Hepatology : official journal of the American Association for the Study of Liver Diseases
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Randomized Controlled Trial Multicenter Study Comparative Study
Covered transjugular intrahepatic portosystemic shunt versus endoscopic therapy + β-blocker for prevention of variceal rebleeding.
Gastroesophageal variceal bleeding in patients with cirrhosis is associated with significant morbidity and mortality, as well as a high rebleeding risk. Limited data are available on the role of transjugular intrahepatic portosystemic shunt (TIPS) with covered stents in patients receiving standard endoscopic, vasoactive, and antibiotic treatment. In this multicenter randomized trial, long-term endoscopic variceal ligation (EVL) or glue injection + β-blocker treatment was compared with TIPS placement in 72 patients with a first or second episode of gastric and/or esophageal variceal bleeding, after hemodynamic stabilization upon endoscopic, vasoactive, and antibiotic treatment. Randomization was stratified according to Child-Pugh score. Kaplan-Meier (event-free) survival estimates were used for the endpoints rebleeding, death, treatment failure, and hepatic encephalopathy. During a median follow-up of 23 months, 10 (29%) of 35 patients in the endoscopy + β-blocker group, as compared to 0 of 37 (0%) patients in the TIPS group, developed variceal rebleeding (P = 0.001). Mortality (TIPS 32% vs. endoscopy 26%; P = 0.418) and treatment failure (TIPS 38% vs. endoscopy 34%; P = 0.685) did not differ between groups. Early hepatic encephalopathy (within 1 year) was significantly more frequent in the TIPS group (35% vs. 14%; P = 0.035), but during long-term follow-up this difference diminished (38% vs. 23%; P = 0.121). ⋯ In unselected patients with cirrhosis, who underwent successful endoscopic hemostasis for variceal bleeding, covered TIPS was superior to EVL + β-blocker for reduction of variceal rebleeding, but did not improve survival. TIPS was associated with higher rates of early hepatic encephalopathy.
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Randomized Controlled Trial
Thrombelastography-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy: A randomized, controlled trial.
Bleeding is a feared complication of invasive procedures in patients with cirrhosis and significant coagulopathy (as defined by routine coagulation tests) and is used to justify preprocedure use of fresh frozen plasma (FFP) and/or platelets (PLT). Thromboelastography (TEG) provides a more comprehensive global coagulation assessment than routine tests (international normalized ratio [INR] and platelet count), and its use may avoid unnecessary blood product transfusion in patients with cirrhosis and significant coagulopathy (defined in this study as INR >1.8 and/or platelet count <50 × 10(9) /L) who will be undergoing an invasive procedure. Sixty patients were randomly allocated to TEG-guided transfusion strategy or standard of care (SOC; 1:1 TEG:SOC). The TEG group would receive FFP if the reaction time (r) was >40 min and/or PLT if maximum amplitude (MA) was <30 mm. All SOC patients received FFP and/or PLT per hospital guidelines. Endpoints were blood product use and bleeding complications. Baseline characteristics of the two groups were similar. Per protocol, all subjects in the SOC group received blood product transfusions versus 5 in the TEG group (100% vs. 16.7%; P < 0.0001). Sixteen SOC (53.3%) received FFP, 10 (33.3%) PLT, and 4 (13.3%) both FFP and PLT. In the TEG group, none received FFP alone (P < 0.0001 vs. SOC), 2 received PLT (6.7%; P = 0.009 vs. SOC), and 3 both FFP and PLT (not significant). Postprocedure bleeding occurred in only 1 patient (SOC group) after large-volume paracentesis. ⋯ In patients with cirrhosis and significant coagulopathy before invasive procedures, TEG-guided transfusion strategy leads to a significantly lower use of blood products compared to SOC (transfusion guided by INR and platelet count), without an increase in bleeding complications. Remarkably, even in patients with significant coagulopathy, postprocedure bleeding was rare, indicating that TEG thresholds should be reevaluated.
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Randomized Controlled Trial Multicenter Study
Ledipasvir and sofosbuvir in patients with genotype 1 hepatitis C virus infection and compensated cirrhosis: An integrated safety and efficacy analysis.
