Transjugular intrahepatic portosystemic shunt (TIPS) versus ...

Relative values of different outcomesThe GDG discussed the merits of various outcome measures that compared transjugular intrahepatic portosystemic shunt (TIPS) with large-volume paracentesis (LVP) plus albumin in people with cirrhosis and refractory ascites. Health-related quality of life, re-accumulation of ascites and transplant-free survival were critical outcomes of interest. Important outcomes were agreed as occurrence of spontaneous bacterial peritonitis, renal failure, hepatic encephalopathy, length of hospital stay and readmission rates.Trade-off between clinical benefits and harmsThere was clinical benefit in favour of TIPS for the critical outcomes of re-accumulation of ascites and transplant-free survival (albeit Low quality evidence).
Only 1 study reported the critical outcome of health-related quality of life using the SF-36 tool. The paper reported that there was an improvement in scores for both groups, but there was no significant difference between the two groups. In the study, the SF-36 score was broken down into physical and mental components but the scale for each was not reported. Therefore, the GDG found it difficult to assess whether the difference between groups was of clinical importance.
Although there was a lack of evidence for quality of life, the GDG discussed the potential benefits of a successful TIPS procedure over repeated LVP. For LVP, patients are required to attend hospital regularly every few weeks. This procedure is not a cure for the refractory ascites. The GDG discussed that avoiding repeated LVP is likely to improve quality of life in the majority of patients who are able to undergo the TIPS procedure. Given this, the GDG felt able to make a ‘consider’ recommendation.
Evidence was available from 2 studies for the outcome of renal failure (Moderate quality) and SBP (Low quality), with contradictory results in small numbers of patients. The GDG, despite the Moderate quality, placed less weight on these results given the small number of reported outcomes.
When considering the evidence the GDG noted that the data available were largely older studies and of Low quality. The GDG felt that if an RCT had been conducted now, patient selection (particularly screening for hepatic encephalopathy and cardiac dysfunction) would have been more stringent and may have shown more benefit for TIPS. The GDG also noted that technical failures affected the outcomes in the TIPS groups and modern radiological techniques and stent design may reduce the effect of these technical failures. For example, even the most recent study (2011) used uncovered stents which are more likely to stenose. In addition, older studies may have included patients with more severe liver disease, who would not be considered for TIPS now.
The GDG discussed the benefits of TIPS in improving the nutritional status of patients with cirrhosis. Whilst the GDG did not look for evidence about nutritional status following both procedures, anecdotally it was felt that, when TIPS was successful, it indirectly improved the person's nutritional status. The GDG noted the suggestion of some benefit of TIPS for health-related quality of life, although this was not clinically significant.
The GDG noted that in patients with hepatic encephalopathy there was a clinical benefit of LVP over TIPS. Hepatic encephalopathy can become disabling and require reversal of the TIPS procedure by blockage of the stent. The GDG noted that the TIPS procedure is unsuitable for people with a past or current history of hepatic encephalopathy.Trade-off between net clinical effects and costsOne cost—consequence analysis (Gines 2002)87 was identified comparing LVP with TIPS in patients with refractory ascites (not responding to low sodium diet). This study reported that TIPS was more costly than LVP for the management of diuretic-resistant ascites (£2104 more per patient) and had 0.06 more deaths per patient, but 8.0 fewer instances of ascites re-accumulation per patient. The difference in total costs was mainly due to the high procedural TIPS costs outweighing lower follow-up costs in comparison to LVP.
The GDG agreed that the largest component to the cost of LVP would be albumin infusions and the main follow-up costs related to TIPS would be the cost of admission related to episodes of hepatic encephalopathy. The GDG also noted that this study was the only study included in the clinical review not favouring TIPS in terms of transplant-free survival, and that the TIPS procedural methodology has improved since the publication of the study meaning that the reported clinical effectiveness data are not representative of the clinical review.
The GDG considered that with clinical outcomes more favourable to TIPS, the follow-up costs of TIPS would be lower, although the initial costs of TIPS would always be higher than for LVP. The relative costs of TIPS and LVP will depend on the number of times LVP needs to be repeated – this can vary very largely between individuals, with some people needing frequent repetition and others re-accumulating fluid very slowly. For example, with TIPS costing £2900 and LVP costing £670 (costs from Parker 2013157), a TIPS procedure that prevented more than 4 LVP procedures would be cost saving in addition to decreasing mortality.
The GDG concluded that the cost-effectiveness of TIPS would vary from person to person depending on their individual circumstances, particularly their suitability for TIPS and the frequency of their need for LVP. In many patients TIPS would be likely to be cost-effective at a threshold of £20,000 per QALY gained as the benefit in transplant-free survival, and the benefit to quality of life from reduced re-accumulation of ascites are likely to justify the increased costs of TIPS. In patients who prior to TIPS had need for repeated LVP, TIPS would even be cost saving. As a result, clinicians should use their judgement regarding which people may be most suitable for TIPS, but for those for whom TIPS is suitable the GDG believes that TIPS should be considered by the clinician and patient.Quality of evidenceFive RCTs were identified (4 had been included in a previous Cochrane review and 1 was a more recent RCT). The Cochrane review papers were individually assessed to identify data for the critical and important outcomes not reported by Cochrane authors. The evidence quality ranged from Very Low to Moderate, and for all critical outcomes the evidence quality was Low. For many outcomes, heterogeneity was observed (re-accumulation of ascites, transplant-free survival and hepatic encephalopathy). It was not possible to explore this heterogeneity using the predefined subgroup analyses due to the small number of studies in each subgroup.
The population identified in the protocol was people with cirrhosis and diuretic refractory ascites. Three papers reported that people were receiving LVP prior to the placement of TIPS; however 2 studies did not report this in their inclusion criteria. It was assumed that this was the case in all studies. The GDG agreed that the phrases ‘total paracentesis’ and ‘large-volume paracentesis’ were, in practical terms, the same or a very similar procedure.
A further study (RCT) by Lebrec 1996119 was subsequently excluded by the GDG. This report was included in the Cochrane review, but the GDG noted that the procedure used for TIPS insertion was significantly different from current TIPS protocols. Individuals in the intervention arm received 2–3 uncovered stents in parallel with the aim of creating a larger shunt than in many other studies. The paper was excluded from the analysis. The GDG noted that the absolute number of patients in this paper was small.
In the paper by Gines 200287 the LVP group continued to receive beta-blockers and the TIPS group did not. The GDG noted that beta-blockers can pre-dispose to hepatic encephalopathy and are associated with mortality in advanced cirrhosis.
For the critical outcome of re-accumulation of ascites either ‘complete response – a complete resolution of ascites’, or ‘incomplete response – leaving some residual ascites’ were considered a positive effect. However, studies used different definitions for the levels of response and this contributed to heterogeneity in the data (represented by the high I2 value).
Trial inclusion criteria selected patients who were ‘fit for TIPS’ which may have improved the outcomes in both groups to above that which could be expected in clinical practice. There was variation in the operational definitions used within studies, for example, hepatic encephalopathy was defined by some studies as ‘Grade 1’ or ‘overt’; others reported new hepatic encephalopathy whilst others cited ‘on-going’ hepatic encephalopathy. This may contribute to the heterogeneic results for the outcome of hepatic encephalopathy. The GDG also noted that in the Gines 200287 study (in which LVP patients were given beta-blockers), for hepatic encephalopathy, less benefit was reported for LVP than in other studies. In addition, variation between studies in the use of covered or uncovered stents and in the use of ‘low salt’ or ‘no added salt’ diets was highlighted by the GDG.Other considerationsThe GDG emphasised that all patients with cirrhosis and refractory ascites should be reviewed by a hepatologist and considered for transplantation. Those who are suitable for transplantation may undergo TIPS as a ‘holding procedure’ while on the transplant waiting list. Those who are not suitable for transplantation would undergo TIPS as a definitive procedure. The GDG was in agreement that there is currently wide variation in UK practice and were concerned that there are patients who may benefit from TIPS but who are not being offered this service.

