A randomized trial to assess whether portal pressure guided therapy to prevent variceal rebleeding improves survival in cirrhosis.

Monitoring the hemodynamic response of portal pressure (PP) to drug therapy accurately stratifies the risk of variceal rebleeding (VRB). We assessed whether guiding therapy with hepatic venous pressure gradient (HVPG) monitoring may improve survival by preventing VRB. Patients with cirrhosis with controlled variceal bleeding were randomized to an HVPG-guided therapy group (N = 84) or to a control group (N = 86). In both groups, HVPG and acute ß-blocker response were evaluated at baseline and HVPG measurements were repeated at 2-4 weeks to determine chronic response. In the HVPG-guided group, acute responders were treated with nadolol and acute nonresponders with nadolol+nitrates. Chronic nonresponders received nadolol+prazosin and had a third HVPG study. Ligation sessions were repeated until response was achieved. The control group was treated with nadolol+nitrates+ligation. Between-group baseline characteristics were similar. During long-term follow-up (median of 24 months), mortality was lower in the HVPG-guided therapy group than in the control group (29% vs. 43%; hazard ratio [HR] = 0.59; 95% confidence interval [CI] = 0.35-0.99). Rebleeding occurred in 19% versus 31% of patients, respectively (HR = 0.53; 95% CI = 0.29-0.98), and further decompensation of cirrhosis occurred in 52% versus 72% (HR = 0.68; 95% CI = 0.46-0.99). The survival probability was higher with HVPG-guided therapy than in controls, both in acute (HR = 0.59; 95% CI = 0.32-1.08) and chronic nonresponders (HR = 0.48; 95% CI = 0.23-0.99). HVPG-guided patients had a greater reduction of HVPG and a lower final value than controls (P < 0.05). CONCLUSION: HVPG monitoring, by stratifying risk and targeting therapy, improves the survival achieved with currently recommended treatment to prevent VRB using ß-blockers and ligation. HVPG-guided therapy achieved a greater reduction in PP, which may have contributed to reduce the risk of rebleeding and of further decompensation of cirrhosis, thus contributing to a better survival. (Hepatology 2017;65:1693-1707).

Relative adrenal insufficiency in severe acute variceal and non-variceal bleeding: influence on outcomes.

BACKGROUND & AIMS: Relative adrenal insufficiency (RAI) is common in critical illness and in cirrhosis, and is related with worse outcomes. The prevalence of RAI may be different in variceal and non-variceal bleeding and whether it may influence outcomes in these settings is unclear. This study assesses RAI and its prognostic implications in cirrhosis with variceal bleeding and in peptic ulcer bleeding. METHODS: Patients with severe bleeding (systolic pressure <100 mmHg and/or haemoglobin <8 g/L) from oesophageal varices or from a peptic ulcer were included. Adrenal function was evaluated within the first 24 h and RAI was diagnosed as delta cortisol <250 nmol/L after 250 µg of i.v. corticotropin. RESULTS: Sixty-two patients were included, 36 had cirrhosis and variceal bleeding and 26 without cirrhosis had ulcer bleeding. Overall, 15 patients (24%) had RAI, 8 (22%) with variceal and 7 (24%) with ulcer bleeding. Patients with RAI had higher rate of bacterial infections. Baseline serum and salivary cortisol were higher in patients with RAI (P < 0.001) while delta cortisol was lower (P < 0.001). There was a good correlation between plasma and salivary cortisol (P < 0.001). The probability of 45-days survival without further bleeding was lower in cirrhotic patients with variceal bleeding and RAI than in those without RAI (25% vs 68%, P = 0.02), but not in non-cirrhotic patients with peptic ulcer bleeding with or without RAI (P = 0.75). CONCLUSION: The prevalence of RAI is similar in ulcer bleeding and in cirrhosis with variceal bleeding. Cirrhotic patients with RAI, but not those with bleeding ulcers, have worse prognosis.

Drugs plus ligation to prevent rebleeding in cirrhosis: an updated systematic review.