Patients with hepatitis C virus (HCV) infection and cirrhosis are underrepresented in clinical trials of interferon-free regimens of direct-acting antiviral agents, making it difficult to optimize therapy. We performed a post-hoc analysis of data from seven clinical trials to evaluate the efficacy and safety of the fixed-dose combination of ledipasvir (LDV) and sofosbuvir (SOF), with and without ribavirin (RBV), in 513 treatment-naïve and previously treated patients with genotype 1 HCV and compensated cirrhosis. All patients received LDV-SOF for 12 or 24 weeks with or without RBV. We determined the rates of sustained virological response (SVR) 12 weeks after treatment (SVR12) overall and for subgroups. Of the 513 patients analyzed, 69% were previously treated and 47% had failed previous treatment with a protease-inhibitor regimen. Overall, 493 patients (96%; 95% confidence interval [CI]: 94%-98%) achieved SVR12, 98% of treatment-naïve and 95% of previously treated patients. SVR12 rates did not vary greatly by treatment duration (95% of patients receiving 12 weeks and 98% of patients receiving 24 weeks of treatment), nor by addition of RBV (95% of patients receiving LDV-SOF alone and 97% of those who received LDV-SOF plus RBV), although previously treated patients receiving 12 weeks of LDV-SOF without RBV had an SVR12 rate of 90%. One patient discontinued LDV-SOF because of an adverse event (AE). The most common AEs were headache (23%), fatigue (16%-19%), and asthenia (14%-16%). One patient (<1%) of those receiving LDV-SOF alone, and 4 (2%) of those receiving LDV-SOF plus RBV had treatment-related serious AEs. ⋯ This analysis suggests that 12 weeks of LDV-SOF is safe and effective for treatment-naïve patients with HCV genotype 1 and compensated cirrhosis. The relatively lower SVR in treatment-experienced patients treated with 12 weeks of LDV-SOF raises the question of whether these patients would benefit from adding RBV or extending treatment duration to 24 weeks.
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Randomized Controlled Trial
Randomized trial of interferon- and ribavirin-free ombitasvir/paritaprevir/ritonavir in treatment-experienced hepatitis C virus-infected patients.
Approximately 2 million Japanese individuals are infected with hepatitis C virus and are at risk for cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Patients in whom interferon (IFN)/ribavirin (RBV) therapy has failed remain at risk as effective therapeutic options are limited. This phase 2, randomized, open-label study evaluated an IFN- and RBV-free regimen of once-daily ombitasvir (ABT-267), an NS5A inhibitor, plus paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (paritaprevir/ritonavir), in pegylated IFN/RBV treatment-experienced Japanese patients with hepatitis C virus subtype 1b or genotype 2 infection. Patients without cirrhosis (aged 18-75 years) with subtype 1b infection received ombitasvir 25 mg plus paritaprevir/ritonavir 100/100 mg or 150/100 mg for 12 or 24 weeks; patients with genotype 2 infection received ombitasvir 25 mg plus paritaprevir/ritonavir 100/100 mg or 150/100 mg for 12 weeks. Sustained virologic response (SVR) at posttreatment week 24 (SVR24 ) was the primary endpoint. Adverse events were collected throughout the study. One hundred ten patients received ≥1 dose of study medication. In the subtype 1b cohort, SVR24 rates were high (88.9%-100%) regardless of paritaprevir dose or treatment duration. In the genotype 2 cohort, SVR24 rates were 57.9% and 72.2% with 100 mg and 150 mg of paritaprevir, respectively. The SVR24 rate was higher in patients with subtype 2a (90%) than 2b (27%). Concordance between SVR12 and SVR24 was 100%. The most common adverse events overall were nasopharyngitis (29%) and headache (14%). ⋯ In this difficult-to-treat population of patients in whom prior pegylated IFN/RBV had failed, ombitasvir/paritaprevir/ritonavir demonstrated potent antiviral activity with a favorable safety profile among Japanese patients with hepatitis C virus genotype 1b or 2a infection.
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Randomized Controlled Trial
Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial).
Ezetimibe inhibits intestinal cholesterol absorption and lowers low-density lipoprotein cholesterol. Uncontrolled studies have suggested that it reduces liver fat as estimated by ultrasound in nonalcoholic steatohepatitis (NASH). Therefore, we aimed to examine the efficacy of ezetimibe versus placebo in reducing liver fat by the magnetic resonance imaging-derived proton density-fat fraction (MRI-PDFF) and liver histology in patients with biopsy-proven NASH. In this randomized, double-blind, placebo-controlled trial, 50 patients with biopsy-proven NASH were randomized to either ezetimibe 10 mg orally daily or placebo for 24 weeks. The primary outcome was a change in liver fat as measured by MRI-PDFF in colocalized regions of interest within each of the nine liver segments. Novel assessment by two-dimensional and three-dimensional magnetic resonance elastography was also performed. Ezetimibe was not significantly better than placebo at reducing liver fat as measured by MRI-PDFF (mean difference between the ezetimibe and placebo arms -1.3%, P = 0.4). Compared to baseline, however, end-of-treatment MRI-PDFF was significantly lower in the ezetimibe arm (15%-11.6%, P < 0.016) but not in the placebo arm (18.5%-16.4%, P = 0.15). There were no significant differences in histologic response rates, serum alanine aminotransferase and aspartate aminotransferase levels, or longitudinal changes in two-dimensional and three-dimensional magnetic resonance elastography-derived liver stiffness between the ezetimibe and placebo arms. Compared to histologic nonresponders (25/35), histologic responders (10/35) had a significantly greater reduction in MRI-PDFF (-4.35 ± 4.9% versus -0.30 ± 4.1%, P < 0.019). ⋯ Ezetimibe did not significantly reduce liver fat in NASH. This trial demonstrates the application of colocalization of MRI-PDFF-derived fat maps and magnetic resonance elastography-derived stiffness maps of the liver before and after treatment to noninvasively assess treatment response in NASH.