Tenofovir alafenamide and tenofovir disoproxil fumarate reduce incidence of hepatocellular carcinoma in patients with chronic hepatitis B.

Background & Aims: Antiviral therapy may attenuate the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We aimed to explore how tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) affect HCC risk in patients with CHB. Methods: The REACH-B, aMAP, and mPAGE-B models were utilized to assess HCC risk in patients with CHB from two global randomized-controlled trials evaluating the impact of TAF vs. TDF treatment. Standard incidence ratios (SIRs) were calculated using data from the REACH-B model as a ratio of observed HCC cases in the TAF- or TDF-treated patients vs. predicted HCC cases for untreated historical controls. Proportions of treated patients shifting aMAP and mPAGE-B risk categories between baseline and Week 240 were calculated. Results: Of the 1,632 patients (TAF, n = 1,093; TDF, n = 539) followed for up to 300 weeks, 22 HCC cases developed. Those receiving TAF had an SIR that was lower compared to the SIR of individuals receiving TDF: 0.32 (p <0.001) vs. 0.56 (p = 0.06). In the general study population, individuals without cirrhosis at baseline had an SIR that was lower compared to the SIR of individuals with cirrhosis at baseline: 0.37 (p <0.001) vs. 0.58 (p = 0.15). Of the patients at low risk of HCC at baseline, the majority (97%) remained low risk by mPAGE-B and aMAP scoring at Week 240. Among those at medium or high risk at baseline, substantial portions shifted to a lower risk category by Week 240 (mPAGE-B: 22% and 42%; aMAP: 39% and 63%, respectively). Conclusions: This evaluation provides evidence that treatment with TAF or TDF can reduce HCC risk in patients with CHB, particularly in patients without cirrhosis. Impact and implications: Despite the substantial impact of HCC on long-term outcomes of patients with CHB, the differential risk of HCC development among those receiving treatment with TAF vs. TDF has not been well elucidated. Using three validated risk prediction models, we found that TAF is at least as effective as TDF in reducing HCC risk in patients with CHB. While TDF is well-studied in the context of HCC risk reduction, our novel findings underscore the effectiveness of TAF as a treatment option for patients with CHB. Clinical trial numbers: NCT01940341; NCT02836249; NCT01940471; NCT02836236.

Epidemiology and Natural History of Elderly-onset Inflammatory Bowel Disease: Results From a Territory-wide Hong Kong IBD Registry.

BACKGROUND: Elderly-onset inflammatory bowel disease [IBD], defined as age ≥60 at diagnosis, is increasing worldwide. We aimed to compare clinical characteristics and natural history of elderly-onset IBD patients with those of adult-onset IBD patients. METHODS: Patients with a confirmed diagnosis of IBD from 1981 to 2016 were identified from a territory-wide Hong Kong IBD registry involving 13 hospitals. Demographics, comorbidities, clinical features, and outcomes of elderly-onset IBD patients were compared with those of adult-onset IBD patients. RESULTS: A total of 2413 patients were identified, of whom 270 [11.2%] had elderly-onset IBD. Median follow-up duration was 111 months (interquartile range [IQR]: 68-165 months). Ratio of ulcerative colitis [UC]: Crohn's disease [CD] was higher in elderly-onset IBD than in adult-onset IBD patients [3.82:1 vs 1.39:1; p <0.001]. Elderly-onset CD had less perianal involvement [5.4% vs 25.4%; p <0.001] than adult-onset CD. Elderly-onset IBD patients had significantly lower cumulative use of immunomodulators [p = 0.001] and biologics [p = 0.04]. Elderly-onset IBD was associated with higher risks of: cytomegalovirus colitis (odds ratio [OR]: 3.07; 95% confidence interval [CI] 1.92-4.89; p <0.001); herpes zoster [OR: 2.42; 95% CI 1.22-4.80; p = 0.12]; and all cancer development [hazard ratio: 2.97; 95% CI 1.84-4.79; p <0.001]. They also had increased number of overall hospitalisations [OR: 1.14; 95% CI 1.09-1.20; p <0.001], infections-related hospitalisation [OR: 1.87; 95% CI 1.47-2.38; p <0.001], and IBD-related hospitalisation [OR: 1.09; 95% CI 1.04- 1.15; p = 0.001] compared with adult-onset IBD patients. CONCLUSIONS: Elderly-onset IBD was associated with increased risk of infections and cancer development, and increased infection- and IBD-related hospitalisations. Specific therapeutic strategies to target this special population are needed.

