Fulvio Spirito

Incidence rates of post-ERCP complications: A systematic survey of prospective studies

OBJECTIVES:To provide health-care providers, patients, and physicians with an exhaustive assessment of prospective studies on rates of complications and fatalities associated with endoscopic retrograde cholangiopancreatography (ERCP).METHODS:We searched MEDLINE (1977–2006) for prospective surveys on adult patients undergoing ERCP. “Grey literature” was sought by looking at cited references to identify further relevant studies. Data on postprocedural pancreatitis, bleeding, infections, perforations, and miscellaneous events as well as their associated fatalities were extracted independently by two reviewers. Sensitivity analysis was performed to test for data consistency between multicenter versus single center studies, and old (1977–1996) versus recent (1997–2005) reports.RESULTS:In 21 selected surveys, involving 16,855 patients, ERCP-attributable complications totaled 1,154 (6.85%, CI 6.46–7.24%), with 55 fatalities (0.33%, CI 0.24–0.42%). Mild-to-moderate events occurred in 872 patients (5.17%, CI 4.83–5.51%), and severe events in 282 (1.67%, CI 1.47–1.87%). Pancreatitis occurred in 585 subjects (3.47%, CI 3.19–3.75%), infections in 242 (1.44%, CI 1.26–1.62%), bleeding in 226 (1.34%, CI 1.16–1.52%), and perforations in 101 (0.60%, CI 0.48–0.72%). Cardiovascular and/or analgesia-related complications amounted to 173 (1.33%, CI 1.13–1.53%), with 9 fatalities (0.07%, CI 0.02–0.12%). As compared with old reports, morbidity rates increased significantly in most recent studies: 6.27% versus 7.51% (Pc = 0.029).CONCLUSIONS:ERCP remains the endoscopic procedure that carries a high risk for morbidity and mortality. Complications continue to occur at a relatively consistent rate. The majority of events are of mild-to-moderate severity.

Individualized treatment duration for hepatitis C genotype 1 patients: A randomized controlled trial

It was hypothesized that in hepatitis C virus (HCV) genotype 1 patients, variable treatment duration individualized by first undetectable HCV RNA is as effective as standard 48‐week treatment. Patients (n = 696) received peginterferon alfa‐2a, 180 mg/week, or peginterferon alfa‐2b, 1.5 mg/kg/week, plus ribavirin, 1000‐1200 mg/day, for 48 weeks (standard, n = 237) or for 24, 48, or 72 weeks if HCV‐RNA–negative at weeks 4, 8, or 12, respectively (variable, n = 459). Sustained virologic response (SVR) was achieved in 45.1% [95% confidence interval (CI) 38.8‐51.4] of the patients in the standard group and in 48.8% (CI 44.2‐53.3) of the patients in the variable group (P = 0.37). The percentages of patients who first achieved undetectable HCV RNA at weeks 4, 8, or 12 were 26.7%, 27.8%, and 11.3%, respectively. In the standard treatment group, 87.1%, 70.3%, and 38.1% of patients who first achieved undetectable HCV RNA at 4, 8, or 12 weeks attained SVRs, respectively. In the variable group, corresponding SVR rates were 77.2%, 71.9%, and 63.5%. Low viremia levels and young age were independent predictors of response at week 4 [rapid virologic response (RVR)]. RVR patients with baseline viremia ≥400,000 IU/mL achieved higher SVR rates when treated for 48 weeks rather than 24 weeks (86.8% versus 73.1%, P = 0.14). The only predictive factor of SVR in RVR patients was advanced fibrosis. Conclusion: Variable treatment duration ensures SVR rates similar to those of standard treatment duration, sparing unnecessary side effects and costs. (HEPATOLOGY 2007.)

