Pancreatic Iodine Density and Fat Fraction on Dual-Energy Computed Tomography in Acute Pancreatitis.

The aim of our study was to investigate iodine density (ID) and fat fraction (FF) on dual-energy computed tomography (DECT) in patients with acute pancreatitis (AP). This retrospective study included 72 patients with clinically confirmed AP and 62 control subjects with DECT of the abdomen. Two radiologists assessed necrosis and measured attenuation values, ID, and FF in three pancreatic segments. We used receiver operating characteristic (ROC) analysis to determine the optimal threshold for ID for the differentiation between AP groups. The ID was significantly higher in interstitial edematous AP compared to necrotizing AP and the control group (both p < 0.05). The ROC curve analysis revealed the thresholds of ID for detecting pancreatic necrosis ≤ 2.2, ≤2.3, and ≤2.4 mg/mL (AUC between 0.880 and 0.893, p > 0.05) for the head, body, and tail, respectively. The FF was significantly higher for pancreatitis groups when compared with the control group in the head and body segments (both p < 0.001). In the tail, the difference was significant in necrotizing AP (p = 0.028). The ID values were independent of attenuation values correlated with the FF values in pancreatic tissue. Iodine density values allow for differentiation between morphologic types of AP.

Machine learning for the prediction of post-ERCP pancreatitis risk: A proof-of-concept study.

BACKGROUND: Predicting Post-Endoscopic Retrograde Cholangiopancreatography (ERCP) pancreatitis (PEP) risk can be determinant in reducing its incidence and managing patients appropriately, however studies conducted thus far have identified single-risk factors with standard statistical approaches and limited accuracy. AIM: To build and evaluate performances of machine learning (ML) models to predict PEP probability and identify relevant features. METHODS: A proof-of-concept study was performed on ML application on an international, multicenter, prospective cohort of ERCP patients. Data were split in training and test set, models used were gradient boosting (GB) and logistic regression (LR). A 10-split random cross-validation (CV) was applied on the training set to optimize parameters to obtain the best mean Area Under Curve (AUC). The model was re-trained on the whole training set with the best parameters and applied on test set. Shapley-Additive-exPlanation (SHAP) approach was applied to break down the model and clarify features impact. RESULTS: One thousand one hundred and fifty patients were included, 6.1% developed PEP. GB model outperformed LR with AUC in CV of 0.7 vs 0.585 (p-value=0.012). GB AUC in test was 0.671. Most relevant features for PEP prediction were: bilirubin, age, body mass index, procedure time, previous sphincterotomy, alcohol units/day, cannulation attempts, gender, gallstones, use of Ringer's solution and periprocedural NSAIDs. CONCLUSION: In PEP prediction, GB significantly outperformed LR model and identified new clinical features relevant for the risk, most being pre-procedural.

Systematic Review with Trial Sequential Analysis of Prophylactic Antibiotics for Acute Pancreatitis.

BACKGROUND/OBJECTIVES: Prophylactic antibiotics (PAB) are being still widely used for treatment of acute pancreatitis (AP) despite trials showing no firm evidence of efficacy. We aimed to evaluate effects of PAB for AP in a meta-analysis and the need for further research by trial sequential analysis (TSA). METHODS: Medline, Scopus and Web of Science were searched for randomized clinical trials. Primary outcomes were all infections and mortality. Secondary outcomes comprised infected pancreatic necrosis (IPN), specific infections, organ failure, surgical interventions, and length of hospital stay. RESULTS: Twenty-one trials with 1383 pts were included. PAB were received by 703 pts, while 680 were controls. Mortality was similar with RR 0.85 (95% CI 0.66-1.10). Infections were significantly reduced (RR 0.60; 95% CI 0.49-0.74), mainly due to decreased risk of sepsis (RR 0.43; 95% CI 0.25-0.73) and urinary tract infections (RR 0.46; 95% CI 0.25-0.86). No significant reduction for IPN was shown (RR 0.81; 95% CI 0.63-1.04). Length of hospital stay was diminished by MD -6.65 (95% CI -8.86 to -4.43) days. TSA for all infections showed that the cumulative Z score crossed both conventional and monitoring boundaries at 526 pts from a heterogeneity-corrected required information size of 1113 pts based on a 40% incidence of infections in the control group, RRR of 30%, alpha 5%, beta 20%, and heterogeneity 56%. CONCLUSIONS: PABs decrease the rate of infections in AP, mainly due to RRR of extra-pancreatic infections, requiring no further research. No significant effect is shown on IPN and mortality, although firmer evidence is needed.

