized controlled trial aimed at investigating if pTIPS improves survival free of rebleeding in patients with gastric fundal varices (GOV2 and/or IGV1) as compared to standard therapy.
Results
The study did not achieve the predefined sample size due to low recruitment. Nevertheless, pTIPS (n=11) was more effective than combined endoscopic and pharmacological therapy (n=10) in improving rebleeding-free survival (per protocol analysis: 100 vs 28%;p=0.017). This was mainly due to a better outcome in Child-Pugh B and C patients. There were no differences in serious adverse events or in the incidence of hepatic encephalopathy.
Conclusion
The use of pTIPS may be considered in Child-Pugh B and C patients bleeding from gastric fundal varices.
Lay Summary
The first-line treatment of gastric fundal varices (GOV2 and/or IGV1) is the combination of pharmacological therapy and endoscopic obliteration with glue. TIPS is considered as the main rescue therapy. Recent data suggest that in high-risk patients (Child-Pugh C or Child-Pugh B + active bleeding at endoscopy) bleeding from esophageal varices, the performance of a preemptive TIPS (pTIPS), a TIPS performed during the first 72h from admission, results in an increased rate of control of bleeding and survival as compared to combined endoscopic and pharmacological therapy. Herein, we presented a randomized controlled trial comparing pTIPS with combined endoscopic (injection of glue) and pharmacological therapy (first, somatostatin or terlipressin, carvedilol after discharge) in the treatment of patients bleeding from GOV2 and/or IGV1. Although we were not able to include the calculated sample size due to the scarcity of these patients, our results show that the use of pTIPS is associated with a significantly higher actuarial rebleeding-free survival when analyzed as per protocol. This is due to a greater efficacy in Child-Pugh B and C patients.
Keywords
Grant Support
This work was supported by the grant number PI 043484 from the Fondo Sanitario de la Seguridad Social, Instituto de Salud Carlos III, Spain, and from the CIBERehd. The CIBERehd is an initiative of the Instituto de Salud Carlos III.www.clinicaltrials.gov; no.: NCT02364297.
Conflict of interest
AE/CV: Travel grant from Gore. JCGP: Advisory board Cook, travel grants from Gore and Mallinkrodt; JB: Consultant / Advisory board Astra Zeneca, BioVie, Boehringer Ingelheim, NovoNordisk, Resolution Therapeutics.
Author’s contribution
All autors have made substantial contributions and satisfy the criteria for authorship. Inclusion and follow-up of included patients: JCGP, EAT, CA, HM, CV. AE was the Pricipal Investigator and, with JB analyzed the results and prepared the manuscript.
Data availability statement
The data shown in this article are available from the corresponding author request.
Introduction
Bleeding from gastric fundal varices represents about 15% of overall variceal bleedings; but carries a higher mortality than bleeding from esophageal varices (including GOV1 varices) (20-30% vs 15% over 6 weeks). Baveno VII
[1]
experts agreed that endoscopic therapy with tissue adhesives is recommended for acute bleeding from isolated gastric varices (IGV1) and gastroesophageal varices type 2 (GOV2) that extend beyond the cardia. However, standard of care therapy is associated with rebleeding in over 1/3 of the patients after reappearance of the varices. TIPS, with or without collateral embolization, is recommended as rescue therapy after rebleeding. Several observational studies and meta-analysis have addressed the use of TIPS as initial therapy in patients bleeding from fundal varices. In the meta-analysis of Alqadi and coworkers, including 209 patients and excluding GOV1 bleeders or use of bare-metal stents for TIPS, 15% of the patients developed variceal rebleeding and 21% rebleeding due to any cause [2]
. The association of variceal embolization reduced the incidence of overall rebleeding to 16% (vs 26% in those patients without collateral embolization). Shah and coworkers presented a comparative single-center study including 40 patients treated by the combined use of TIPS and collateral embolization (n=18) or TIPS alone (n=22). The results of the study showed a significantly higher rate of eradication of the varices with the TIPS plus collateral embolization and a trend towards reduced variceal rebleeding [3]
. Lo and coworkers showed that TIPS (not preemptive but as secondary prophylaxis after initial control of gastric bleeding) proved more effective than glue injection in preventing rebleeding from gastric varices - Shah KY
- Ren A
- Simpson RO
- Kloster ML
- Mijolajczyk A
- Bui JT
- et al.
Combined transjugular intrahepatic portosystemic shunt plus variceal obliteration versus transjugular intrahepatic portosystemic shunt alone for the management of gastric varices: comparative single-center clinical outcomes.
