Early HVPG measurement and TIPS for acute variceal hemorrhage: Is sooner really better?

Abstract

Monescillo A, Martınez-Lagares F, Ruiz-del-Arbol L, Sierra A, Guevara C, Jiménez E, Marrero JM, Buceta E, Sá;nchez J, Castellot A, Peñate M, Cruz A, Peña E (Hospital University Insular Gran Canaria, Canary Islands; and Hospital Ramon y Cajal, Madrid, Spain). Influence of portal hypertension and its early decompression by TIPS placement on the outcome of variceal bleeding. Hepatology 2004;40:793–801. Variceal bleeding occurs in approximately one third of patients with cirrhosis and portal hypertension, and it remains a major cause of mortality and morbidity in this patient population (Gastroenterology 1989;96:1552–1559). Mortality for each bleeding episode is the range of 20%–30%. The current standard of care for acute variceal bleeding is the use of combined pharmacological and endoscopic therapy, which has been shown to decrease the rebleeding rate in numerous randomized controlled trials (Semin Liver Dis 1999;19:475–505). Early rebleeding after therapy occurs in 10%–20% of patients (Hepatology 2003;38:599–612) and is strongly associated with patient mortality. Impairment of liver function, indicated by the Child-Turcotte-Pugh score (CTP) is a predictor of rebleeding and mortality from variceal hemorrhage (Endoscopy 1987;19:181–184, Gastroenterology 1981;80:800–809). Measurement of the hepatic venous pressure gradient (HVPG), defined as the difference between the wedged and free (unwedged) hepatic venous pressures, has also been studied as a predictor of rebleeding and survival in variceal bleeding (Gastroenterology 1999;117:626–631). Transjugular intrahepatic portosystemic shunt (TIPS) is an alternative treatment for variceal hemorrhage. This angiographic procedure creates a low-pressure communication between the portal and the hepatic venous systems, reducing portal pressure and decreasing pressure in collateral circulation. In acute variceal bleeding refractory to standard therapy, TIPS has been shown to control hemorrhage in more than 90% of cases (Gastroenterology 2004;127:621–629), but confers no survival advantage over endoscopic therapy. The aims of the current study by Monescillo et al were to assess the accuracy of HVPG as a predictor of treatment failure in acute variceal bleeding and to determine if early TIPS placement would reduce the risk of treatment failure and improve survival in a subset of high-risk patients. A total of 116 patients aged 18–75 years were randomized in this study. Inclusion criteria included a diagnosis of cirrhosis (either by biopsy or by clinical and radiological criteria, clinical evidence of upper GI bleeding [hematemesis or melena] in the 24 hours before hospital admission, and endoscopically verified variceal hemorrhage). Patients were excluded if they had hepatocellular carcinoma, portal vein thrombosis, human immunodeficiency virus, prior TIPS placement, history of cardiac or renal failure, and sepsis. Of 134 patients evaluated for the study, 10 were excluded by these criteria, along with 5 patients who did not have portal venous pressure measurements, plus 1 who refused entry and 3 with other unspecified chronic illnesses. Patients who entered the study underwent one session of endoscopic sclerotherapy as treatment of acute variceal hemorrhage. Patients also received an intravenous somatostatin infusion begun prior to endoscopy and discontinued after the endoscopic procedure. HVPG was measured in all patients within 24 hours of admission. Using a cutoff value of 20 mm Hg, 64 patients had an HVPG below this value and were placed into a low-risk (LR) category. The 52 patients with an HVPG >20 mm Hg were deemed high-risk (HR) and randomized into 1 of 2 treatment arms of the study: 26 patients underwent TIPS placement within 24 hours of admission (HR TIPS), while the other 26 patients received standard therapy without TIPS (HR non-TIPS). All patients received lactulose and norfloxacin. Patients in the LR and HR non-TIPS groups received beta-blocker therapy as prophylaxis against rebleeding; endoscopic band ligation was used in patients intolerant of beta-blockers. Treatment failure (TF) was defined as either failure to control acute bleeding or rebleeding within 5 days of initial therapy. TF was re-treated with a second round of endoscopic sclerotherapy, with TIPS used as a “rescue” therapy when pharmacologic and endoscopic therapy was ineffective. The primary endpoints of the study were: (1) an assessment of an HVPG cutoff value of 20 mm Hg as a predictor of TF, and (2) an assessment of TF and survival in the 3 study arms. The HR and LR groups were similar except for a higher CTP score in the HR group and a greater incidence of active variceal hemorrhage at index endoscopy. The sensitivity of an HVPG of 20 mm Hg as a predictor of TF was 62%, with a specificity of 81%; positive and negative predictive values were calculated as 50% and 87%, respectively. When compared with CTP score, the HVPG was not significantly better at predicting TF (AUC, 0.744 vs 0.704). Comparison was made between the LR group and the HR non-TIPS group, demonstrating an OR of 7.00 (95% confidence interval [CI], 2.40–20.36) for