The characteristics and prognostic role of acute abdominal on-admission pain in acute pancreatitis: A prospective cohort analysis of 1432 cases.

INTRODUCTION: Pain is the most common symptom in acute pancreatitis (AP) and is among the diagnostic criteria. Therefore, we aimed to characterize acute abdominal pain in AP. METHODS: The Hungarian Pancreatic Study Group prospectively collected multicentre clinical data on 1435 adult AP patients between 2012 and 2017. Pain was characterized by its intensity (mild or intense), duration prior to admission (hours), localization (nine regions of the abdomen) and type (sharp, dull or cramping). RESULTS: 97.3% of patients (n = 1394) had pain on admission. Of the initial population with acute abdominal pain, 727 patients answered questions about pain intensity, 1148 about pain type, 1134 about pain localization and 1202 about pain duration. Pain was mostly intense (70%, n = 511/727), characterized by cramping (61%, n = 705/1148), mostly starting less than 24 h prior to admission (56.7%, n = 682/1202). Interestingly, 50.9% of the patients (n = 577/1134) had atypical pain, which means pain other than epigastric or belt-like upper abdominal pain. We observed a higher proportion of peripancreatic fluid collection (19.5% vs. 11.0%; p = 0.009) and oedematous pancreas (8.4% vs. 3.1%; p = 0.016) with intense pain. Sharp pain was associated with AP severity (OR = 2.481 95% CI: 1.550-3.969) and increased mortality (OR = 2.263, 95% CI: 1.199-4.059) compared to other types. Longstanding pain (>72 h) on admission was not associated with outcomes. Pain characteristics showed little association with the patient's baseline characteristics. CONCLUSION: A comprehensive patient interview should include questions about pain characteristics, including pain type. Patients with sharp and intense pain might need special monitoring and tailored pain management. SIGNIFICANCE: Acute abdominal pain is the leading presenting symptom in acute pancreatitis; however, we currently lack specific guidelines for pain assessment and management. In our cohort analysis, intense and sharp pain on admission was associated with higher odds for severe AP and several systemic and local complications. Therefore, a comprehensive patient interview should include questions about pain characteristics and patients with intense and sharp pain might need closer monitoring.

Non-Alcoholic Fatty Liver Disease and COVID-19-Two Pandemics Hitting at the Same Time.

The COVID-19 pandemic was and still is a global burden with more than 178,000,000 cases reported so far. Although it mainly affects respiratory organs, COVID-19 has many extrapulmonary manifestations, including, among other things, liver injury. Many hypotheses have been proposed to explain direct and indirect impacts of the SARS-CoV-2 virus on the liver. Studies have shown that around 15-30% of patients with COVID-19 have underlying liver disease, and 20-35% of patients with COVID-19 had altered liver enzymes at admission. One of the hypotheses is reactivation of an underlying liver disease, such as non-alcoholic fatty liver disease (NAFLD). Some studies have shown that NAFLD is associated with severe COVID-19 and poor outcome; nevertheless, other studies showed no significant difference between groups in comparing complications and clinical outcomes. Patients with NAFLD may suffer severe COVID-19 due to other comorbidities, especially cardiovascular diseases. The link between NAFLD and COVID-19 is not clear yet, and further studies and research are needed.

Glucose levels show independent and dose-dependent association with worsening acute pancreatitis outcomes: Post-hoc analysis of a prospective, international cohort of 2250 acute pancreatitis cases.