Low Risk of Variceal Bleeding in Patients With Cirrhosis After Variceal Screening Stratified by Liver/Spleen Stiffness.

We previously demonstrated the possible noninferiority of a screening strategy for varices guided by liver and spleen stiffness measurement (LSSM) compared to universal endoscopic screening in detecting clinically significant varices in patients with cirrhosis. We now report the long-term outcome of the patients recruited in this trial for incident variceal bleeding and other hepatic events. This was a prospective follow-up study of a noninferiority, open-label, randomized controlled trial (NCT02024347) of 548 adult patients with known chronic liver diseases, radiological evidence of liver cirrhosis, and compensated liver function. The primary outcome of this prospective study was incident variceal bleeding confirmed with upper endoscopy. Between October 2013 and June 2016, 548 patients were randomized to an LSSM arm (n = 274) and a conventional arm (n = 274). Patients in both study arms were predominantly middle-aged men (mean age 59 years, male 68.9%) with viral hepatitis-related cirrhosis (85%). Upper endoscopy examination was performed in 127 (46.4%) patients in the LSSM arm and 263 (96.0%) in the conventional arm. During the follow-up period of 41.3 ± 12.6 months, 12/274 patients in the LSSM arm (4.4%) and 11/274 in the conventional arm (4.0%) developed incident variceal bleeding (log-rank test P = 0.724). The incident rates of hepatic events were also similar in both arms (P = 0.327). Conclusions: Patients with liver cirrhosis who had undergone LSSM-guided variceal screening were at similarly low risk of incident variceal bleeding in the future; patients with cirrhosis may first have LSSM measured to save up to half of the upper endoscopy examinations.

Contrasting Timing of Virological Relapse After Discontinuation of Tenofovir or Entecavir in Hepatitis B e Antigen-Negative Patients.

Stopping long-term nucleos(t)ide analogue therapy increases hepatitis B virus (HBV) surface antigen (HBsAg) loss rates in HBV e antigen (HBeAg)-negative patients. Viral rebound may induce immune responses facilitating functional cure. We analyzed which factors are associated with timing of virological relapse in 220 Asian HBeAg-negative patients from the prospective ABX203 vaccine study. Unexpectedly, only the type of antiviral therapy was significantly associated with early virological relapse, defined as an HBV DNA load of >2000 IU/mL until week 12, and relapse occurred earlier in patients treated with tenofovir versus those treated with entecavir (median time, 6 vs 24 weeks; P < .0001). This should be considered for future trials and monitoring of patients after treatment discontinuation.

Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial.

