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Transplant-Free Survival Rates After Covered Transjugular Intrahepatic Portosystemic Shunt
Gastroenterology 2017;-:1
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CORRESPONDENCE Readers may submit letters to the editor concerning articles that appeared in Gastroenterology within one month of publication. Detailed guidelines regarding the content are included in the Instructions to Authors.
Transplant-Free Survival Rates After Covered Transjugular Intrahepatic Portosystemic Shunt Dear Editors: We acknowledge the challenges identified by the authors in the management of recurrent or refractory ascites.1 Although data identifying candidate suitability for transjugular intrahepatic portosystemic shunt (TIPSS) is satisfactory, the optimum timing of TIPSS remains challenging. This randomized, controlled trial proposes to establish whether such patients might be best managed using large volume paracentesis with supplementary albumin (LVPþA) or TIPSS using a covered stent. Although the reported transplant-free survival rates at the 1-year follow-up seem to be compelling at 52% and 93%, respectively, we feel that aspects of the manuscript raise important questions with regard to patient selection, reasons for the rates of treatment failure, and patient outcomes. There are a number of important inconsistencies in the presentation of the data that warrant clarification. First, the authors report an overall transplant-free survival rate of 93% (26/28) among the TIPSS cohort, yet Table 2 indicates that 11 out of 62 patients were alive without liver transplantation at 1 year. Second, in the survival analysis there seem to be a number of patients censored before 6 months in both groups, but the number at risk presented for the TIPS group does not decrease sufficiently to reflect this. It is important to understand the rate of early censoring in both groups because this factor may have an impact on the outcome of the survival analysis. The main conclusion from the manuscript is that covered TIPSS improve survival in individuals with refractory ascites. There are, however, several issues that question this finding. First, there was a numerical excess of individuals with SBP in the LVPþA group at baseline (5/33 vs 2/29) although whilst there was no statistically significant difference, in a small trial this may have been relevant. Second, a significant number of individuals in the LVPþA group were censored within 6 months of randomization. The majority of these patients were censored because the number of sequential LVP’s performed reached the maximum number of procedures (ie, >6 in 3 months) before proceeding to TIPSS. Censoring these individuals opposes the intention-to-treat principle and the analysis presented is therefore per protocol. If such an LVP frequency is a conventional indication for TIPSS, then these patients should be included in the analysis to reflect outcomes that might be expected in day-to-day clinical practice. Indeed, it is noteworthy that randomization to LVPþA did not lead to a statistically significant increase in patient mortality or need for transplantation. Finally, the rate of participant recruitment to this trial seemed to be problematic, as highlighted by the small
numbers recruited and the need to revise the power calculation during the course of the trial. Furthermore, the difficulties encountered with adherence to the protocol, thereby necessitating the exclusion of certain trial centers, not only questions the applicability of their findings on a wider health care platform, but may partly explain why their survival rates for TIPSS surpass those of previous trials by >10%. The requirement to register clinical trials on public registries was driven by a desire to increase the transparency of trial conduct, reporting, and reproducibility of findings. In the initial power calculation, a total number of participants required was estimated at 120. In light of additional studies being reported during the conduct of the trial, the power calculation was revised to 60 participants.2,3 It is, however, not apparent from the manuscript as to the timing of the revised power calculation in relation to recruitment, as the clinicaltrials.gov (NCT00222014) update would imply that this occurred after completion of recruitment in 2013. It is well-recognized that trials, especially those with limited study populations, that stop prematurely may overestimate treatment benefits.4,5 The benefits of covered TIPSS insertion in individuals with refractory ascites are well-known in terms of improvements in symptoms and a reduction in the need for regular LVP. Bureau et al1 have taken significant steps into understanding the survival benefits of covered TIPSS over LVP. However, in parallel their study certainly highlights the ongoing challenges that we face with regards study design, recruitment, patient selection, and applicability of their findings to all centers that undertake TIPSS. Until their findings are replicated in a larger study population, we would caution against the use of their current findings to influence clinical guidance and practice. DANIEL SCHMIDT-MARTIN MATT J. ARMSTRONG Liver Transplant Unit Queen Elizabeth University Hospital Birmingham Birmingham, UK
Q3 Q1
IAN A. ROWE Liver Transplant Unit St James University Hospital Leeds, UK
References 1. 2. 3. 4. 5.
Bureau C, et al. Gastroenterology 2017;152:157–163. Salerno F, et al. Gastroenterology 2007;133:825–834. Narahara Y, et al. Journal of gastroenterology 2011; 46:78–85. Guyatt GH, et al. BMJ 2012;344:e3863. Bassler D, et al. JAMA 2010;303:1180–1187.