BACKGROUND: Metabolic risk factors, such as obesity, hypertension, and hyperlipidemia are independent risk factors for the development of various complications in acute pancreatitis (AP). Hypertriglyceridemia dose-dependently elicits pancreatotoxicity and worsens the outcomes of AP. The role of hyperglycemia, as a toxic metabolic factor in the clinical course of AP, has not been examined yet. METHODS: We analyzed a prospective, international cohort of 2250 AP patients, examining associations between (1) glycosylated hemoglobin (HbA1c), (2) on-admission glucose, (3) peak in-hospital glucose and clinically important outcomes (mortality, severity, complications, length of hospitalization (LOH), maximal C-reactive protein (CRP)). We conducted a binary logistic regression accounting for age, gender, etiology, diabetes, and our examined variables. Receiver Operating Characteristic Curve (ROC) was applied to detect the diagnostic accuracy of the three variables. RESULTS: Both on-admission and peak serum glucose are independently associated with AP severity and mortality, accounting for age, gender, known diabetes and AP etiology. They show a dose-dependent association with severity (p < 0.001 in both), mortality (p < 0.001), LOH (p < 0.001), maximal CRP (p < 0.001), systemic (p < 0.001) and local complications (p < 0.001). Patients with peak glucose >7 mmol/l had a 15 times higher odds for severe AP and a five times higher odds for mortality. We found a trend of increasing HbA1c with increasing LOH (p < 0.001), severity and local complications. CONCLUSIONS: On-admission and peak in-hospital glucose are independently and dose-dependently associated with increasing AP severity and mortality. In-hospital laboratory control of glucose and adequate treatment of hyperglycemia are crucial in the management of AP.

Association between Gastroesophageal Reflux Disease and Elastographic Parameters of Liver Steatosis and Fibrosis: Controlled Attenuation Parameter and Liver Stiffness Measurements.

Aim: Our aim was to investigate the association among elastographic parameters of liver steatosis and fibrosis, controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), with gastroesophageal reflux disease (GERD). Methods: In this prospective, cross-sectional study, we have evaluated 937 patients with one or more components of the metabolic syndrome who had an esophagogastroduodenoscopy (EGD) due to GERD symptoms. In all patients, a laboratory analysis, an abdominal ultrasound, and FibroScan measurements were done. GERD was defined by EGD. Results: The mean body mass index (BMI) of the study population was 30.95 ± 5.45 kg/m2. The prevalence of increased CAP was 82.6% (774/937). Patients with increased CAP were younger, were more obese, had higher prevalence of hypertension, diabetes, and dyslipidemia, and had higher values of aminotransferases. Similar results of higher prevalence in patients with elevated CAP were observed with GERD, hiatal hernia, and insufficient cardia (defined as deficient or absent closure of the gastric inlet in relation to the esophagus). Additionally, patients with elevated CAP had a higher prevalence of GERD grades B and C in comparison to those without elevated CAP. Consequently, patients who did not have elevated CAP had a higher prevalence of GERD grade A. Even though we have found an upward trend in the prevalence of GERD, hiatal hernia, and insufficient cardia, there was no significant difference between subjects with fibrosis (F) 1-2 and F3-4 stage of fibrosis or F1 and F2-4. In a binary logistic regression, a significant positive association with GERD was obtained for CAP. Furthermore, a significant positive association with hiatal hernia was obtained for BMI and CAP. Finally, a significant positive association with hiatal hernia was obtained with CAP in multivariate analysis. Conclusion: To the best of our knowledge, our study is the first to reveal a positive association between CAP as a surrogate marker of liver steatosis and GERD after adjustments for other clinical variables.

OPPORTUNISTIC SCREENING FOR COLORECTAL CANCER IN HIGH-RISK PATIENTS IN FAMILY MEDICINE PRACTICES IN THE REPUBLIC OF CROATIA.