BACKGROUND: Tenofovir alafenamide is a novel prodrug formulated to deliver the active metabolite to target cells more efficiently than tenofovir disoproxil fumarate at a lower dose, thereby reducing systemic exposure. In patients with HIV, tenofovir alafenamide was as efficacious as tenofovir disoproxil fumarate, with reduced bone and renal toxic effects. We compared the efficacy and safety of the two drugs in patients with HBeAg-positive chronic hepatitis B virus (HBV) infection in a non-inferiority study. METHODS: We did this ongoing double-blind, non-inferiority study in 161 outpatient centres in 19 countries. Patients with chronic HBV infection who were positive for the hepatitis B e antigen (HBeAg) were randomly assigned (2:1) to receive either 25 mg tenofovir alafenamide or 300 mg tenofovir disoproxil fumarate with matching placebo. Randomisation was done by a computer-generated allocation sequence (block size six) stratified by plasma HBV DNA concentration and previous treatment experience. The primary efficacy endpoint was the proportion of patients with HBV DNA less than 29 IU/mL at week 48 in all patients who were randomly assigned and received at least one dose of study drug using a missing-equals-failed approach. The pre-specified non-inferiority margin was 10%. Key prespecified safety endpoints were bone and renal parameters at week 48. This study is registered with ClinicalTrials.gov, number NCT01940471. FINDINGS: Of the 1473 patients screened from Sept 11, 2013, to Dec 20, 2014, 875 eligible patients were randomly assigned and 873 received treatment (581 with tenofovir alafenamide and 292 with tenofovir disoproxil fumarate). 371 (64%) patients receiving tenofovir alafenamide had HBV DNA less than 29 IU/mL at week 48, which was non-inferior to the 195 (67%) of patients receiving tenofovir disoproxil fumarate who had HBV DNA less than 29 IU/mL (adjusted difference -3·6% [95% CI -9·8 to 2·6]; p=0·25). Patients given tenofovir alafenamide had a significantly smaller decrease in bone mineral density at hip (mean change -0·10% [95% CI -0·29 to 0·09] vs -1·72% [-2·02 to -1·41]; adjusted difference 1·62 [1·27 to 1·96]; p<0·0001) and at spine (mean change -0·42% [-0·66 to -0·17] vs -2·29% [-2·67 to -1·92]; adjusted difference 1·88 [1·44 to 2·31]; p<0·0001) as well as smaller mean increases in serum creatinine at week 48 (0·01 mg/dL [0·00-0·02] vs 0·03 mg/dL [0·02-0·04]; p=0·02). The most common adverse events overall were upper respiratory tract infection (51 [9%] of 581 patients receiving tenofovir alafenamide vs 22 [8%] of 292 patients receiving tenofovir disoproxil fumarate), nasopharyngitis (56 [10%] vs 16 [5%]), and headache (42 [7%] vs 22 [8%]). 22 (4%) patients receiving tenofovir alafenamide and 12 (4%) patients receiving tenofovir disoproxil fumarate experienced serious adverse events, none of which was deemed by the investigator to be related to study treatment. 187 (32%) of 581 patients in the tenofovir alafenamide group and 96 (33%) of 292 patients in the tenofovir disoproxil fumarate group had grade 3 or 4 laboratory abnormalities, the most common of which were elevations in ALT (62 [11%] of 577 patients receiving tenofovir alafenamide and 36 [13%] of 288 patients receiving tenofovir disoproxil fumarate) and AST (20 [3%] of 577 patients receiving tenofovir alafenamide and 19 [7%] of 288 patients receiving tenofovir disoproxil fumarate). INTERPRETATION: In patients with HBeAg-positive HBV infection, tenofovir alafenamide was non-inferior to tenofovir disoproxil fumarate, and had improved bone and renal effects. Longer term follow-up is needed to better understand the clinical impact of these changes. FUNDING: Gilead Sciences.

Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial.

