Development and validation of a histological index for UC.

OBJECTIVE: Although the Geboes score (GS) and modified Riley score (MRS) are commonly used to evaluate histological disease activity in UC, their operating properties are unknown. Accordingly, we developed an alternative instrument. DESIGN: Four pathologists scored 48 UC colon biopsies using the GS, MRS and a visual analogue scale global rating. Intra-rater and inter-rater reliability for each index and individual index items were measured using intraclass correlation coefficients (ICCs). Items with high reliability were used to develop the Robarts histopathology index (RHI). The responsiveness/validity of the RHI and multiple histological, endoscopic and clinical outcome measures were evaluated by analyses of change scores, standardised effect size (SES) and Guyatt's responsiveness statistic (GRS) using data from a clinical trial of an effective therapy. RESULTS: Inter-rater ICCs (95% CIs) for the total GS and MRS scores were 0.79 (0.63 to 0.87) and 0.80 (0.69 to 0.87). The correlation estimates between change scores in RHI and change score in GS and MRS were 0.75 (0.67 to 0.82) and 0.84 (0.79 to 0.88), respectively. The SES and GRS estimates for GS, MRS and RHI were: 1.87 (1.54 to 2.20) and 1.23 (0.97 to 1.50), 1.29 (1.02 to 1.56) and 0.88 (0.65 to 1.12), and 1.05 (0.79 to 1.30) and 0.88 (0.64 to 1.12), respectively. CONCLUSIONS: The RHI is a new histopathological index with favourable operating properties.

Systematic Review and Meta-analysis: Placebo Rates in Induction and Maintenance Trials of Ulcerative Colitis.

BACKGROUND AND AIMS: Minimisation of the placebo responses in randomised controlled trials [RCTs] is essential for efficient evaluation of new interventions. Placebo rates have been high in ulcerative colitis [UC] clinical trials, and factors influencing this are poorly understood. We quantify placebo response and remission rates in UC RCTs and identify trial design factors influencing them. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched from inception through April 2014 for placebo-controlled trials in adult patients with UC of a biological agent, corticosteroid, immunosuppressant, or aminosalicylate. Data were independently doubly extracted. Quality was assessed using the Cochrane risk of bias tool. RESULTS: In all, 51 trials [48 induction and 10 maintenance phases] were identified. Placebo response and remission rates were pooled according to random-effects models, and mixed-effects meta-regression models were used to evaluate effects of study-level characteristics on these rates. Pooled estimates of placebo remission and response rates for induction trials were 10% (95% confidence interval [CI] 7-13%) and 33% [95% CI 29-37%], respectively. Corresponding values for maintenance trials were 19% [95% CI 11-30%] and 22% [95% CI 17-28%]. Trials enrolling patients with more active disease confirmed by endoscopy [endoscopy subscore ≥ 2] were associated with lower placebo rates. Conversely, placebo rates increased with increasing trial duration and number of study visits. CONCLUSIONS: Objective assessment of greater disease activity at trial entry by endoscopy lowered placebo rates, whereas increasing trial duration and more interactions with healthcare providers increased placebo rates. These findings have important implications for design and conduct of clinical trials.

Reliability among central readers in the evaluation of endoscopic findings from patients with Crohn's disease.