Colorectal cancer is a malignant neoplasm which has an increasing incidence and represents a global public health problem. The majority of patients are diagnosed after the age of 50, and the risk of developing it over lifetime is 5%. Development of preventive, diagnostic and treatment methods has resulted in a significant reduction in mortality and other negative clinical outcomes. Precisely because of the efficient method of prevention and early detection of this disease, numerous countries, including Croatia, have organized national colorectal cancer screening and monitoring programs. However, these programs are primarily organized for the population with the usual, i.e. average risk of developing colorectal cancer. High-risk groups include persons with endoscopically detected and removed colon polyps, persons surgically treated for colon cancer, persons with a positive family history of colorectal cancer, persons with inflammatory bowel diseases, individuals and families with hereditary disorders or genetic mutations that increase the risk of this disease several fold, persons with acromegaly, and patients who have undergone ureterosigmoidostomy. Recommendations for the detection and monitoring of high-risk groups are often not defined clearly, and some of the existing ones are based mostly on scarce scientific evidence. It is commonly accepted that screening in high-risk groups should start at an earlier age, with shorter intervals between follow-ups. The basic diagnostic method for screening and monitoring in these patient groups is endoscopic monitoring, or colonoscopy. The aim of this review paper is to present the characteristics of the abovementioned risk groups and provide clear screening recommendations.

Predictive value of abdominal drain amylase for postoperative pancreatic fistula following gastric resection: A systematic review and meta-analysis.

BACKGROUND: Radical dissection of lymph nodes, accompanying gastric cancer resection, can lead to collateral damage to the pancreas and development of postoperative pancreatic fistula (POPF). METHODS: We searched the Cochrane Library, MEDLINE, Embase, and Web of Science up to April 21, 2020, to identify studies documenting the value of abdominal drain amylase level (d-AMY) on postoperative day 1 (POD1) as a predictor of POPF after gastric surgery. The quality of selected studies was assessed using the QUADAS-2 tool. The diagnostic value of d-AMY on POD1 for prediction of POPF was first assessed by calculation of pooled estimates of sensitivity, specificity, likelihood ratios (LR), and the diagnostic odds ratio (DOR). Secondly, the accuracy was further demonstrated graphically with the hierarchical summary receiver operating curve (hSROC). PROSPERO registration number: CRD42020181145. RESULTS: DOR of nine studies (cases n = 1856) observing the occurrence of POPF after measurement of d-AMY on POD1 was 18.7 (95%CI: 10.0, 34.8), and the area under hSROC was 0.88 ± 0.02. The pooled sensitivity was 0.74 (95%CI: 0.66, 0.81) and specificity 0.84 (95%CI: 0.82, 0.86). The negative LR was at the lowest point of 0.16 (95%CI: 0.07, 0.37) at the cutoff value for d-AMY of 941 IU/L, while the positive LR ranged from 4.4 (cutoff 2119 IU/L) to 6.2 (cutoff 5000 IU/L). CONCLUSION: d-AMY on POD1 can be used as an accurate and non-invasive predictor of POPF in the earliest stage of postoperative course following gastric cancer resection; value ≤ 941 IU/L warrants early drain removal and low probability of POPF (any grade).

Chronic use of statins and acetylsalicylic acid and incidence of post-endoscopic retrograde cholangiopancreatography acute pancreatitis: A multicenter, prospective, cohort study.

OBJECTIVES: Post-endoscopic retrograde cholangiopancreatography (ERCP) acute pancreatitis (PEP) is a frequent complication of this endoscopic procedure. Chronic statin intake has been linked to lower incidence and severity of acute pancreatitis (AP). Periprocedural rectal administration of non-steroidal anti-inflammatory drugs is protective against PEP, but the role of chronic acetylsalicylic acid (ASA) treatment is unclear. We aimed to investigate whether statins and chronic ASA intake are associated with lower risk of PEP. METHODS: An international, multicenter, prospective cohort study. Consecutive patients undergoing ERCP in seven European centers were included. Patients were followed-up to detect those with PEP. Multivariate analysis by means of binary logistic regression was performed, and adjusted odds ratios (aORs) were calculated. RESULTS: A total of 1150 patients were included, and 70 (6.1%) patients developed PEP. Among statins users, 8.1% developed PEP vs. 5.4% among non-users (P = 0.09). Multivariate analysis showed no association between statin use and PEP incidence (aOR 1.68 (95% CI 0.94-2.99, P = 0.08)). Statin use had no effect on severity of PEP, being mild in 92.0% of statin users vs. 82.2% in non-statin users (P = 0.31). Chronic ASA use was not associated with PEP either (aOR 1.02 (95% CI 0.49-2.13), P = 0.96). Abuse of alcohol and previous endoscopic biliary sphincterotomy were protective factors against PEP, while >1 pancreatic guidewire passage, normal bilirubin values, and duration of the procedure >20 minutes, were risk factors. CONCLUSIONS: The use of statins or ASA is not associated with a lower risk or a milder course of PEP.