BACKGROUND: The novel prodrug tenofovir alafenamide delivers the nucleotide reverse transcriptase inhibitor tenofovir to target cells more efficiently at a lower dose than tenofovir disoproxil fumarate, thereby reducing systemic exposure. We compared the efficacy and safety of the two drugs in patients with HBeAg-negative chronic hepatitis B virus (HBV) infection in a non-inferiority study. METHODS: In this ongoing randomised, double-blind, phase 3, non-inferiority study in 105 centres in 17 countries, patients with HBeAg-negative chronic HBV were randomly assigned (2:1) by a computer-generated allocation sequence (block size six), stratified by plasma HBV DNA concentration and previous treatment status, to receive once-daily oral doses of tenofovir alafenamide 25 mg or tenofovir disoproxil fumarate 300 mg, each with matching placebo. Participants, investigators, and those assessing outcomes were masked to group assignment. Eligible patients were aged at least 18 years with HBeAg-negative chronic HBV infection (with plasma HBV DNA concentrations of >20 000 IU/mL), serum alanine aminotransferase concentrations of greater than 60 U/L in men or greater than 38 U/L in women and at no more than ten times the upper limit of normal, and estimated creatinine clearance of at least 50 mL/min (by the Cockcroft-Gault method). The primary efficacy endpoint was the proportion of patients who had HBV DNA less than 29 IU/mL at week 48 in those who received at least one dose of study drug; the study was powered to show non-inferiority with a 10% efficacy margin of tenofovir alafenamide compared with tenofovir disoproxil fumarate. Bone and renal safety, and key secondary safety endpoints were assessed sequentially. The study will be conducted for a total of 3 years as a double-blind comparison to assess the longer term response to treatment. This study is registered with ClinicalTrials.gov, number NCT01940341. FINDINGS: Between Sept 12, 2013, and Oct 31, 2014, 426 patients were randomly assigned (285 assigned to tenofovir alafenamide and 141 assigned to tenofovir disoproxil fumarate; one patient assigned to tenofovir disoproxil fumarate did not receive the treatment. 268 (94%) of 285 patients receiving tenofovir alafenamide had HBV DNA less than 29 IU/mL at week 48 versus 130 (93%) of 140 patients receiving tenofovir disoproxil fumarate (difference 1·8% [95% CI -3·6 to 7·2]; p=0·47), which demonstrates non-inferiority. Patients receiving tenofovir alafenamide had significantly smaller mean percentage declines in bone mineral density than those receiving tenofovir disoproxil fumarate (hip -0·29% [95% CI -0·55 to -0·03] vs -2·16% [-2·53 to -1·79], adjusted percentage difference 1·87% [95% CI 1·42 to 2·32; p<0·0001]; spine -0·88% [-1·22 to -0·54] vs -2·51% [-3·09 to -1·94], adjusted percentage difference 1·64% [95% CI 1·01 to 2·27]; p<0·0001). At week 48, mean change in serum creatinine was small in both groups (tenofovir alafenamide 0·01 mg/dL [95% CI 0·00 to 0·02] vs tenofovir disoproxil fumarate 0·02 mg/dL [0·00 to 0·04], adjusted percentage difference -0·01 mg/dL [95% CI -0·03 to 0·01]; p=0·32), but patients receiving tenofovir alafenamide had a smaller reduction in creatinine clearance (median change in estimated glomerular filtration rate -1·8 mL/min [IQR -7·8 to 6·0] vs -4·8 mL/min [-12·0 to 3·0]; p=0·004). Most adverse events were mild to moderate in severity in the two treatment groups. The most common adverse events overall were headache (tenofovir alafenamide 40 [14%] patients vs tenofovir disoproxil fumarate 14 [10%] patients), nasopharyngitis (30 [11%] vs 15 [11%]), and upper respiratory tract infection (35 [12%] vs ten [7%]). 14 (5%) patients receiving tenofovir alafenamide and nine (6%) patients receiving tenofovir disoproxil fumarate had serious adverse events, none of which was deemed by investigators to be related to study treatment; one patient in the tenofovir disoproxil fumarate group died, but this was not deemed to be related to study treatment. INTERPRETATION: In patients with HBeAg-negative chronic HBV, the efficacy of tenofovir alafenamide was non-inferior to that of tenofovir disoproxil fumarate, and had improved bone and renal effects. Longer term follow-up is needed to better understand the clinical impact of these changes. FUNDING: Gilead Sciences.

Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B: a multicentre prospective study.

