Rosa Maria Morillas

Paracentesis with Intravenous Infusion of Albumin as Compared with Peritoneovenous Shunting in Cirrhosis with Refractory Ascites

BACKGROUND There is no satisfactory treatment for refractory ascites in patients with cirrhosis. Both peritoneovenous shunts and paracentesis have been used, but there is uncertainty about their relative merits. METHODS We studied 89 patients with cirrhosis and refractory ascites who were randomly assigned to receive either repeated large-volume paracentesis plus intravenous albumin or a LeVeen peritoneovenous shunt. Patients in the paracentesis group in whom recurrent tense ascites developed during follow-up were treated with paracentesis, and those in the peritoneovenous-shunt group with diuretic agents or by the insertion of a new shunt if there was shunt obstruction. RESULTS During the first hospitalization, ascites was removed in all 41 patients in the paracentesis group and in 44 of the 48 patients in the peritoneovenous-shunt group. The mean (+/- SD) duration of hospitalization in the two groups was 11 +/- 5 and 19 +/- 9 days, respectively (P less than 0.01). There were no significant differences in the number of patients who had complications or died. During follow-up, 37 patients in each group were hospitalized again. In the paracentesis group, the number of rehospitalizations for any reason (174 vs. 97 in the peritoneovenous-shunt group) or for ascites (125 vs. 38) was significantly higher, and the median time to a first readmission for any reason (1 +/- 1 vs. 2 +/- 2 months) or for ascites (2 +/- 2 vs. 8 +/- 17 months) was significantly shorter than in the peritoneovenous-shunt group. The total times in the hospital during follow-up, however, were similar in the two groups (48 +/- 49 and 44 +/- 39 days, respectively). Three patients had obstructions of their peritoneovenous shunts during their first hospitalizations, and 15 patients had a total of 20 obstructions during follow-up. Survival was similar in both groups. CONCLUSIONS The LeVeen shunt and paracentesis are equally effective in relieving refractory ascites. The former may provide better long-term control of ascites, but shunt occlusion is common and survival is not improved.

Spironolactone alone or in combination with furosemide in the treatment of moderate ascites in nonazotemic cirrhosis. A randomized comparative study of efficacy and safety

BACKGROUND/AIMS The most rational treatment of moderate ascites is spironolactone alone or in combination with furosemide. However, it is unknown which of these two treatment schedules is preferable. METHODS One hundred nonazotemic cirrhotic patients with moderate ascites were randomly assigned to be treated with spironolactone and furosemide (Group 1: 50 patients) or with spironolactone alone (Group 2: 50 patients). If no response was obtained, the doses of diuretics were increased up to 400 mg/day of spironolactone and 160 mg/day of furosemide. In patients of group 2 not responding to 400 mg/day of spironolactone, furosemide was added. In cases with an excessive response, the dosage of diuretics was reduced. RESULTS The response rate (98% in Group 1 vs. 94% in Group 2), the rapidity of ascites mobilization and the incidence of complications induced by diuretic therapy was similar in both groups. The need to reduce the diuretic dosage was significantly higher in Group 1 than Group 2 (68% vs. 34%; P=0.002). CONCLUSIONS In the treatment of moderate ascites, spironolactone alone seems to be as safe and effective as spironolactone associated with furosemide. Since spironolactone alone requires less dose adjustment, it would be more suitable for treating ascites on an outpatient basis.

Obesity is an independent risk factor for clinical decompensation in patients with cirrhosis

Obesity is associated with an aggressive course in chronic viral hepatitis; however, its impact in the development of clinical decompensation (CD) in patients with established cirrhosis is uncertain. We evaluated the role of obesity, in relationship to other recognized predictors, in the development of CD in patients with compensated cirrhosis. The study population, a subset of patients included in a randomized trial of beta‐blockers in the prevention of varices in whom data on body mass index (BMI) was available, consisted of 161 patients with compensated cirrhosis. Laboratory tests and portal pressure (assessed by the hepatic venous pressure gradient or HVPG) were assessed on inclusion. Patients were followed until CD (ascites, hepatic encephalopathy, or variceal hemorrhage), or until September 2002. Altogether, 29% had a normal BMI, 40% were overweight, and 30% were obese. In a median follow‐up of 59 months, CD occurred in 48/161 (30%) patients with an increasingly higher rate according to BMI group (15% in those with normal BMI; 31% in overweight; 43% in obese patients, P = 0.011). The actuarial probability of developing CD was significantly higher in the abnormal BMI groups (P = 0.022). In a multivariate model that included parameters previously identified as being predictive of CD (HVPG, albumin, Mayo endstage liver disease score), etiology, and treatment group, BMI (hazard ration 1.06; 95% confidence interval 1.01‐1.12), P = 0.02] was an independent predictor of decompensation, together with HVPG and albumin. Conclusion: Obesity has a deleterious effect on the natural history of compensated cirrhosis of all etiologies, independent of portal pressure and liver function. Weight reduction may be a valuable therapeutic measure in this patient population. (HEPATOLOGY 2011;)

