The hidden face of preemptive TIPS
Authors: Càndid Villanueva
Journal: Hepatology (2023)

In this issue of Hepatology, an updated individual participant data meta-analysis (IPD-MA) reinforces the value of preemptive TIPS (p-TIPS) in high-risk patients with variceal bleeding.1 This is a strategy consisting of placing a TIPS in patients at high risk of failure before they fail to prevent further bleeding and the associated risk of death. As suggested in the landmark study by Garcia-Pagan et al and in other randomized controlled trials (RCTs),2 this IPD-MA shows a clear survival benefit favoring p-TIPS. Demonstrating a significant survival improvement in this setting is not an easy task when comparing a new therapy with an effective standard of care (SOC). This has not been achieved in many RCTs investigating therapies to prevent variceal rebleeding. The present IPD-MA suggests potential benefit favoring p-TIPS to ameliorate prognosis in patients with variceal bleeding. However, TIPS can also be associated with undesirable effects such as encephalopathy, worsening liver function, procedural complications, or cardiac failure. Therefore, to achieve a maximal gain from p-TIPS, it is crucial to adequately select potential candidates who may benefit the most and to avoid the procedure when it offers no benefit or may even harm. Elucidating the effects through which p-TIPS can improve survival is relevant to achieving this goal. By decompressing the portal venous system, p-TIPS induces a rapid and marked decrease in portal pressure. The sustained decrease in portal pressure allows to effectively control complications related to portal hypertension, such as bleeding or ascites. In patients with variceal bleeding, this confers the possibility of efficiently prevent recurrent bleeding. By preventing rebleeding, a survival benefit can be expected, particularly in patients with advanced liver dysfunction, since the risk of death is low in those with preserved hepatic function. In keeping with this, old RCTs comparing active therapy, either with non-selective beta-blockers (NSBBs) or endoscopic sclerotherapy versus a control group without active therapy, had shown less rebleeding and better survival favoring active therapy.3 However, using an effective therapy as control arm trials assessing new treatments rarely have shown survival improvement despite reducing rebleeding risk. This has been the case in RCTs comparing endoscopic variceal ligation versus sclerotherapy or in RCTs comparing endoscopic therapy plus NSBBs versus either monotherapy.3,4 Similarly, using elective TIPS created with uncovered stents as first-line therapy to prevent rebleeding, RCTs comparing such TIPS with endoscopic sclerotherapy or with NSBBs plus nitrates showed much more efficacy to prevent rebleeding favoring uncovered-TIPS, without significant survival benefit.5,6 Altogether, it suggests that the impact on survival achieved by preventing rebleeding is limited in trials seeking to improve the efficacy of therapies already associated with a reduced risk of death. In such cases, demonstrating further improvement would require very large sample sizes. Nevertheless, investigating p-TIPS included in the present IPD-MA have shown survival improvement despite not recruiting large sample sizes and despite using as control arm the current SOC combining NSBBs plus endoscopic variceal ligation, which is associate with a death risk below 20%–25% at 1 year. The significant benefit favoring covered p-TIPS may be related in part to the use of covered stents, which, by preventing the TIPS dysfunction frequently associated with bare stents, have increased efficacy.5,6 In addition, there are a couple of relevant issues that likely account for such improvement in survival, which is worth analyzing in some detail. One refers to risk stratification by selecting a population concentrating on a high probability of death with SOC. The other concerns the effect of p-TIPS on other portal–hypertension-related complications in addition to recurrent bleeding. Regarding the impact of p-TIPS on complications related to portal hypertension, this updated IPD-MA shows a significant effect markedly improving the likelihood of developing new or worsening ascites with a risk reduction of almost 70% (subdistribution hazard ratio= 0.32, 95% CI = 0.17 to 0.59).1 Such a positive effect is not a minor issue since ascites is the most common and severe decompensating event, both in compensated and in decompensated patients, even in those presenting with variceal bleeding.4,7 Concordantly, another recent IPD-MA shows that TIPS effectively prevents further decompensation in cirrhosis,8 which in the last Baveno-VII conference was defined as a second or a recurrent or complicated decompensating event. This is a key point since further decompensation very markedly increases the risk of death, as nicely demonstrated recently by a large cohort study.7 Certainly, the last commented IPD-MA showed (as expected) an increased risk of encephalopathy with TIPS.8 However, this was absolutely offset by a much lower incidence of both rebleeding and ascites favoring TIPS. Currently, less than 15% of patients presenting first variceal bleeding die as a result of bleeding (within the first 42 days), while at 1 year, mortality is double, and most deaths occur after developing further decompensation.7,9 Noteworthy, ascites – and not bleeding – is the most frequent decompensation in these patients.7 All these data suggest that the beneficial effect of p-TIPS on survival may likely be related to the effect of preventing further decompensation overall, not just rebleeding but also ascites and its related complications. Risk stratification is another key issue