OBJECTIVE: The Crohn's Disease Endoscopic Index of Severity (CDEIS) and Simple Endoscopic Score for Crohn's Disease (SES-CD) are commonly used to assess Crohn's disease (CD) activity; however, neither instrument has been fully validated. We assessed intra-rater and inter-rater reliability of these indices. DESIGN: Video recordings of colonoscopies obtained from 50 patients with CD who participated in an induction trial of a biological therapy were triplicated and reviewed in random order by four central readers. Data were used to assess intra-rater and inter-rater reliability for CDEIS, SES-CD and a global evaluation of lesion severity (GELS). Subsequently, readers participated in a consensus process that identified common sources of disagreement. RESULTS: Intraclass correlation coefficients (ICCs) for intra-rater reliability for CDEIS, SES-CD and GELS (95% CIs) were 0.89 (0.86 to 0.93), 0.91 (0.89 to 0.95) and 0.81 (0.77 to 0.89), respectively, with standard error of measurement (SEM) of 2.10, 2.42 and 1.15. The corresponding ICCs for inter-rater reliability were 0.71 (0.63 to 0.76), 0.83 (0.75 to 0.88) and 0.62 (0.52 to 0.70), with SEM of 3.42, 3.07 and 1.63, respectively. Correlation between CDEIS and GELS was 0.75, between SES-CD and GELS was 0.74 and between CDEIS and SES-CD was 0.92. The most common sources of disagreement were interpretation of superficial ulceration, definition of disease site at the ileocolonic anastomosis, assessment of anorectal lesions and grading severity of stenosis. CONCLUSIONS: Central reading of CDEIS and SES-CD had 'substantial' to 'almost perfect' intra-rater and inter-rater reliability; however, the responsiveness of these instruments is yet to be determined. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT01466374.

Early combined immunosuppression for the management of Crohn's disease (REACT): a cluster randomised controlled trial.

BACKGROUND: Conventional management of Crohn's disease features incremental use of therapies. However, early combined immunosuppression (ECI), with a TNF antagonist and antimetabolite might be a more effective strategy. We compared the efficacy of ECI with that of conventional management for treatment of Crohn's disease. METHODS: In this open-label cluster randomised controlled trial (Randomised Evaluation of an Algorithm for Crohn's Treatment, REACT), we included community gastroenterology practices from Belgium and Canada that were willing to be assigned to either of the study groups, participate in all aspects of the study, and provide data on up to 60 patients with Crohn's disease. These practices were randomly assigned (1:1) to either ECI or conventional management. The computer-generated randomisation was minimised by country and practice size. Up to 60 consecutive adult patients were assessed within practices. Patients who were aged 18 years or older; documented to have Crohn's disease; able to speak or understand English, French, or Dutch; able to access a telephone; and able to provide written informed consent were followed up for 2 years. The primary outcome was the proportion of patients in corticosteroid-free remission (Harvey-Bradshaw Index score ≤ 4) at 12 months at the practice level. This trial is registered with ClinicalTrials.gov, number NCT01030809. FINDINGS: This study took place between March 15, 2010, and Oct 1, 2013. Of the 60 practices screened, 41 were randomly assigned to either ECI (n=22) or conventional management (n=19). Two practices (one in each group) discontinued because of insufficient resources. 921 (85%) of the 1084 patients at ECI practices and 806 (90%) of 898 patients at conventional management practices completed 12 months follow-up and were included in an intention-to-treat analysis. The 12 month practice-level remission rates were similar at ECI and conventional management practices (66·0% [SD 14·0] and 61·9% [16·9]; adjusted difference 2·5%, 95% CI -5·2% to 10·2%, p=0·5169). The 24 month patient-level composite rate of major adverse outcomes defined as occurrence of surgery, hospital admission, or serious disease-related complications was lower at ECI practices than at conventional management practices (27·7% and 35·1%, absolute difference [AD] 7·3%, hazard ratio [HR]: 0·73, 95% CI 0·62 to 0·86, p=0·0003). There were no differences in serious drug-related adverse events. INTERPRETATION: Although ECI was not more effective than conventional management for controlling Crohn's disease symptoms, the risk of major adverse outcomes was lower. The latter finding should be considered hypothesis-generating for future trials. ECI was not associated with an increased risk of serious drug-related adverse events or mortality. FUNDING: AbbVie Pharmaceuticals.

Reproducibility of histological assessments of disease activity in UC.