Pharmacologic treatment can prevent pancreatic injury after ERCP: a meta-analysis

BACKGROUND The identification of therapeutic agents that can prevent the pancreatic injury after endoscopic retrograde cholangiopancreatography (ERCP) is of considerable importance. METHODS We performed a meta-analysis including 28 clinical trials on the use of somatostatin (12 studies), octreotide (10 studies), and gabexate mesilate (6 studies) after ERCP. Outcome measures evaluated were the incidence of acute pancreatitis, hyperamylasemia, and pancreatic pain. Three analyses were run separately: for all available studies, for randomized trials only, and for only those studies published as complete reports. RESULTS When all available studies were analyzed, somatostatin and gabexate mesilate were significantly associated with improvements in all three outcomes. Odds ratios (OR) for gabexate mesilate were 0.27 (95% CI [0.13, 0. 57], p = 0.001) for acute pancreatitis, 0.66 (95% CI [0.48, -0.89], p = 0.007) for hyperamylasemia, and 0.33 (95% CI [0.18, 0.58], p = 0. 0005) for post-procedural pain. Somatostatin reduced acute pancreatitis (OR 0.38: 95% CI [0.22, 0.65], p < 0.001), pain (OR 0. 24: 95% CI [0.14, 0.42], p < 0.001), and hyperamylasemia (OR 0.65: 95% CI [0.48, 0.90], p = 0.008). Octreotide was associated only with a reduced risk of post-ERCP hyperamylasemia (OR 0.51: 95% CI [0.31, 0.83], p = 0.007) but had no effect on acute pancreatitis and pain. The statistical significance of data did not change after analyzing randomized trials only or studies published as complete reports. For each considered outcome, the publication bias assessment and the number of patients that need to be treated to prevent one adverse effect were, respectively, higher and lower for somatostatin than for gabexate mesilate. CONCLUSIONS The pancreatic injury after ERCP can be prevented with the administration of either somatostatin or gabexate mesilate, but the former agent is more cost-effective. Additional studies comparing the efficacy of short-term infusion of somatostatin versus gabexate mesilate in patients at high risk for post-ERCP complications seem warranted.

Prophylaxis of ERCP-related pancreatitis: A randomized, controlled trial of somatostatin and gabexate mesylate

BACKGROUND & AIMS It still is debated whether post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis can be prevented by administering either somatostatin or gabexate mesylate. The aim of the study is to assess the efficacy of a 6.5-hour infusion of somatostatin or gabexate mesylate in preventing ERCP-related complications. METHODS In a double-blind multicenter trial, 1127 patients undergoing ERCP were randomly assigned to intravenous administration of somatostatin (750 microg; n = 351), gabexate mesylate (500 mg; n = 381), or placebo (saline; n = 395). The drug infusion started 30 minutes before and continued for 6 hours after endoscopy. Patients were evaluated clinically, and serum amylase levels were determined at 4, 24, and 48 hours after endoscopy. RESULTS No significant differences in incidences of pancreatitis, hyperamylasemia, or abdominal pain were observed among the placebo (4.8%, 32.6%, and 5.3%, respectively), somatostatin (6.3%, 26.8%, and 5.1%, respectively), and gabexate mesylate groups (5.8%, 31.5%, and 6.3%, respectively). Univariate analysis of patient characteristics and endoscopic maneuvers showed that a Freeman score >1 (P < 0.0001), >/=3 pancreatic injections (P < 0.00001), and precut sphincterotomy (P = 0.01) were significantly associated with post-ERCP pancreatitis. At multiple logistic regression analysis, >/=3 pancreatic injections (odds ratio [OR], 1.95; 95% confidence interval [CI], 1.45-2.63) and a Freeman score >1 (OR, 1.47; 95% CI, 1.11-1.94) retained their predictive power. CONCLUSIONS Long-term (6.5-hr) administration of either somatostatin or gabexate mesylate is ineffective for the prevention of post-ERCP pancreatitis. Pancreatic injury seems to be related to difficulty in common bile duct access.

A randomized controlled trial of pegylated interferon alpha-2a (40 KD) or interferon alpha-2a plus ribavirin and amantadine vs interferon alpha-2a and ribavirin in treatment-naïve patients with chronic hepatitis C.