probably contributing to the survival benefit observed favoring p-TIPS. In contrast to p-TIPS, no survival improvement has been observed in trials assessing elective first-line therapy with covered TIPS versus SOC in secondary prophylaxis, despite lower rebleeding risk with TIPS.5,6 No risk stratification was used in these trials. By contrast, the studies encompassing the present IPD-MA selected a high-risk population consisting of Child-Pugh class C patients (with a score < 14) and class B patients with active bleeding at endoscopy.1 Dealing with patients at a much higher risk of death likely contributed to obtaining a survival gain in p-TIPS studies. In any case, optimizing risk stratification is essential to properly select patients who can benefit most from p-TIPS. The use of active bleeding at endoscopy raises concern since it is subjective and has high interobserver variability.6 Furthermore, although it may reflect rebleeding risk, it is unclear whether it captures the risk of further decompensation. Refinement of risk stratification has been proposed by using the Model For End-Stage Liver Disease score or other scores.5,6 The IPD-MA in this issue reassessed risk in patients with Child-Pugh class B and suggests that only those with scores > 7 benefit from p-TIPS, along with patients with class C.1 In clinical practice, most of these patients frequently have some other decompensation in addition to bleeding (ie, ascites and/or encephalopathy). Both, the risk of further decompensation and the risk of death, are much higher in patients who, in addition to bleeding, have other complications (mainly ascites) than in those with bleeding alone.7,9,10 As previously commented, p-TIPS may be greatly valuable to prevent further decompensation and thus, to improve survival in high-risk patients. According to available data, patients who, in addition to bleeding, already have ascites (with or without encephalopathy) and also have a Child-Pugh score greater than 7, are at the highest risk of developing further decompensation. Therefore, they are most likely to benefit from p-TIPS. It should be clarified whether this is also the case in patients who, in addition to bleeding, have encephalopathy without ascites, since portal-systemic shunting may play a relevant role in such cases. Patients who only have bleeding, without any previous decompensating event, have a much lower risk of further decompensation, even if the Child-Pugh score is greater than 7.7,9 The present IPD-MA, in a post hoc analysis, shows better survival with p-TIPS also in patients who only had bleeding.1 However, it is not clear if these patients had been completely compensated before bleeding. Whether patients with bleeding and no other previous or concomitant decompensation benefit from p-TIPS should be clarified. Figure 1 suggests a potential approach to select suitable candidates to benefit the most from p-TIPS. However, an adequate stratification of risk deserves further investigation.FIGURE 1: Potential approach to treatment according to risk stratification after acute variceal bleeding. Patients who, in addition to bleeding, have ascites (with or without encephalopathy) and have a Child-Pugh score > 7 and < 14 will very likely benefit from first-line therapy with p-TIPS. The benefit is uncertain, and further research is required if these patients have a Child-Pugh score ≤ 7 or if ascites is uncomplicated and was not present before bleeding. This is also the case in patients who in addition to bleeding have encephalopathy without ascites. The benefit from p-TIPS may be unlikely in patients who only have bleeding without any other previous or present decompensating event. Abbreviations: EVL, endoscopic variceal ligation; NSBBs, non selective β-blockers; p-TIPS, preemptive TIPS.The efficacy of p-TIPS relies in part on its prompt implementation.5,6 In most of the studies included in the current IPD-MA, p-TIPS was performed early (within the first 72 h). However, such an early insertion of p-TIPS faces some challenges in real-world clinical practice. Moreover, in many cases, it may not be necessary. Early p-TIPS will be mainly helpful in patients at high risk of failure to control acute bleeding (ie, achieving hemostasis without early rebleeding within the first few days). With current SOC, this occurs only in 10%–15% of cases but carries high mortality.4,7 Patients at risk of such failure are most likely to benefit from an early performance of TIPS to avoid further bleeding. However, the currently available parameters to identify these patients are the same used to identify patients at risk of death despite permanent control of bleeding. Selectively identifying patients at risk of failure to control bleeding would allow the implementation of emergency p-TIPS according to the feasibility and practicality of real-world clinical practice.6 Patients with bleeding alone have a lower risk of uncontrolled bleeding than those with another decompensation and have low mortality when it occurs. It seems possible that rescue TIPS may be as effective as early p-TIPS in these patients. However, this will require a specific investigation. To advance towards precision medicine and provide p-TIPS only to those who will benefit the most, while avoiding it when it offers no benefit or even harm, some other issues warrant further assessment. HVPG measurements provide strong prognostic information. Although HVPG is not widely accessible, the availability may be greater in centers providing p-TIPS. It should be clarified whether p-TIPS provides benefit in patients at low risk according to HVPG measurements, such as those with baseline HVPG < 16 or < 12 mm Hg, or those with good response to NSBBs in an acute test.9,10