J Vasc Interv Radiol. 2021; 32: 282-291
[4]
. Finally, although preemptive TIPS (pTIPS) was more effective than combined endoscopic and pharmacological therapy in the prevention of both rebleeding and death in high-risk patients bleeding from esophageal varices; the role of pTIPS (± collateral embolization) in patients with gastric fundal variceal bleeding has not been adequately investigated.Methods
The aim of this randomized, multicenter, controlled trial in patients bleeding from IGV1 and/or GOV2 was to investigate the efficacy of pTIPS (from 1 to 5 days of admission), combined or not with collateral embolization according to the results of immediate post-TIPS portography, Vs standard of care. Both groups had similar initial therapy using vasoactive drugs + endoscopic variceal obturation with tissue adhesive . Main end-point was survival free of rebleeding at 1-year of follow-up or until the last available control. Secondary objectives were incidence of rebleeding and survival at 6 weeks and during the overall follow-up.
The study was conducted in accord with the Declaration of Helsinki and was approved by the ethical committee of the nine participating hospitals and by the Ministry of Health and fulfilled the guidelines of Good Clinical Practice in clinical trials. The study was registered in an independent clinical trial database (www.clinicaltrials.gov; identifier: NCT02364297). Written informed consent was obtained from each participant or legal representative or next of kin depending on the clinical condition of the patient.
The calculated sample size, assumed an efficacy of pTIPS of 83% and 53% for the combined therapy, with alpha 0.05 and beta 0.2 was of 30 patients per group.
Results
Twenty-two patients were included in a 4-year inclusion period, in 5 different centers. The low incidence of fundal bleeding and technical aspects regarding pTIPS precluded the inclusion of the initially calculated sample size. One of the randomized patients resulted in a protocol violation due to identification of portal hypertension gastropathy as the cause of bleeding at second endoscopy to perform glue sclerotherapy.
Thus, we included 21 patients with a median age of 63 years (ranging from 34 to 73), 50% with alcoholic cirrhosis and a moderate to severe liver insufficiency (median Child-Pugh score: 8; ranging from 6 to 10). IGV1 was the cause of bleeding in 12 cases, whereas the remaining 9 cases were due to GOV2. All the included patients received vasoactive therapy and antibiotics from admission. Table 1 shows the comparison of the 2 groups according to randomized therapy (TIPS n=11; standard of care n=10). Table 2 shows the same items according to per protocol analysis.
Table 1Demographic and clinical variables in the overall series of patients and according to the Intention to Treat.
| Variable | Early TIPS n=11 | Standard of care n=10 | p |
|---|---|---|---|
| Age | 59±11 | 64±7 | 0.29 |
| Gender (M/F) | 8/3 | 8/2 | 0.70 |
| Etiology of cirrhosis (HCV/ Alcohol/HCV+alcohol/ NASH/Other) | 1/5/1/2/2 | 3/4/1/2/0 | 0.55 |
| Cause of bleeding (IGV1/GOV2) | 5/6 | 7/3 | 0.26 |
| Shock at admission (Y/N) | 8/3 | 4/6 | 0.13 |
| Child-Pugh score at admission | 7.3±1.9 | 7.7±1.1 | 0.60 |
| Child-Pugh class (A/BC) | 4/7 | 4/6 | 0.86 |
| Hct at admission (%) | 26±6 | 28±8 | 0.57 |
| 5-day failure (Y/N) | 1/10 | 2/8 | 0.47 |
| Rescue therapy (Y/N) | 0/11 | 2/8 | 0.12 |
| 6-week death (Y/N) | 1/10 | 2/8 | 0.48 |
Outcome 6w:
| 1 10 | 2 8 | 0.48 |
| Follow-up (months) | 14±12 | 14±13 | 0.93 |
| Rebleeding at FU (Y/N) | 0/10 | 2/8 | 0.13 |
Outcome FU*:
| 1 10 | 5 5 | 0.055 |
| Patients with SAE (Y/N) | 5/6 | 5/5 | 0.83 |
SAE (description):
| 2 2 1 | 1 4 0 |
IGV1 (isolated gastric varices type 1); GOV2 (gastroesophageal varices type 2); AVB (acute variceal bleeding); TIPS (transjugular intrahepatic portosystemic shunt); FU (follow-up); OLT (orthotopic liver transplantation); SAE (serious adverse event); ACLF (acute-on-chronic liver failure); HE (hepatic encephalopathy requiring admission).
Quantitative data were analyzed by Student’s t test and qualitative data using Chi-Square tests except for the main end-point*, where a Fischer exact test was used.
Levels of significance: p<0.05.
a mean±SD;
b Excluding one patient who died before the 5-day period.