Summary.  We determined whether triple therapy comprising amantadine (AMA), ribavirin (RBV) and either peginterferon (PEG‐IFN) α‐2a or conventional IFN α‐2a would improve sustained virological response (SVR) rates over dual therapy with IFN α‐2a and RBV in patients with chronic HCV infection. A total of 362 treatment‐naïve patients were randomized to 48 weeks of treatment with: PEG‐IFN α‐2a 180 μg/week (group A) or IFN α‐2a 3 MU tiw (groups B and C). All patients received RBV 1000 or 1200 mg/day and those in groups A and B received AMA 200 mg/day. SVR was defined as an undetectable HCV RNA after 24 weeks of untreated follow‐up. At the end of therapy, 74.4% (95% CI 0.66–0.82) of patients in group A were HCV RNA‐negative compared with 42.5% (95% CI 0.33–0.50) of those in group B (P = 0.0001) and 48.8% (95% CI 0.40–0.56) of those in group C. SVR was achieved in a significantly greater proportion of patients in group A compared with groups B and C: 65.3% (95% CI 0.53–0.56), 33.3% (95% CI 0.25–0.41) and 44.6% (95% CI 0.36–0.53; P = 0.0001) respectively. In patients with genotype 1, SVR rates were 55.2, 22.8 and 28.8% with the three regimens respectively. Factors independently associated with SVR were HCV genotype 2 or 3, therapy with PEG‐IFN, female gender and age. In treatment‐naïve patients with chronic hepatitis C, triple therapy with PEG‐IFN α‐2a, RBV and AMA produces higher SVR than dual or triple therapy with conventional IFN α‐2a.

HCV genotypes in patients with liver disease of different stages and severity

UNLABELLED AIMS/MATERIAL: Hepatitis C virus (HCV) genotyping was performed in 213 anti-HCV-positive patients with chronic liver disease ranging from minimal histological changes to hepatocellular carcinoma. One hundred and twenty-two patients had non-cirrhotic chronic active or persistent hepatitis (including 29 who were asymptomatic with persistently normal ALT levels) (chronic liver disease group). The other 91 had hepatocellular carcinoma and, in all but three cases, cirrhosis (hepatocellular carcinoma group). RESULTS The overall prevalence of HCV variants was: 54.9% type 1b, 37.8% type 2, 2.5% type 1a, 2.0% type 3a, 2.0% type 4a. The genotype distribution showed no relation to the stage (chronic liver disease vs. hepatocellular carcinoma) or severity (chronic active vs. chronic persistent hepatitis) of the liver disease, or to the duration of the disease (<10 years vs. >10 years). Within the hepatocellular carcinoma group, the duration of type-1b disease was similar to that of type-2 infections. Ages at the time of infection and genotype were both independently associated with progression to cirrhosis and hepatocellular carcinoma, but multivariate analysis revealed that the effect of age was much stronger than that of genotype 1b. CONCLUSIONS The predominance of HCV type 1b in this study reflects the higher frequency of this variant in our area. Our findings indicate that infections caused by each HCV genotype are capable of progressing to hepatocellular carcinoma.

Prolonged treatment (2 years) with different doses (3 versus 6 MU) of interferon α-2b for chronic hepatitis type C: Results of a multicenter randomized trial

BACKGROUND/AIMS To examine the effect of prolonged treatment with different doses of interferon alpha-2b on the relapse rate in patients with chronic hepatitis C. METHODS One hundred and seventy-one patients with non-cirrhotic chronic hepatitis C were enrolled in an Italian multicenter trial. All patients were treated for 3 months with 3,000,000 Units (3 MU) of interferon alpha-2b given subcutaneously three times a week (t.i.w.). Patients with abnormal alanine aminotransferase (ALT) values were given 6 MU of interferon for an additional 3 months. If ALT remained persistently abnormal, therapy was then suspended. If ALT levels were normal, therapy was continued (6 MU t.i.w.) for an additional 18 months (total=2 years). Patients with normal ALT were randomly assigned to two groups, one receiving 3 MU and the other receiving 6 MU t.i.w. for an additional 21 months (total=2 years). Follow-up continued for 2 years after therapy withdrawal. RESULTS Seven patients stopped treatment during the first 3 months. Of the remaining 164 patients, 76 (46%) showed abnormal ALT levels after 3 months of therapy: 11 of these (14%) normalized ALT values when given 6 MU and a sustained response was maintained in eight during the follow-up. Overall, 54 and 34 patients were allocated respectively to the groups receiving the 3 MU and 6 MU long-term treatment. At the end of therapy, 35/54 patients of the group 3 MU and 21/34 patients of the group 6 MU showed normal ALT levels (65% vs 62%, p=N.S.). After 2 years of follow-up, 24/35 (69%) patients of the group 3 MU and 16/21 (76%) of the group 6 MU were still in remission (p=N.S.). In an intention-to-treat analysis, 48/171 (28%) patients showed a long-term response (normal ALT values, HCV-RNA negative). About 65% of the sustained responders showed low baseline viremia compared with 33% of non-responders (p=0.005) while genotype 1b was more frequently found among non-responders than in long-term responders (84% vs 25%, p=0.0001). CONCLUSIONS About 14% of patients who do not respond to a 3-month course of 3 MU of interferon normalize ALT levels when given 6 MU. In prolonged treatment, there is no significant difference between 3 and 6 MU in inducing a sustained response. Patients with low baseline viremia and genotype 2a respond significantly better to prolonged interferon therapy than highly viremic patients with genotype 1b.