Vitamin D for treatment of non-alcoholic fatty liver disease detected by transient elastography: A randomized, double-blind, placebo-controlled trial.

AIM: To evaluate the effects of vitamin D on transient elastography (TE, FibroScan) indices of liver steatosis (controlled attenuation parameter [CAP]) and fibrosis (liver stiffness measurement [LSM]) in adults with non-alcoholic fatty liver disease (NAFLD). PATIENTS AND METHODS: In this randomized (2:1), double-blind, single-centre, 12-month trial, patients with NAFLD were treated with vitamin D (1000 IU/day) (n = 201) or a matching placebo (n = 110). Two co-primary outcomes were changes in CAP and LSM after 360 days of treatment versus baseline. Two main secondary outcomes were CAP/LSM changes after 180 days of treatment. RESULTS: Both CAP and LSM gradually decreased in vitamin D-treated patients and slightly increased in the placebo arm. Vitamin D was superior to placebo for both primary outcomes (mean differences in CAP and LSM changes (-49.5 dB/m [95% CI -59.5 to -39.4] and -0.72 kPa [95% CI -1.43 to 0.00], respectively) and both secondary outcomes (-22.1 dB/m [-32.1 to -12.1] and -0.89 kPa [-1.61 to -0.17], respectively). Of a number of exploratory outcomes (change at 12 months vs. baseline), vitamin D reduced serum uric acid (-17.9 µmol/L [-30.6 to -5.2]), gamma-glutamyltransferase (-8.9 IU/L [-15.5 to -2.3)] and fasting serum insulin levels (-5.1 pmol/L [-9.3 to -0.8]) as well as the homeostatic model assessment of insulin resistance index (-1.6 [-3.1 to -0.2]) (false discovery rate [5%]-adjusted P-values between .0572 and .0952). CONCLUSION: Low-medium dose supplementation of vitamin D (1000 IU/day) over 12 months reduces TE indices of liver steatosis (CAP) and fibrosis (LSM) in NAFLD patients.

Prevention of Infectious Complications in Acute Pancreatitis: Results of a Single-Center, Randomized, Controlled Trial.

OBJECTIVES: This study aimed to investigate the efficiency of imipenem to prevent infectious complications in predicted severe acute pancreatitis (AP). METHODS: Consecutive AP patients were randomized to imipenem 3 × 500 mg intravenously daily or an identical placebo. Exclusion criteria were prior AP, chronic pancreatitis, active malignancy, immune deficiency, active infection, concomitant antibiotic treatment, pregnancy, and patients younger than 18 years. Infectious complications including infected pancreatic necrosis, pneumonia, urinary tract infection, positive blood cultures, sepsis, and other infections were assessed as the primary outcome. Secondary outcomes included mortality, persistent organ failure, systemic inflammatory response syndrome, local complications, serious adverse events, and need for surgical intervention. RESULTS: Forty-nine patients were randomized to each group. Infectious complications were present in 10 versus 12 of 49 patients (relative risk [RR], 0.833; 95% confidence interval [CI], 0.398-1.747). There were no significant differences in infected pancreatic necrosis (RR, 1.5; 95% CI, 0.262-8.588), pneumonia (RR, 1.5; 95% CI, 0.262-8.588), urinary tract infection (RR, 0.6; 95% CI, 0.152-2.374), positive blood cultures (RR, 0.5; 95% CI, 0.047-5.336), sepsis (RR, 0.333; 95% CI, 0.036-3.095), and other (RR, 1.333; 95% CI, 0.315-5.648). We found no significant differences in secondary outcomes. CONCLUSIONS: Concordantly to available evidence, there is currently no ground to support prophylactic use of antibiotics in predicted severe AP.