TF in the HR non-TIPS patients. Multivariate analysis revealed 2 independent predictors of TF: HVPG >20 mm Hg (odds ratio [OR], 1.247; 95% CI, 1.084–1.434) and CTP score (OR, 1.345; 95% CI, 1.037–1.745). A significant mortality difference (P < .001) was noted between the 2 groups at hospitalization (35% vs 5%), 6 weeks (38% vs 5%), and at 1 year (65% vs 17%). HVPG was a significantly better predictor of 6-week mortality than CTP (AUC of 0.904 for HVPG compared with 0.754 for CTP). Multivariate analysis demonstrated the following independent risk factors for 6-week mortality: HVPG >20 mm Hg (hazard ratio, 1.360), CTP score (hazard ratio, 1.467), and active bleeding at index endoscopy (hazard ratio, 0.129). Patients in the HR non-TIPS group also had a significantly greater number of complications (OR, 3.05; 95% CI, 1.19–7.85) and a greater number of patients requiring ICU care (OR, 6.80; 95% CI, 1.40–33.11). Comparison of the HR groups (TIPS vs non-TIPS) revealed similar baseline characteristics except for a higher mean serum bilirubin in the HR-TIPS group. Treatment failure was significantly reduced in the TIPS group (12% vs 50%; OR, 7.66; P = .003). Survival was significantly better in the TIPS group at index hospitalization (11% vs 31%; P = .02) and at 1 year (31% vs 65%; P = .01); 6-week mortality was also improved, but this did not reach statistical significance. Deaths caused by variceal bleeding were significantly reduced in the TIPS group over the follow-up period (4% vs 27%; OR, 9.21; P < .05). TIPS placement did not increase the rate of new onset hepatic encephalopathy in the treatment group. In the TIPS group, 19% of patients had complications related to TIPS placement, but none were fatal. From this study, the investigators concluded that the early measurement of HVPG reliably predicts TF and survival, and that early TIPS placement in a high-risk group defined by HVPG measurement reduces TF and improves survival. In this study, the authors address 2 important issues in the management of portal hypertensive complications: the utility of early HVPG measurement and the effectiveness of TIPS in the evaluation and treatment of variceal hemorrhage. Hepatic venous pressure measurement has been performed since the 1950s and has had an important role in portal hypertension research. The identification of a threshold portal pressure of 12 mm Hg, above which variceal bleeding can occur (Hepatology 1985;5:419–424), has allowed evaluation of prophylactic therapies that are currently the mainstay of hepatologic practice. Recent data using HVPG measurements have demonstrated that reduction in portal pressure to <12 mm Hg or to 20% below baseline is the key determinant of effectiveness in pharmacologic therapy for the prevention of variceal rebleeding (Lancet 1995;346:1056–1059, Gastroenterology 1990;99:1401–1407). The increased use of TIPS has led to more frequent measurements of HVPG because the decrease in HVPG is a measure of the effectiveness of shunt post-TIPS. The clinical use of HVPG measurement, however, has lagged behind its utility as a research tool, in part because of controversy surrounding interpretation and its performance in diverse settings (Hepatology 2004;39:280–282, 286–290, 295–298). The study by Monescillo et al uses early (≤24 hours after admission) measurement HVPG to stratify patients with acute variceal hemorrhage into high- and low-risk groups for rebleeding. Their observation that patients with HVPGs >20 mm Hg were at increased risk of TF compared to those with values <20 mm Hg corroborates previously published data (Gastroenterology 1999;117:626–631). Nevertheless, the predictive value of HVPG with respect to TF failure was not significantly different from that of the CTP score, a noninvasive, easily measured index of severity of liver dysfunction. HVPG, however, was superior to the CTP score for predicting 6-week survival, thus affirming its prognostic significance with respect to survival following acute variceal hemorrhage (Gastroenterology 1999;117:626–631, Gastroenterology 2002;123:1013–1019, Korean J Intern Med 2004;19:165–170). Assuming that early HVPG measurement is, in fact, a reliable predictor of TF and 6-week survival after variceal hemorrhage, issues related to the feasibility and costs associated with widespread use in the clinical setting must be considered. Although the authors describe the measurement of HVPG as “easy,” other authors have recently commented on the wide variability in both equipment and technical skill at centers routinely performing portal pressure measurements (Hepatology 2004;39:280–282). Variability in readings has also been shown to depend on the branch of the hepatic vein that is cannulated (Scand J Gastroenterol 2002;37:960–964). Added to this is the challenge of performing these studies in the urgent setting during active variceal hemorrhage, especially in centers that perform this procedure infrequently. Both patient safety and the financial cost of HVPG measurement need to be considered as well. If TF rates can be predicted nearly as well using CTP scores, then the better 6-week mortality prediction may not be of sufficient value to justify the routine use of HVPG