Nadolol plus isosorbide mononitrate alone or associated with band ligation in the prevention of recurrent bleeding: a multicentre randomised controlled trial

Background and aims: Previous clinical trials suggest that adding non-selective beta-blockers improves the efficacy of endoscopic band ligation (EBL) in the prevention of recurrent bleeding, but no study has evaluated whether EBL improves the efficacy of beta-blockers + isosorbide-5-mononitrate. The present study was aimed at evaluating this issue in a multicentre randomised controlled trial (RCT) and to correlate changes in hepatic venous pressure gradient (HVPG) during treatment with clinical outcomes Methods: 158 patients with cirrhosis, admitted because of variceal bleeding, were randomised to receive nadolol+isosorbide-5-mononitrate alone (Drug: n = 78) or combined with EBL (Drug+EBL; n = 80). HVPG measurements were performed at randomisation and after 4–6 weeks on medical therapy. Results: Median follow-up was 15 months. One-year probability of recurrent bleeding was similar in both groups (33% vs 26%: p = 0.3). There were no significant differences in survival or need of rescue shunts. Overall adverse events or those requiring hospital admission were significantly more frequent in the Drug+EBL group. Recurrent bleeding was significantly more frequent in HVPG non-responders than in responders (HVPG reduction ⩾20% or ⩽12 mm Hg). Among non-responders recurrent bleeding was similar in patients treated with Drugs or Drugs+EBL. Conclusions: Adding EBL to pharmacological treatment did not reduce recurrent bleeding, the need for rescue therapy, or mortality, and was associated with more adverse events. Furthermore, associating EBL to drug therapy did not reduce the high rebleeding risk of HVPG non-responders. ISRCTN26221020

Portacaval shunt versus endoscopic sclerotherapy in the elective treatment of variceal hemorrhage.

Eighty-two consecutive Child-Campbell class A and B cirrhotic patients were included in a prospective controlled trial to assess the efficacy and safety of portacaval anastomosis vs. endoscopic sclerotherapy as elective treatment of variceal hemorrhage. Forty-one patients were randomized to portacaval anastomosis and 41 to sclerotherapy. After excluding dropouts, 34 patients were treated with portacaval anastomosis and 35 with sclerotherapy. The incidence of variceal rebleeding during follow-up (mean +/- SD, 20.6 +/- 14.2 months) was significantly higher in the sclerotherapy than in the portacaval groups, either considering the overall treated group or only patients completing sclerotherapy (40% and 25% vs. 2.9%; P = 0.0002 and P = 0.01, respectively). The 2-year probability of suffering from at least one episode of hepatic encephalopathy was significantly higher in patients submitted to portacaval anastomosis than in those treated with endoscopic sclerotherapy (40% vs. 12%; P = 0.04). However, disabling encephalopathy only appeared in 3 of 34 patients who underwent surgery (8.8%). Early and long-term mortality did not differ between the therapeutic groups; 2-year survival rates were 83% for portacaval anastomosis and 79% for sclerotherapy. It is concluded that portacaval anastomosis is more effective than endoscopic sclerotherapy in preventing variceal rebleeding in spite of the greater incidence of hepatic encephalopathy. The role of portacaval anastomosis in the elective treatment of variceal rebleeding should be reassessed.

Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial

BACKGROUND The once-daily, ribavirin-free, pangenotypic, direct-acting antiviral regimen, glecaprevir coformulated with pibrentasvir, has shown high rates of sustained virological response in phase 2 and 3 studies. We aimed to assess the efficacy and safety of 12 weeks of coformulated glecaprevir and pibrentasvir in patients with hepatitis C virus (HCV) infection and compensated cirrhosis. METHODS We did this single-arm, open-label, multicentre phase 3 study at 40 sites in Belgium, Canada, Germany, South Africa, Spain, and the USA. We enrolled patients aged 18 years or older with HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. Patients were either HCV treatment-naive or had not responded to treatment with interferon or pegylated interferon with or without ribavirin, or sofosbuvir plus ribavirin with or without pegylated interferon. Oral glecaprevir (300 mg) coformulated with pibrentasvir (120 mg) was administered once daily for 12 weeks. The primary efficacy endpoint was sustained virological response at post-treatment week 12 (HCV RNA <15 IU/mL). We assessed efficacy and safety in all patients who received at least one dose of study drug (intention-to-treat population). This study is registered with ClinicalTrials.gov, number NCT02642432. FINDINGS Between Dec 7, 2015, and May 4, 2016, we enrolled 146 patients with compensated cirrhosis, of whom 48 (33%) had genotype 1a HCV infection, 39 (27%) had genotype 1b infection, 34 (23%) had genotype 2 infection, 16 (11%) had genotype 4 infection, two (1%) had genotype 5 infection, and seven (5%) had genotype 6 infection. 12 weeks after treatment, 145 patients (99%, 95% CI 98-100) achieved sustained virological response, with one (1%) relapse at post-treatment week 8. We recorded 101 (69%) adverse events, of which 65 (64%) were mild. The most common adverse events were fatigue (n=28 [19%]) and headache (n=20 [14%]). 11 (8%) patients had serious adverse events, none of which were deemed related to study drugs. No patients had elevations in alanine aminotransferase and no patients prematurely discontinued treatment because of adverse events. INTERPRETATION Our results show that 99% of patients treated with once-daily glecaprevir plus pibrentasvir achieved a sustained virological response at 12 weeks. Furthermore, this drug regimen had a favourable safety profile in previously treated or untreated patients with chronic HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. These findings could help simplify treatment algorithms and reduce treatment burden. FUNDING AbbVie.