Statin use is not associated with an increased risk of acute pancreatitis-A meta-analysis of observational studies.

BACKGROUND: Statins are perceived as potential etiological factors for acute pancreatitis (AP), but recent evidence suggests the opposite. Our aim was to evaluate the association between statin use and risk of AP in observational studies. METHODS: Medline, Scopus, and Web of Science were searched for cohort (C) and case-control (CC) studies evaluating statins as intervention and AP as outcome. Pooled adjusted odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated. RESULTS: Thirteen studies (seven CC, six C) with 34,899 AP patients and 5,377,894 controls were included. Prevalence of statin use was 9.8% among AP patients and 25% among controls. Pooled adjusted OR was 1.00 (95% CI = 0.63 to 1.59) with considerable heterogeneity (I 2 = 98%). CC studies were associated with increased AP risk (OR = 1.33; 95% CI = 1.20 to 1.47), unlike C studies (OR = 0.69; 95% CI = 0.37 to 1.31). No association with increased risk was found for studies from Western countries (OR = 0.90; 95% CI = 0.52 to 1.56), unlike for studies conducted in Asia (OR = 1.39; 95% CI = 1.10 to 1.75). CONCLUSION: Statin use is not associated with increased risk of AP. Increased risk was limited to CC studies, which are more prone to bias, while C studies showed no global effect. Further research is needed to clarify whether statin type, dosage, treatment duration or AP etiology might account for this difference.

Endoscopic retrograde cholangiopancreatography-induced and non-endoscopic retrograde cholangiopancreatography-induced acute pancreatitis: Two distinct clinical and immunological entities?

Acute pancreatitis (AP) is common gastrointestinal disease of varied aetiology. The most common cause of AP is gallstones, followed by alcohol abuse as an independent risk factor. With the increased need for invasive techniques to treat pancreatic and bile duct pathologies such as endoscopic retrograde cholangiopancreatography (ERCP), AP has emerged as the most frequent complication. While severe AP following ERCP is rare (0.5%), if it does develop it has a greater severity index compared to non-ERCP AP. Development of a mild form of AP after ERCP is not considered a clinically relevant condition. Differences in the clinical presentation and prognosis of the mild and severe forms have been found between non-ERCP AP and post-endoscopic pancreatitis (PEP). It has been proposed that AP and PEP may also have different immunological responses to the initial injury. In this review, we summarise the literature on clinical and inflammatory processes in PEP vs non-ERCP AP.

Chronic use of statins and risk of post-ERCP acute pancreatitis (STARK): Study protocol for an international multicenter prospective cohort study.

BACKGROUND: Acute pancreatitis (AP) is the most common complication after endoscopic retrograde cholangiopancreatography (ERCP). Statins have been traditionally associated to an increased risk of AP, however, recent evidence suggests that statins may have a protective role against this disease. AIMS: Our primary aim is to investigate whether the use of statins has a protective effect against post-ERCP pancreatitis (PEP). Secondary outcomes are: to evaluate the effect of other drugs on the incidence of PEP; to ascertain the relationship between the use of statins and the severity of PEP; and to evaluate the effect of other risk and protective factors on the incidence of PEP. METHODS: STARK is an international multicenter prospective cohort study. Centers from Spain, Italy, Croatia, Finland and Sweden joined this study. The total sample size will include about 1016 patients, which was based on assuming a 5% incidence of PEP among non-statin (NSt) users, a 1-3 ratio of statin (St) and NSt consumers respectively, a 70% decrease in PEP among St consumers, an alpha-error of 0.05 and beta-error of 0.20. All patients aged ≥18 years scheduled for ERCP will be offered to enter the study. DISCUSSION: STARK study will ascertain whether statins, a safe, widely used and inexpensive drug, can modify the incidence of PEP.

ERCP induced and non-ERCP-induced acute pancreatitis: Two distinct clinical entities?