Table 2Demographic and clinical variables in the overall series of patients according to Per Protocol Analysis.
| Variable | Early TIPS n=9 | Standard of care n=12 | p |
|---|---|---|---|
| Age | 59±12 | 63±7 | 0.42 |
| Gender (M/F) | 6/3 | 10/2 | 0.37 |
| Etiology of cirrhosis (HCV/Alcohol/HCV+alcohol/ NASH/Others) | 1/3/1/2/2 | 3/6/1/2/0 | 0.46 |
| Cause of bleeding (IGV1/GOV2) | 4/5 | 8/4 | 0.31 |
| Shock at admission (Y/N) | 6/3 | 6/6 | 0.44 |
| Child-Pugh class (A/BC) at admission | 3/6 | 5/7 | 0.69 |
| Child-Pugh score at admission | 7.2±1.6 | 7.8±1.3 | 0.42 |
| Hct at admission | 26±7 | 28±7 | 0.55 |
| 5-day failure (Y/N) | 0/9 | 3/9 | 0.10 |
| Rescue therapy (Y/N) | 0/9 | 2/10 | 0.19 |
| 6-week death (Y/N) | 0/9 | 3/9 | 0.105 |
Outcome at 6-week:
| 0 9 | 3 9 | 0.105 |
| Follow-up (months) | 17±11 | 12±13 | 0.38 |
| Rebleeding at FU (Y/N) | 0/9 | 5/7 | 0.027 |
Outcome FU*:
| 0 9 | 6 6 | 0.017 |
| Patients with SAE (Y/N) | 4/5 | 5/7 | 0.89 |
SAE (description):
| 2 1 1 | 1 4 0 | 0.30 |
IGV1 (isolated gastric varices type 1); GOV2 (gastroesophageal varices type 2); AVB (acute variceal bleeding); TIPS (transjugular intrahepatic portosystemic shunt); FU (follow-up); OLT (orthotopic liver transplantation); SAE (serious adverse event); ACLF (acute-on-chronic liver failure); HE (hepatic encephalopathy requiring admission).
Quantitative data were analyzed by Student’s t test and qualitative data using Chi-Square tests except for the main end-point*, where a Fischer exact test was used.
Levels of significance: p<0.05
a mean±SD
All the 10 patients of the combined therapy group received endoscopic therapy (cyanoacrylate injection) and vasoactive drugs (initially somatostatin or terlipressin followed by propranolol or carvedilol at discharge and in the absence of refractory ascites and bradycardia < 55 bpm). In the pTIPS group, 3 patients did not receive initial cyanoacrylate injection because TIPS was performed during the first 24h following admission. One patient randomized to pTIPS died before TIPS could be performed (massive bleeding despite the use of a Linton balloon); another patient did not receive TIPS due to technical difficulties (this patient was treated by combined endoscopic and pharmacological therapy) and in one case collateral vessels were embolized without the concomitant performance of TIPS (this patient was considered as a pTIPS in both randomization and per protocol analysis due to the invasive character of the therapy). Four patients received collateral embolization on top of TIPS. In one case due to a final portal pressure gradient (PPG) higher than 12 mmHg (13.5 mmHg) and in the other 3 cases due to post-TIPS portography showing persistent filling of large collaterals. PPG before pTIPS had a median value of 17 mmHg (ranging from 9 to 20mmHg) and after pTIPS of 8.5 mmHg (ranges: 4.5-13.5 mmHg). The pTIPS used PTFE-covered stents (Gore-Viatorr prosthesis) in all cases, dilated to 8 or 10 mm. No stent was overdilated to 12 mm.
Median follow-up was 12 months ranging from 0 to 40 months.
On intent-to-treat analysis (Table 1), survival free of rebleeding was almost significantly higher in patients randomized to pTIPS than in the control group (90% vs 50%; p=0.055).Moreover actuarial probability of survival free of rebleeding did not reach statistical significance Supplementary Figure 1) (long-rank p=0.198). Per protocol analysis showed that both overall rebleeding and survival free of rebleeding were significantly better in the pTIPS group (Table 2). The actuarial probability of survival without rebleeding was significantly higher in pTIPS group (Supplementary Figure 2) (log-rank p=0.047).
We repeated the analysis of the main end-point (survival free of rebleeding) excluding the patient treated by collateral embolization without a concomitant pTIPS. In this analysis the results were the same as in the whole series, i.e.differences in outcomes between the two groups according to randomization were not significant (p=0.051), while, a significant difference was observed when analyzing patients as per protocol (p=0.017).
Sub-analysis according to Child-Pugh class showed that all Child-Pugh A patients (n=8) survived and all but one were free of rebleeding on follow-up, without significant differences between the two arms (p=0.28). On the contrary, among Child-Pugh B/C patients (n=13) only one patient in the pTIPS group Vs 4 patients in the standard of care group rebled or died on follow-up (p=0.053). On per protocol analysis, there were no significant differences in the main outcome in Child-Pugh A patients. However, no patient in the pTIPS group vs 5 out of 7 Child-Pugh B/C patients receiving control therapy rebled or died on follow-up (p=0.008).