BACKGROUND & AIMS: Combined therapy with endoscopic variceal ligation (EVL) and ß-blockers ± isosorbide mononitrate (ISMN) is currently recommended to prevent variceal rebleeding. However, the role of this combined therapy has been challenged by some studies. We performed a systematic review to assess the value of combined therapy with EVL and ß-blockers ± ISMN as compared with each treatment alone to prevent rebleeding. METHODS: Databases, references and meeting abstracts were searched to retrieve randomized trials comparing combined therapy with EVL and ß-blockers ± ISMN vs either treatment alone, to prevent variceal rebleeding in cirrhosis. Random-effects model was used for meta-analysis. RESULTS: We identified five studies comparing EVL alone or combined with drugs, including a total of 476 patients. Combination therapy reduced overall rebleeding [risk ratios (RR) = 0.44, 95% confidence interval (CI) = 0.28-0.69], and showed a trend towards lower mortality (RR = 0.58, 95% CI = 0.33-1.03), without increasing complications. We identified four trials comparing drugs alone or associated with EVL, including 409 patients. All used ß-blockers plus ISMN. Variceal rebleeding decreased with combined therapy (P < 0.01) but rebleeding from oesophageal ulcers increased (P = 0.01). Overall, there was a trend towards lower rebleeding (RR = 0.76, 95% CI = 0.58-1.00) without effect on mortality (RR = 1.24, 95% CI = 0.90-1.70). CONCLUSIONS: The addition of drug therapy to EVL improves the efficacy of EVL alone. However, the addition of EVL to ß-blockers and ISMN achieves a non-significant decrease of rebleeding with no effect on mortality. Although combination therapy with EVL plus ß-blockers ± ISMN is adequate to prevent rebleeding, ß-blockers + ISMN alone may be a valid alternative.

Transfusion strategies for acute upper gastrointestinal bleeding.

BACKGROUND: The hemoglobin threshold for transfusion of red cells in patients with acute gastrointestinal bleeding is controversial. We compared the efficacy and safety of a restrictive transfusion strategy with those of a liberal transfusion strategy. METHODS: We enrolled 921 patients with severe acute upper gastrointestinal bleeding and randomly assigned 461 of them to a restrictive strategy (transfusion when the hemoglobin level fell below 7 g per deciliter) and 460 to a liberal strategy (transfusion when the hemoglobin fell below 9 g per deciliter). Randomization was stratified according to the presence or absence of liver cirrhosis. RESULTS: A total of 225 patients assigned to the restrictive strategy (51%), as compared with 61 assigned to the liberal strategy (14%), did not receive transfusions (P<0.001) [corrected].The probability of survival at 6 weeks was higher in the restrictive-strategy group than in the liberal-strategy group (95% vs. 91%; hazard ratio for death with restrictive strategy, 0.55; 95% confidence interval [CI], 0.33 to 0.92; P=0.02). Further bleeding occurred in 10% of the patients in the restrictive-strategy group as compared with 16% of the patients in the liberal-strategy group (P=0.01), and adverse events occurred in 40% as compared with 48% (P=0.02). The probability of survival was slightly higher with the restrictive strategy than with the liberal strategy in the subgroup of patients who had bleeding associated with a peptic ulcer (hazard ratio, 0.70; 95% CI, 0.26 to 1.25) and was significantly higher in the subgroup of patients with cirrhosis and Child-Pugh class A or B disease (hazard ratio, 0.30; 95% CI, 0.11 to 0.85), but not in those with cirrhosis and Child-Pugh class C disease (hazard ratio, 1.04; 95% CI, 0.45 to 2.37). Within the first 5 days, the portal-pressure gradient increased significantly in patients assigned to the liberal strategy (P=0.03) but not in those assigned to the restrictive strategy. CONCLUSIONS: As compared with a liberal transfusion strategy, a restrictive strategy significantly improved outcomes in patients with acute upper gastrointestinal bleeding. (Funded by Fundació Investigació Sant Pau; ClinicalTrials.gov number, NCT00414713.).

Current endoscopic therapy of variceal bleeding.

Variceal ligation has proved more effective and safer than sclerotherapy and is currently the endoscopic treatment of choice for oesophageal varices. In acute bleeding, vasoactive drugs should be started before endoscopy and maintained for 2-5 days. The efficacy of drugs is improved when associated with emergency endoscopic therapy. Antibiotic prophylaxis should also be used. To prevent rebleeding, both endoscopic ligation and the combination of beta-blockers and nitrates may be used. Adding beta-blockers improves the efficacy of ligation. Haemodynamic responders to beta-blockers+/-nitrates (those with a decrease in portal pressure gradient HVPG to <12 mmHg or by >20% of baseline) have a marked reduction in the risk of haemorrhage and will not need further treatment. Beta-blockers significantly reduce the risk of a first haemorrhage in patients with large varices, and they improve survival. As compared to beta-blockers, endoscopic ligation reduces the risk of first bleeding without affecting mortality, and should be used in patients with contraindications or intolerance to beta-blockers.