Acute pancreatitis (AP) is a common gastrointestinal disease of varied etiology; however, the most common causes of AP are gallstones and alcohol abuse. AP has emerged as the most frequent complication after endoscopic retrograde cholangiopancreatography (ERCP). Post-ERCP pancreatitis is generally a clinically irrelevant condition; however, it can be severe or even fatal in up to 0.8% of cases. Different clinical courses and outcomes have been observed between mild and severe AP of different etiologies (i.e., non-ERCP AP and post-ERCP AP), which opens the discussion as to whether they are the same or distinct clinical entities.

Direct-acting antivirals for chronic hepatitis C.

BACKGROUND: Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs), e.g. sofosbuvir, are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). Sustained virological response (SVR) is used by investigators and regulatory agencies as a surrogate outcome for morbidity and mortality, based solely on observational evidence. However, there have been no randomised trials that have validated that usage. OBJECTIVES: To assess the benefits and harms of DAAs in people with chronic HCV. SEARCH METHODS: We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016. SELECTION CRITERIA: Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and health-related quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and SVR. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. We evaluated the overall quality of the evidence, using GRADE. MAIN RESULTS: We included a total of 138 trials randomising a total of 25,232 participants. The trials were generally short-term trials and designed primarily to assess the effect of treatment on SVR. The trials evaluated 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered DAAs that were discontinued or withdrawn from the market. Study populations were treatment-naive in 95 trials, had been exposed to treatment in 17 trials, and comprised both treatment-naive and treatment-experienced individuals in 24 trials. The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.We could not reliably determine the effect of DAAs on the market or under development on our primary outcome of hepatitis C-related morbidity or all-cause mortality. There were no data on hepatitis C-related morbidity and only limited data on mortality from 11 trials (DAA 15/2377 (0.63%) versus control 1/617 (0.16%); OR 3.72, 95% CI 0.53 to 26.18, very low-quality evidence). We did not perform Trial Sequential Analysis on this outcome.There is very low quality evidence that DAAs on the market or under development do not influence serious adverse events (DAA 5.2% versus control 5.6%; OR 0.93, 95% CI 0.75 to 1.15 , 15,817 participants, 43 trials). The Trial Sequential Analysis showed that there was sufficient information to rule out that DAAs reduce the relative risk of a serious adverse event by 20% when compared with placebo. The only DAA that showed a lower risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, the meta-analysis result showed no evidence of a difference.DAAs on the market or under development may reduce the risk of no SVR from 54.1% in untreated people to 23.8% in people treated with DAA (RR 0.44, 95% CI 0.37 to 0.52, 6886 participants, 32 trials, low quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).There was insufficient evidence from trials on withdrawn or discontinued DAAs to determine their effect on hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79; 5 trials, very low-quality evidence). However, these DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73; 29 trials, very low-quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma). AUTHORS' CONCLUSIONS: The evidence for our main outcomes of interest come from short-term trials, and we are unable to determine the effect of long-term treatment with DAAs. The rates of hepatitis C morbidity and mortality observed in the trials are relatively low and we are uncertain as to how DAAs affect this outcome. Overall, there is very low quality evidence that DAAs on the market or under development do not influence serious adverse events. There is insufficient evidence to judge if DAAs have beneficial or harmful effects on other clinical outcomes for chronic HCV. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs may reduce the number of people with detectable virus in their blood, but we do not have sufficient evidence from randomised trials that enables us to understand how SVR affects long-term clinical outcomes. SVR is still an outcome that needs proper validation in randomised clinical trials.

Direct-acting antivirals for chronic hepatitis C.