Serious adverse events leading to patient readmission during follow-up were not different among the two groups, with 2 patients in the pTIPS group and 4 control patients developing overt hepatic encephalopathy. One patient in the pTIPS group developed portopulmonary syndrome.
Discussion
In patients bleeding from gastric fundal varices, TIPS, associated or not to collateral embolization, has been recommended as rescue therapy in cases of failure of endoscopic therapy with tissue adhesives plus pharmacological therapy (vasoactive drugs during the acute bleeding episode; non-selective beta-blockers thereafter)
[1]
,[5]
. Its role as a first line therapy in acute gastric variceal bleeding has been suggested in single center studies and meta-analysis including low number of patients (largest 209 patients) [3]
,- Shah KY
- Ren A
- Simpson RO
- Kloster ML
- Mijolajczyk A
- Bui JT
- et al.
Combined transjugular intrahepatic portosystemic shunt plus variceal obliteration versus transjugular intrahepatic portosystemic shunt alone for the management of gastric varices: comparative single-center clinical outcomes.
J Vasc Interv Radiol. 2021; 32: 282-291
[6]
. Moreover, TIPS performed after initial control of gastric variceal bleeding (secondary prophylaxis) proved to be more effective than glue injection in the prevention of rebleeding from gastric varices [4]
.As far as we know, this is the first randomized controlled trial in Western countries comparing the standard of care therapy with preemptive TIPS (pTIPS) in fundal variceal bleeding. Standard of care therapy was the combination of endoscopic cyanoacrylate injection plus iv somatostatin or terlipressin, followed by repeated cyanoacrylate injection (until variceal obliteration) concomitantly with non-selective beta-blockers (carvedilol in our patients). Patients in the pTIPS group also received initially combined endoscopic and pharmacological therapy, followed by TIPS performed during days 1 to 5 except in the 3 cases where pTIPS was performed during the first 24h (according to what specified in the protocol).
Our study faced more difficulties in recruitment than foreseen. This was mainly due to the scarcity of patients bleeding from IGV1 or GOV2. Actually, most old studies used for estimating feasibility of recruitment included as gastric varices patients with GOV1, which are more frequent but that behave and should be treated like patients bleeding from esophageal varices according to Baveno VI and Baveno VII recommendations
[1]
,[7]
. Another limitation in old studies was the use of TIPS using bare stents, with much worse outcomes than current covered stents. Moreover, patients randomized to pTIPS were not all treated on the first 2-days (the ideal situation) but had to use the full bracket of 5 days in some centers due to difficulties in scheduling early TIPS. This probably adds heterogeneity of outcomes, but closely reflects real life practice in many centers [8]
.Patients were stratified according to the Child-Pugh score, i.e. Child-Pugh A or B/C. Thus, the 2 series were not different regarding the Child-Pugh score.
The main result of the study was that patients randomized to receive pTIPS showed a closely to significance higher survival free of rebleeding than those randomized to receive combined pharmacological and endoscopic therapy. Due to the low number of patients the results should be considered supportive rather than strongly conclusive. In fact, the actuarial probability of being free of death or rebleeding did not reach statistical significance, except when using a per protocol approach. Anyhow, the different outcomes in the two arms exceeded the assumptions done in the sample size calculation and are of undeniable clinical relevance.
It is important to remark that the benefit of pTIPS was limited to the Child-Pugh B and C patients. Therefore, as in bleeding from esophageal varices, pTIPS should probably be restricted to Child B-C patients, indicating that contrary to our assumption, bleeding from gastric fundal varices does not per se changes the indication for early TIPS.
The low number of included patients precluded any conclusion on whether adding variceal embolization to pTIPS contributes to a higher efficacy of TIPS. However, a recently published RCT showed that concomitant collateral embolization did not significantly reduce the incidence of variceal rebleeding in patients with cirrhosis receiving a TIPS for bleeding gastro-esophageal varices
[9]
.Low numbers precluded also the evaluation of the impact of therapy on ascites. However, the incidence of overt hepatic encephalopathy was not different between the two groups. It may be that collateral embolization, done in half of the patients receiving a pTIPS, contributed to the low incidence of HE in pTIPS treated patients, as shown in another recent RCT
[10]
. As already commented, the main limitation of our study is the low number of patients included. It was initially planned to expand the duration of the RCT to minimize the problem, but this was not possible due to COVID pandemic. However, even in the context of the short number of patients included, this RCT suggests that pTIPS could be more effective than combined endoscopic and medical therapy in patients bleeding from GOV2 or IGV1 varices, without a significant increase in the incidence of HE, in analogy with what demonstrated for cirrhotic patients bleeding from esophageal varices.Appendix A. Supplementary data
The following is/are the supplementary data to this article:
References
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Article info
Publication history
Accepted:
February 18,
2023
Received in revised form:
February 15,
2023
Received:
December 15,
2022
Handling Editor: Jessica Zucman-RossiPublication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).
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