BACKGROUND AND OBJECTIVE: The off-treatment durability of nucleos(t)ide analogue therapy in Asian hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) and the role of hepatitis B surface antigen (HBsAg) levels in predicting off-treatment durability has not been well investigated. METHODS: Following Asia-Pacific Association for the Study of the Liver guidelines, entecavir was stopped in Asian HBeAg negative patients treated for ≥ 2 years with undetectable HBV DNA levels on ≥ 3 separate occasions 6 months apart before treatment cessation. HBsAg and HBV DNA levels were prospectively monitored every 6-12 weeks for 48 weeks. Entecavir was restarted if there was virologic relapse (defined as HBV DNA >2000IU/mL). RESULT: 184 patients (mean age 53.9 years, 67.9% male) were recruited. The cumulative rate of virologic relapse at 24 and 48 weeks was 74.2% and 91.4%, respectively. The median HBV DNA level at virologic relapse was 11000 (range 2115 to >1.98×10(8)) IU/mL. 42 (25.8%) patients had elevated alanine aminotransferase (median level 97 U/L, range 37-1058 U/L) during virologic relapse. Mean rate of off-treatment HBsAg decline was 0.018 (± 0.456) log IU/mL/year. No patients cleared HBsAg. There was no correlation between off-treatment serial HBsAg and HBV DNA levels (r=-0.026, p=0.541). HBsAg levels at the time of entecavir commencement, entecavir cessation and the subsequent rate of HBsAg reduction were not associated with virologic relapse (all p>0.05). CONCLUSIONS: Entecavir cessation in Asian HBeAg negative CHB resulted in high rates of virologic relapse, suggesting nucleos(t)ide analogue therapy should be continued indefinitely until the recognised treatment endpoint of HBsAg seroclearance.

Randomized, controlled pharmacokinetic and pharmacodynamic evaluation of albinterferon in patients with chronic hepatitis B infection.

BACKGROUND AND AIMS: Albinterferon is a fusion of albumin and interferon-α2b developed to improve the pharmacokinetics, convenience, and potential efficacy of interferon-α for the treatment of chronic hepatitis infections. METHODS: This open-label, randomized, active-controlled, multicenter study investigated the safety and efficacy of albinterferon in patients with chronic hepatitis B virus (HBV) infection who were e-antigen (HBeAg) positive. One hundred and forty-one patients received one of four albinterferon doses/regimens or pegylated-interferon-α2a. Primary efficacy outcomes were changes in serum HBeAg and antibody, HBV-DNA, and alanine aminotransferase. Principal safety outcomes were changes in laboratory values, pulmonary function, and adverse events. RESULTS: The study was prematurely terminated as phase III trials in hepatitis C infection indicated noninferior efficacy but inferior safety compared with pegylated-interferon-α2a. Here, all treatment groups had a significant reduction in HBV-DNA from baseline. Reductions in HBV-DNA were not significantly different, except the 1200 µg every 4 weeks albinterferon dose which was inferior compared with pegylated-interferon-α2a. The serum alanine aminotransferase levels decreased in all arms. The per-patient incidence of adverse events was not significantly different for albinterferon (96.4-100%) and pegylated-interferon-α2a (93.1%). Total adverse events, however, were higher for albinterferon and correlated to dose. Decreased lung function was found in all arms (∼93% of patients), and was more common in some albinterferon groups. CONCLUSIONS: Albinterferon doses with similar anti-HBV efficacy to pegylated-interferon-α2a had higher rates of certain adverse events, particularly changes in lung diffusion capacity (http://www.clinicaltrials.gov number NCT00964665).

Effects of tenofovir disoproxil fumarate in hepatitis B e antigen-positive patients with normal levels of alanine aminotransferase and high levels of hepatitis B virus DNA.