BACKGROUND: Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs) are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). However, it is still questionable if eradication of hepatitis C virus in the blood eliminates hepatitis C in the body, and improves survival and leads to fewer complications. OBJECTIVES: To assess the benefits and harms of DAAs in people with chronic HCV. SEARCH METHODS: We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016. SELECTION CRITERIA: Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and sustained virological response. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. The overall quality of the evidence was evaluated using GRADE. MAIN RESULTS: We included a total of 138 trials randomising a total of 25,232 participants. The 138 trials assessed the effects of 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered withdrawn or discontinued DAAs. Trial participants were treatment-naive (95 trials), treatment-experienced (17 trials), or both treatment-naive and treatment-experienced (24 trials). The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.Meta-analysis of the effects of all DAAs on the market or under development showed no evidence of a difference when assessing hepatitis C-related morbidity or all-cause mortality (OR 3.72, 95% CI 0.53 to 26.18, P = 0.19, I² = 0%, 2,996 participants, 11 trials, very low-quality evidence). As there were no data on hepatitis C-related morbidity and very few data on mortality (DAA 15/2377 (0.63%) versus control 1/617 (0.16%)), it was not possible to perform Trial Sequential Analysis on hepatitis C-related morbidity or all-cause mortality.Meta-analysis of all DAAs on the market or under development showed no evidence of a difference when assessing serious adverse events (OR 0.93, 95% CI 0.75 to 1.15, P = 0.52, I² = 0%, 15,817 participants, 43 trials, very low-quality evidence). The Trial Sequential Analysis showed that the cumulative Z-score crossed the trial sequential boundary for futility, showing that there was sufficient information to rule out that DAAs compared with placebo reduced the relative risk of a serious adverse event by 20%. The only DAA that showed a significant difference on risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, then the meta-analysis result showed no evidence of a difference.DAAs on the market or under development seemed to reduce the risk of no sustained virological response (RR 0.44, 95% CI 0.37 to 0.52, P < 0.00001, I² = 77%, 6886 participants, 32 trials, very low-quality evidence) and Trial Sequential Analysis confirmed this meta-analysis result.Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).Withdrawn or discontinued DAAs had no evidence of a difference when assessing hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79, P = 0.40, I² = 0%; 5 trials, very low-quality evidence). However, withdrawn DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73, P = 0.001, I² = 0%, 29 trials, very low-quality evidence), and Trial Sequential Analysis confirmed this meta-analysis result.Most of all outcome results were short-term results; therefore, we could neither confirm nor reject any long-term effects of DAAs. None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma). AUTHORS' CONCLUSIONS: Overall, DAAs on the market or under development do not seem to have any effects on risk of serious adverse events. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs seemed to reduce the risk of no sustained virological response. The clinical relevance of the effects of DAAs on no sustained virological response is questionable, as it is a non-validated surrogate outcome. All trials and outcome results were at high risk of bias, so our results presumably overestimate benefit and underestimate harm. The quality of the evidence was very low.

Diclofenac sodium versus ceftazidime for preventing pancreatitis after endoscopic retrograde cholangiopancreatography: a prospective, randomized, controlled trial.

BACKGROUND AND AIMS: We aimed to compare the efficacy of prophylactic, parenterally administered ceftazidime and rectally applied diclofenac sodium for the prophylaxis of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). METHODS: We prospectively enrolled patients who underwent ERCP. In a double-blind, randomized, controlled trial, patients received a suppository containing diclofenac sodium rectally (100 mg) and placebo intravenously (group A) or ceftazidime intravenously (1 g) and placebo rectally (group B) immediately before the procedure. The serum and urine amylase levels were recorded and the patients were clinically evaluated after ERCP. RESULTS: Of the 272 patients enrolled (group A: 129; group B: 143), 32 developed pancreatitis (group A: 11 [8.5 %]; group B: 21 [14.7 %]; P = 0.17; relative risk = 1.72; 95 % confidence interval [CI] = 0.86-3.43). The severity of the pancreatitis or complications did not significantly differ between the groups. A serum amylase level of ≥560 U/L and urine amylase level of ≥1150 U/L indicated a positive likelihood ratio for post-ERCP pancreatitis of ≥10. Moreover, the threshold visual analog scale score of ≤5 for abdominal pain after ERCP had excellent diagnostic potential for predicting the presence or absence of post-ERCP pancreatitis. CONCLUSIONS: The PEP incidence did not differ between the ceftazidime and diclofenac sodium groups. In patients with nonsteroidal anti-inflammatory drug contraindications, antibiotics can be considered a safe alternative to diclofenac sodium for PEP prevention. Moreover, the visual analog scale for abdominal pain has excellent diagnostic value for predicting PEP. CLINICAL TRIALS. GOV NUMBER: NCT 01784445.