Conflicts of interest The author discloses no conflicts.
http://dx.doi.org/10.1053/j.gastro.2017.02.051
COR 5.5.0 DTD YGAST61287_proof 3 August 2017 3:02 pm ce
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
CORRESPONDENCE Readers may submit letters to the editor concerning articles that appeared in Gastroenterology within one month of publication. Detailed guidelines regarding the content are included in the Instructions to Authors.
Transplant-Free Survival Rates After Covered Transjugular Intrahepatic Portosystemic Shunt Dear Editors: We acknowledge the challenges identified by the authors in the management of recurrent or refractory ascites.1 Although data identifying candidate suitability for transjugular intrahepatic portosystemic shunt (TIPSS) is satisfactory, the optimum timing of TIPSS remains challenging. This randomized, controlled trial proposes to establish whether such patients might be best managed using large volume paracentesis with supplementary albumin (LVPþA) or TIPSS using a covered stent. Although the reported transplant-free survival rates at the 1-year follow-up seem to be compelling at 52% and 93%, respectively, we feel that aspects of the manuscript raise important questions with regard to patient selection, reasons for the rates of treatment failure, and patient outcomes. There are a number of important inconsistencies in the presentation of the data that warrant clarification. First, the authors report an overall transplant-free survival rate of 93% (26/28) among the TIPSS cohort, yet Table 2 indicates that 11 out of 62 patients were alive without liver transplantation at 1 year. Second, in the survival analysis there seem to be a number of patients censored before 6 months in both groups, but the number at risk presented for the TIPS group does not decrease sufficiently to reflect this. It is important to understand the rate of early censoring in both groups because this factor may have an impact on the outcome of the survival analysis. The main conclusion from the manuscript is that covered TIPSS improve survival in individuals with refractory ascites. There are, however, several issues that question this finding. First, there was a numerical excess of individuals with SBP in the LVPþA group at baseline (5/33 vs 2/29) although whilst there was no statistically significant difference, in a small trial this may have been relevant. Second, a significant number of individuals in the LVPþA group were censored within 6 months of randomization. The majority of these patients were censored because the number of sequential LVP’s performed reached the maximum number of procedures (ie, >6 in 3 months) before proceeding to TIPSS. Censoring these individuals opposes the intention-to-treat principle and the analysis presented is therefore per protocol. If such an LVP frequency is a conventional indication for TIPSS, then these patients should be included in the analysis to reflect outcomes that might be expected in day-to-day clinical practice. Indeed, it is noteworthy that randomization to LVPþA did not lead to a statistically significant increase in patient mortality or need for transplantation. Finally, the rate of participant recruitment to this trial seemed to be problematic, as highlighted by the small
numbers recruited and the need to revise the power calculation during the course of the trial. Furthermore, the difficulties encountered with adherence to the protocol, thereby necessitating the exclusion of certain trial centers, not only questions the applicability of their findings on a wider health care platform, but may partly explain why their survival rates for TIPSS surpass those of previous trials by >10%. The requirement to register clinical trials on public registries was driven by a desire to increase the transparency of trial conduct, reporting, and reproducibility of findings. In the initial power calculation, a total number of participants required was estimated at 120. In light of additional studies being reported during the conduct of the trial, the power calculation was revised to 60 participants.2,3 It is, however, not apparent from the manuscript as to the timing of the revised power calculation in relation to recruitment, as the clinicaltrials.gov (NCT00222014) update would imply that this occurred after completion of recruitment in 2013. It is well-recognized that trials, especially those with limited study populations, that stop prematurely may overestimate treatment benefits.4,5 The benefits of covered TIPSS insertion in individuals with refractory ascites are well-known in terms of improvements in symptoms and a reduction in the need for regular LVP. Bureau et al1 have taken significant steps into understanding the survival benefits of covered TIPSS over LVP. However, in parallel their study certainly highlights the ongoing challenges that we face with regards study design, recruitment, patient selection, and applicability of their findings to all centers that undertake TIPSS. Until their findings are replicated in a larger study population, we would caution against the use of their current findings to influence clinical guidance and practice. DANIEL SCHMIDT-MARTIN MATT J. ARMSTRONG Liver Transplant Unit Queen Elizabeth University Hospital Birmingham Birmingham, UK
Q3 Q1
IAN A. ROWE Liver Transplant Unit St James University Hospital Leeds, UK
References 1. 2. 3. 4. 5.
Bureau C, et al. Gastroenterology 2017;152:157–163. Salerno F, et al. Gastroenterology 2007;133:825–834. Narahara Y, et al. Journal of gastroenterology 2011; 46:78–85. Guyatt GH, et al. BMJ 2012;344:e3863. Bassler D, et al. JAMA 2010;303:1180–1187.
Conflicts of interest The author discloses no conflicts.
http://dx.doi.org/10.1053/j.gastro.2017.02.051
COR 5.5.0 DTD YGAST61287_proof 3 August 2017 3:02 pm ce
Q2
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