BACKGROUND & AIMS: Little is known about the benefit of antiviral therapy for hepatitis B e antigen (HBeAg)-positive patients with high viral load and normal levels of alanine aminotransferase. We evaluated the effects of single and combination therapies in immune-tolerant patients with chronic hepatitis B. METHODS: In a double-blind study, nucleos(t)ide-naïve patients with high levels of hepatitis B virus (HBV) DNA who were positive for HBeAg and had normal levels of alanine aminotransferase were randomly assigned to groups given either oral tenofovir disoproxil fumarate (TDF, 300 mg) and placebo (n = 64) or a combination of TDF (300 mg) and emtricitabine (200 mg, n = 62) for 192 weeks. The primary end point was proportion of patients with serum levels of HBV DNA <69 IU/mL at week 192. RESULTS: The study population (mean age was 33 years; 89% were Asian) was predominantly infected with HBV genotypes B and C (93%), 99% were HBeAg positive with a mean baseline level of HBV DNA of 8.41 log10 IU/mL. At week 192, 55% of patients (35 of 64) in the TDF+placebo group and 76% of patients (47 of 62) in the TDF+emtricitabine group had levels of HBV DNA <69 IU/mL (P = .016). No patients were found to have viral resistance to therapy. HBeAg seroconversion occurred in 3 patients (5%), all in the TDF+placebo group; no patient had loss of hepatitis B surface antigen. In multivariate analysis, female sex (odds ratio = 7.05; P = .002) and TDF+emtricitabine treatment (odds ratio = 3.9; P = .01) were associated with a favorable response. Both regimens were well tolerated. CONCLUSIONS: In HBeAg-positive patients with chronic HBV infection, high viral loads, normal levels of alanine aminotransferase, and therapy with the combination of TDF and emtricitabine provided better viral suppression than TDF alone, although rates of HBeAg seroconversion and hepatitis B surface antigen loss were low.

A randomized comparison of ultrathin and standard colonoscope in cecal intubation rate and patient tolerance.

BACKGROUND: Complete colonoscopy examination cannot be performed in as many as 10% of cases. The new 9.2-mm ultrathin colonoscope (UTC) with an extra bending section may improve procedure tolerance and allow improvement in colonoscopy completion rate compared with a 12.9-mm standard colonoscope (SC). OBJECTIVE: To compare the performance of the 9.2-mm UTC with that of the 12.9-mm SC. DESIGN: Prospective, randomized, controlled trial. SETTING: Academic endoscopic unit. PATIENTS: Subjects 18 years and older undergoing their first colonoscopy. INTERVENTION: Subjects were randomized to either the UTC or SC group. MAIN OUTCOME MEASUREMENTS: First and rescue successful cecal intubation rates, subject satisfaction scores, and sedation requirements were compared. RESULTS: A total of 1121 patients (56% women, mean age 53.6 years) were randomized to the UTC group (n = 551) or the SC group (n = 570). There was no statistically significant difference in the first successful cecal intubation rate between the UTC and SC groups (98.9% vs 97.4%, P = .057). The mean (standard deviation) dose of midazolam and pethidine used was significantly lower in the UTC group (2.65 [0.65] mg vs 2.82 [0.85] mg, P < .001 and 27.6 [7.4] mg vs 29.7 [9.6] mg, P < .001, respectively). The mean (standard deviation) patient satisfaction score was similar between groups (6.99 [2.89] vs 7.04 [3.06], P = .762). Of the 21 patients (1.9%) with an incomplete initial colonoscopy (6 in the UTC group and 15 in the SC group), all 6 in the UTC group had their procedure completed with an SC. Eleven of 15 patients in the SC group had their procedures completed with a UTC in the same session. LIMITATIONS: Low failure rate may mask any difference between the 2 colonoscopes as a rescue instrument. CONCLUSIONS: The 9.2-mm UTC has performance characteristics similar to those of an SC in Chinese subjects undergoing their first colonoscopy performed by experienced and trainee endoscopists. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01142167.).

High incidence of mortality and recurrent bleeding in patients with Helicobacter pylori-negative idiopathic bleeding ulcers.

BACKGROUND & AIMS: The long-term prognosis of peptic ulcers associated with neither Helicobacter pylori nor nonsteroidal anti-inflammatory drugs (NSAIDs) is unknown. METHODS: This 7-year prospective cohort study recruited patients with bleeding ulcers from January to December 2000. H pylori-negative idiopathic bleeding ulcers were defined as having tested negative for H pylori, having no exposure to aspirin or analgesics within 4 weeks before endoscopy, and having no other identifiable causative factors. After ulcers healed, patients were divided into 2 groups: patients with prior H pylori-negative idiopathic bleeding ulcers (H pylori-negative idiopathic ulcer cohort; n = 120) and those with H pylori-positive, NSAID-negative bleeding ulcers who received eradication therapy (H pylori ulcer cohort; n = 213). Both groups were followed for

Efficacy of cap-assisted colonoscopy in comparison with regular colonoscopy: a randomized controlled trial.