Incidence and Prognosis of Different Types of Functional Renal Failure in Cirrhotic Patients With Ascites

BACKGROUND & AIMS Hepatorenal syndrome is a well-characterized type of terminal renal failure that occurs in patients with cirrhosis with ascites. Information about other types of functional renal failure in these patients is scarce. We assessed the incidence and prognosis of different types of functional renal failure in cirrhotic patients with ascites and investigated prognostic factors for these disorders. METHODS Consecutive cirrhotic patients (n = 263) were followed for 41 +/- 3 months after their first incidence of ascites. Three types of functional renal failure were considered: pre-renal failure (when renal failure was associated with a depletion of intravascular volume), renal failure induced by infection that did not result in hepatorenal syndrome, and hepatorenal syndrome. RESULTS During the follow-up period, 129 (49%) patients developed some type of functional renal failure. The most frequent was pre-renal failure (27.4%), followed by renal failure induced by infection (14.1%), and then hepatorenal syndrome (7.6%). The 1-year probability of developing the first episode of any functional renal failure was 23.6%. The independent predictors of functional renal failure development were baseline age, Child-Pugh score, and serum creatinine. Although the 1-year probability of survival was 91% in patients without renal failure, it decreased to 46.9% in those patients who developed any functional renal failure (P = .0001). CONCLUSIONS Approximately 50% of the cirrhotic patients with ascites developed some type of functional renal failure during the follow-up period; renal failure was associated with worse prognosis. Efforts should be made to prevent renal failure in cirrhotic patients with ascites.

Esophageal balloon tamponade versus esophageal stent in controlling acute refractory variceal bleeding: A multicenter randomized, controlled trial

Balloon tamponade is recommended only as a “bridge” to definitive therapy in patients with cirrhosis and massive or refractory esophageal variceal bleeding (EVB), but is frequently associated with rebleeding and severe complications. Preliminary, noncontrolled data suggest that a self‐expandable, esophageal covered metal stent (SX‐ELLA Danis; Ella‐CS, Hradec Kralove, Czech Republic) may be an effective and safer alternative to balloon tamponade. We conducted a randomized, controlled trial aimed at comparing esophageal stent versus balloon tamponade in patients with cirrhosis and EVB refractory to medical and endoscopic treatment. Primary endpoint was success of therapy, defined as survival at day 15 with control of bleeding and without serious adverse events (SAEs). Twenty‐eight patients were randomized to Sengstaken‐Blakemore tube (n = 15) or SX‐ELLA Danis stent (n = 13). Patients were comparable in severity of liver failure, active bleeding at endoscopy, and initial therapy. Success of therapy was more frequent in the esophageal stent than in balloon tamponade group (66% vs. 20%; P = 0.025). Moreover, control of bleeding was higher (85% vs. 47%; P = 0.037) and transfusional requirements (2 vs 6 PRBC; P = 0.08) and SAEs lower (15% vs. 47%; P = 0.077) in the esophageal stent group. TIPS was used more frequently in the tamponade group (4 vs. 10; P = 0.12). There were no significant differences in 6‐week survival (54% vs. 40%; P = 0.46). Conclusion: Esophageal stents have greater efficacy with less SAEs than balloon tamponade in the control of EVB in treatment failures. Our findings favor the use of esophageal stents in patients with EVB uncontrolled with medical and endoscopic treatment. (Hepatology 2016;63:1957‐1967)

Development of hyperdynamic circulation and response to β-blockers in compensated cirrhosis with portal hypertension.