measurement in acute variceal bleeding. It would be interesting to compare the predictive power of HVPG measurements to the model for end-stage liver disease (MELD) criteria, which are currently used to predict 3-month mortality in cirrhotic patients and determine placement on liver transplant lists (Liver Transplantation 2004;10[Suppl 2]:S2–S3). Despite these concerns, the present findings suggest that if performed accurately, early HVPG measurement may be able to guide us in the effective management of variceal hemorrhage (Hepatology 2004;39:283–285), but more data from well-designed randomized controlled trials is needed before this invasive procedure can be recommended as a standard practice. The second aim of this study was to evaluate early TIPS placement with respect to rebleeding and survival after acute variceal hemorrhage. Currently, TIPS is most often performed as a “salvage therapy” for refractory variceal bleeding after pharmacological therapy and at least 2 attempts at endoscopic therapy (Gastroenterology 2004;127:621–629). To date, 12 randomized controlled trials comparing TIPS to endoscopic therapy have been performed, and 11 of these were analyzed in a recent meta-analysis (Liver Transplantation 2003;9:207–217). TIPS was associated with a lower rebleeding rate in nearly all studies, but a mortality benefit was seen in only one (Hepatology 1999;29:27–32). The current study reports a significant mortality benefit in the HR-TIPS group compared with the HR non-TIPS arm. It should be noted, however, that of the 13 patients in the HR non-TIPS group who experienced TF, failure to control the index bleed rather than early rebleeding was responsible in 10; in contrast, failure to control acute bleeding with combined endoscopic and pharmacological therapy occurred in only 2 patients in the HR TIPS group, thus biasing the TF data in favor of the early TIPS arm. Furthermore, 5 patients (19%) in the HR non-TIPS group did not survive long enough to undergo either a second endoscopic procedure or salvage TIPS, again skewing the mortality data in favor of the early TIPS group. Thus, it is reasonable to conclude that the favorable outcome data for TIPS in this study should be interpreted cautiously. Complications of TIPS are uncommon in experienced hands, with a low rate of technical failure or procedural complications (Gastroenterology 2003;124:1700–1710). One of the most common adverse effects of TIPS, however, is the onset or worsening of hepatic encephalopathy, which was observed in 23%–55% of patients receiving TIPS in previously reported randomized controlled trials (Liver Transplantation 2003;9:207–217), significantly higher than in the patients treated with endoscopic therapy. The current study reports no increase in encephalopathy in the TIPS arm, a distinctly uncommon occurrence in past trials. A common difficulty with TIPS therapy is the incidence of shunt dysfunction over time, due to pseudointimal hyperplasia that gradually narrows the shunt lumen (Hepatology 1999;29:710–718, Hepatology 1998;28:22–32). This often requires revision of the TIPS to maintain patency. Although patients in this study were followed for 1 year, data on long-term shunt patency and need for TIPS revision were not presented. Interestingly, recent studies using polytetrafluoroethylene (PTFE)-coated stents in TIPS seems to greatly reduce the incidence of shunt dysfunction (Gastroenterology 2004;126:469–475). Future studies using these technically superior stents may improve the success rates of TIPS in controlling variceal bleeding and ascites. In conclusion, the study by Monescillo et al further supports the accuracy of HVPG measurements in identifying high-risk patients after variceal bleeding. The utility of this measurement, however, remains questionable, given the technical limitations of TIPS in less experienced centers along with the availability of noninvasive prognostic indices such as the CTP score. If measurement of HVPG can be standardized and performed more widely, HVPG may be a helpful addition to the CTP and MELD criteria for predicting mortality and perhaps improving our selection and listing of patients for transplantation. The conclusions regarding improved treatment success and survival in patients receiving early TIPS are difficult to interpret because of the large difference between the treatment arms with respect to control of acute hemorrhage. Further randomized controlled trials will be needed before early TIPS can be proven to improve survival after acute variceal hemorrhage. ReplyGastroenterologyVol. 128Issue 4PreviewIt is well established that CTP is a main determinant of survival and TF (Gastroenterology 1981;80:800–809). The HVPG measurement is a prognostic factor during variceal bleeding in cirrhotic patients (Gastroenterology 1991;100:1403–1410, Gastroenterology 1999;117:626–631). CTP and HVPG have their own disadvantages. However, we think there is no concern about the variability of HVPG measurements. In fact, our HVPG cut-off value is 19 mm Hg and the HVPG cut-off value in the study from Moitinho et al (Gastroenterology 1999;117:626–631) is 20 mm Hg, so the variability in both studies is less than 5%. Full-Text PDF