OBJECTIVES: Colonoscopy cannot be completed in up to 10% of cases. We postulate that cap-assisted colonoscopy (CAC), by fitting a mucosectomy cap to the tip of a colonoscope, could improve the outcome. METHODS: We conducted a prospective randomized controlled trial in two regional endoscopy centers. All colonoscopies were performed by experienced colonoscopists. Patients 18 years or older undergoing their first colonoscopy were recruited. Patients were randomized to the CAC group or to the regular colonoscopy (RC) group. The first successful cecal intubation rate, rescue cecal intubation rate, cecal intubation and total colonoscopy times, and polyp detection rate were compared. RESULTS: One thousand patients were enrolled (mean age 52.6 years, 46% men). There was no statistically significant difference in the first successful cecal intubation rate between CAC and RC groups (96.2% vs. 94.6%, P=0.23). The cecal intubation and total colonoscopy times were shorter in the CAC group than in the RC group (6.0+/-4.0 min vs. 7.2+/-4.8 min, P<0.001; 14.7+/-8.6 min vs. 16.7+/-10.3 min, P=0.001). The adenoma detection rate was significantly lower in the CAC group than in the RC group (30.5% vs. 37.5%, P=0.018), but there was no significant difference in the detection of advanced lesions. In case of failing cecal intubation, use of CAC as a rescue method could achieve a higher success rate than RC (66.7% vs. 21.1%, P=0.003). CONCLUSIONS: Among experienced colonoscopists, CAC did not improve the initial cecal intubation rate and had a lower adenoma detection rate. However, it shortened the cecal intubation time and performed better as a rescue method. Its utilization should be reserved for selected cases, especially when initial cecal intubation fails.

Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial.

BACKGROUND: Guidelines on pain management recommend that patients at risk of ulcers receive either a cyclo-oxygenase (COX 2) inhibitor or a non-steroidal anti-inflammatory drug (NSAID) with a proton-pump inhibitor (PPI). These two treatments have similar effectiveness, but they are insufficient for protection of patients at very high risk for ulcer bleeding. We aimed to test the hypothesis that in patients with previous ulcer bleeding induced by non-selective NSAIDs, combined treatment with the COX 2 inhibitor celecoxib and the PPI esomeprazole would be better than celecoxib alone for prevention of recurrent ulcer bleeding. METHODS: 441 consecutively presenting patients who were taking non-selective NSAIDs for arthritis were recruited to our single-centre, prospective, randomised, double-blind trial after admission to hospital with upper-gastrointestinal bleeding. Patients were enrolled after their ulcers had healed and a histological test for Helicobacter pylori was negative. All patients were given 200 mg celecoxib twice daily. 137 patients were randomly assigned to receive 20 mg esomeprazole twice daily (combined-treatment group), and 136 to receive a placebo (control group) for 12 months. The primary endpoint was recurrent ulcer bleeding during treatment or within 1 month of the end of treatment. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00365313. FINDINGS: Combination treatment was more effective than celecoxib alone for prevention of ulcer bleeding in patients at high risk. The 13-month cumulative incidence of the primary endpoint was 0% in the combined-treatment group and 12 (8.9%) in the controls (95% CI difference, 4.1 to 13.7; p=0.0004). The median follow-up was 13 months (range 0.4-13.0). Discontinuation of treatment and the incidence of adverse events were similar in the two treatment groups. INTERPRETATION: Patients at very high risk for recurrent ulcer bleeding who need anti-inflammatory analgesics should receive combination treatment with a COX 2 inhibitor and a PPI. Our findings should encourage guideline committees to review their recommendations for patients at very high risk of recurrent ulcer bleeding.