Nonselective β‐blockers are useful to prevent bleeding in patients with cirrhosis and large varices but not to prevent the development of varices in those with compensated cirrhosis and portal hypertension (PHT). This suggests that the evolutionary stage of PHT may influence the response to β‐blockers. To characterize the hemodynamic profile of each stage of PHT in compensated cirrhosis and the response to β‐blockers according to stage, we performed a prospective, multicenter (tertiary care setting), cross‐sectional study. Hepatic venous pressure gradient (HVPG) and systemic hemodynamic were measured in 273 patients with compensated cirrhosis before and after intravenous propranolol (0.15 mg/kg): 194 patients had an HVPG ≥10 mm Hg (clinically significant PHT [CSPH]), with either no varices (n = 80) or small varices (n = 114), and 79 had an HVPG >5 and <10 mm Hg (subclinical PHT). Patients with CSPH had higher liver stiffness (P < 0.001), worse Model for End‐Stage Liver Disease score (P < 0.001), more portosystemic collaterals (P = 0.01) and splenomegaly (P = 0.01) on ultrasound, and lower platelet count (P < 0.001) than those with subclinical PHT. Patients with CSPH had lower systemic vascular resistance (1336 ± 423 versus 1469 ± 335 dyne · s · cm‐5, P < 0.05) and higher cardiac index (3.3 ± 0.9 versus 2.8 ± 0.4 L/min/m2, P < 0.01). After propranolol, the HVPG decreased significantly in both groups, although the reduction was greater in those with CSPH (‐16 ± 12% versus ‐8 ± 9%, P < 0.01). The HVPG decreased ≥10% from baseline in 69% of patients with CSPH versus 35% with subclinical PHT (P < 0.001) and decreased ≥20% in 40% versus 13%, respectively (P = 0.001). Conclusion: Patients with subclinical PHT have less hyperdynamic circulation and significantly lower portal pressure reduction after acute β‐blockade than those with CSPH, suggesting that β‐blockers are more suitable to prevent decompensation of cirrhosis in patients with CSPH than in earlier stages. (Hepatology 2016;63:197–206)

Effectiveness, safety and clinical outcomes of direct-acting antiviral therapy in HCV genotype 1 infection: results from a Spanish real world cohort.

BACKGROUND & AIMS Clinical trials evaluating second-generation direct-acting antiviral agents (DAAs) have shown excellent rates of sustained virologic response (SVR) and good safety profiles in patients with chronic hepatitis C virus (HCV) genotype 1 infection. We aimed to investigate the effectiveness and safety of two oral DAA combination regimens, ombitasvir/paritaprevir/ritonavir plus dasabuvir (OMV/PTV/r+DSV) and ledipasvir/sofosbuvir (LDV/SOF), in a real-world clinical practice. METHODS Data from HCV genotype 1 patients treated with either OMV/PTV/r+DSV±ribavirin (RBV) (n=1567) or LDV/SOF±RBV (n=1758) in 35 centers across Spain between April 1, 2015 and February 28, 2016 were recorded in a large national database. Demographic, clinical and virological data were analyzed. Details of serious adverse events (SAEs) were recorded. RESULTS The two cohorts were not matched with respect to baseline characteristics and could not be compared directly. The SVR12 rate was 96.8% with OMV/PTVr/DSV±RBV and 95.8% with LDV/SOF±RBV. No significant differences were observed in SVR according to HCV subgenotype (p=0.321 [OMV/PTV/r+DSV±RBV] and p=0.174 [LDV/SOF]) or degree of fibrosis (c0.548 [OMV/PTV/r/DSV±RBV] and p=0.085 [LDV/SOF]). Only baseline albumin level was significantly associated with failure to achieve SVR (p<0.05) on multivariate analysis. Rates of SAEs and SAE-associated treatment discontinuation were 5.4% and 1.7%, in the OMV/PTV/r+DSV subcohort and 5.5% and 1.5% in the LDV/SOF subcohort, respectively. Hepatocellular carcinoma (HCC) recurred in 30% of patients with a complete response to therapy for previous HCC. Incident HCC was reported in 0.93%. CONCLUSIONS In this large cohort of patients managed in the real-world setting in Spain, OMV/PTV/r+DSV and LDV/SOF achieved high rates of SVR12, comparable to those observed in randomized controlled trials, with similarly good safety profiles. LAY SUMMARY In clinical trials, second-generation direct-acting antiviral agents (DAAs) have been shown to cure over 90% of patients chronically infected with the genotype 1 hepatitis C virus and have been better tolerated than previous treatment regimens. However, patients enrolled in clinical trials do not reflect the real patient population encountered in routine practice. The current study, which includes almost 4,000 patients, demonstrates comparable rates of cure with two increasingly used DAA combinations as those observed in the clinical trial environment, confirming that clinical trial findings with DAAs translate into the real-world setting, where patient populations are more diverse and complex.