Research recommendation
Prior to TIPS, people may have had several problems resulting from portal hypertension, including variceal bleeding from veins in the stomach, oesophagus, or intestines, ascites or hydrothorax – all of which will have had a detrimental effect on their quality of life. TIPS should alleviate these problems, but little is known about the consequential effect on quality of life and any effects that potential problems following TIPS (for example, hepatic encephalopathy, shunt blockages, infection and cardiac problems) have on each person. It is therefore important to assess what benefits TIPS has to the quality of life of people with advanced liver disease.

In people with liver failure and cirrhosis, the liver is incapable of processing blood from the bowel. As a result, abnormally high pressure develops within the veins that drain blood from the bowels as the body tries to form other channels for the blood to empty into the main (systemic) circulation.

These alternate pathways of blood drainage are known as portosystemic collaterals and consist of fragile veins that surround the esophagus, stomach or other areas in the digestive tract. Because of the fragility of these veins, they are prone to rupturing, which can result in massive amounts of bleeding. The abnormally high pressure within the veins draining into the liver (portal hypertension) can also result in the formation of fluid seeping from the surface of the liver and collecting in large quantities in the abdominal cavity. This is known as ascites. Therapies that lower the blood pressure within the veins draining into the liver can lessen the formation of ascites and lower the risk of bleeding from the fragile veins (varices).

What treatments can lower the blood pressure in the portal venous system?

A number of therapies can lower the pressure of the veins that drain from the bowel into the liver. The first choice of therapy usually consists of drug therapy with medications known as non-selective beta-blockers. These medications need to be taken every day to produce an effect. Some people may not be able to remain on beta-blocker therapy if they develop side effects from taking them. Other people on beta-blocker therapy will remain at risk for bleeding from varices and from the development of fluid formation (ascites).

Another approach is to seal off the veins to prevent rupturing. In sclerotherapy, a camera (endoscope) is passed down through the esophagus to inject the abnormal veins with substances that close them off. With variceal band ligation, the abnormal veins are tied off with small rubber bands. Although sclerotherapy and variceal band ligation are very effective in targeting the abnormal and fragile veins around the esophagus, they do not lower the pressure of the blood inside the portal venous system. This portal hypertension may continue to allow fluid to develop inside the abdominal cavity, or may allow bleeding to occur from other areas of the bowel such as the stomach (portal gastropathy).