High doses of interferon in combination with ribavirin are more effective than the standard regimen in patients with HCV genotype 1 chronic hepatitis.

BACKGROUND/AIMS The aim of the present, open-labelled, controlled study was to determine whether 5 MU of interferon (IFN) alpha 2b combined with a standard dose of ribavirin might increase the rate of viral clearance in all patients with chronic HCV hepatitis or at least in those with an unfavourable genotype. METHODS A total of 298 previously untreated patients with chronic hepatitis C were randomized to 5 or 3 MU of interferon alpha 2b 3 times per week with 1000-1200 mg of ribavirin daily (148 and 150 patients, respectively). Patients were treated for 12 months and observed for 6 months posttreatment. RESULTS In patients infected with HCV genotype 1, the sustained virologic response was 37.8% (95% CI 27.3-48.1) with IFN 5 MU and 19.2% (95% CI 10.1-28.2) with IFN 3 MU (P=0.008). Out of 45 sustained responders with genotype 1, 31 (69%) had received 5 MU and 14 (31.1%) the standard 3 MU dose of IFN in combination with ribavirin (P=0.01). Of the 86 responders infected with genotype non-1, 39 (45.3%) were from the 5 MU IFN group and 47 (54.6%) were from the 3 MU IFN group; these figures were not significant. At the multivariate analysis of baseline features for all patients, the variables with an independent effect for a sustained response were genotype non-1 (odds ratio (OR) 3.98, 95% CI 2.36-6.40), and the histological grading (score 0-2) (OR 2.48, 95% CI 1.12-5.51) and staging (score 0-1) (OR 1.73, 95% CI 1.02-2.95). For patients with genotype 1 only the high regimen of IFN entered the model (OR 2.39, 95% CI 1.13-5.05), whereas for patients with genotype non-1 an age of <40 years (OR 2.64, 95% CI 1.23-5.70) and staging (score 0-1) (OR 2.38, 95% CI 1.07-5.28) were independent predictors of a sustained response. CONCLUSIONS Our study suggests that when treating naive patients with genotype 1, there is a significant increase in the rate of sustained virologic clearance by increasing the dose of IFN given in combination with ribavirin.

93 HCV genotype 2 and 3 can be cured by PEG-IFN-alfa-2B and RBV for 12 wks: A randomized controlled study

A. Mangia1, N. Minerva3, G.L. Ricci10, M. Romano8, V. Carretta4, M. Persico9, D. Bacca6, F. Spirito1, F. Vinelli2, M. Annese5, A. Giangaspero7, G. Scotto2, A. Andriulli1. 1IRCCS CSS San Giovanni Rotondo (FG), San Giovanni Rotondo, Italy; 2Ospedali Riuniti Foggia, Universita Di Foggia, Foggia, Italy; 3Medicina Ospedali Di Canosa, Canosa, Italy; 4Medicina Ospedali Di Venosa, Venosa, Italy; 5Medicina Ospedali Di Policoro, Policoro, Italy; 6Medicina Ospedali Di Casarano, Casarano, Italy; 7Medicina Ospedali Di Bari, Bari, Italy; 8Ospedale ’S. Pertini’, Roma, Italy; 9Universita Di Napoli, Napoli, Italy; 10Universita ‘La Sapienza’, Roma, Italy