OBJECTIVE: Histopathology is potentially an important outcome measure in UC. Multiple histological disease activity (HA) indices, including the Geboes score (GS) and modified Riley score (MRS), have been developed; however, the operating properties of these instruments are not clearly defined. We assessed the reproducibility of existing measures of HA. DESIGN: Five experienced pathologists with GI pathology fellowship training and expertise in IBD evaluated, on three separate occasions at least two weeks apart, 49 UC colon biopsies and scored the GS, MRS and a global rating of histological severity using a 100 mm visual analogue scale (VAS). The reproducibility of each grading system and for individual instrument items was quantified by estimates of intraclass correlation coefficients (ICCs) based on two-way random effects models. Uncertainty of estimates was quantified by 95% two-sided CIs obtained using the non-parametric cluster bootstrap method. Biopsies responsible for the greatest disagreement based on the ICC estimates were identified. A consensus process was used to determine the most common sources of measurement disagreement. Recommendations for minimising disagreement were subsequently generated. RESULTS: Intrarater ICCs (95% CIs) for the total GS, MRS and VAS scores were 0.82 (0.73 to 0.88), 0.71 (0.63 to 0.80) and 0.79 (0.72 to 0.85), respectively. Corresponding inter-rater ICCs were substantially lower: 0.56 (0.39 to 0.67), 0.48 (0.35 to 0.66) and 0.61 (0.47 to 0.72). Correlation between the GS and VAS was 0.62 and between the MRS and VAS was 0.61. CONCLUSIONS: Although 'substantial' to 'almost perfect' ICCs for intrarater agreement were found in the assessment of HA in UC, ICCs for inter-rater agreement were considerably lower. According to the consensus process results, standardisation of item definitions and modification of the existing indices is required to create an optimal UC histological instrument.

Histologic evaluation of ulcerative colitis: a systematic review of disease activity indices.

BACKGROUND: Ulcerative colitis (UC) is an idiopathic inflammatory disorder. Currently, the main goals of treatment are to induce and maintain clinical and/or endoscopic remission. However, evidence indicates that persistent disease activity on colonic biopsies in the setting of clinical or endoscopic remission is an independent predictor of poor outcomes. A number of previous studies have proposed histologic indices for use in specific trials of UC. The aim of this study was to systematically review the existing histological indices for UC and assess their potential use in both patient management and clinical trials. METHODS: We performed a systematic review of histological indices evaluating disease activity in UC. MEDLINE (Ovid), EMBASE (Ovid), PubMed, the Cochrane Library (CENTRAL), and Digestive Diseases Week (DDW) abstracts of randomized and/or controlled trials clinical trials were searched from inception to February 2013 for applicable studies. Data from these studies were reviewed and analyzed. RESULTS: After systematically applying inclusion criteria, we identified 108 scientific articles including 88 clinical studies and 21 related clinical reviews. Eighteen indices of histological activity in UC were identified and reviewed. CONCLUSIONS: Although multiple histological scoring indices for assessment of UC disease activity currently exist, none of these instruments were developed using a formal validation process and their operating properties remain poorly understood. Future studies are needed to address this deficiency.

Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn's disease.

BACKGROUND & AIMS: Methotrexate and infliximab are effective therapies for Crohn's disease (CD). In the combination of maintenance methotrexate-infliximab trial, we evaluated the potential superiority of combination therapy over infliximab alone. METHODS: In a 50-week, double-blind, placebo-controlled trial, we compared methotrexate and infliximab with infliximab alone in 126 patients with CD who had initiated prednisone induction therapy (15-40 mg/day) within the preceding 6 weeks. Patients were assigned randomly to groups given methotrexate at an initial weekly dose of 10 mg, escalating to 25 mg/week (n = 63), or placebo (n = 63). Both groups received infliximab (5 mg/kg of body weight) at weeks 1, 3, 7, and 14, and every 8 weeks thereafter. Prednisone was tapered, beginning at week 1, and discontinued no later than week 14. The primary outcome was time to treatment failure, defined as a lack of prednisone-free remission (CD Activity Index, <150) at week 14 or failure to maintain remission through week 50. RESULTS: Patients' baseline characteristics were similar between groups. By week 50, the actuarial rate of treatment failure was 30.6% in the combination therapy group compared with 29.8% in the infliximab monotherapy group (P = .63; hazard ratio, 1.16; 95% confidence interval, 0.62-2.17). Prespecified subgroup analyses failed to show a benefit in patients with short disease duration or an increased level of C-reactive protein. No clinically meaningful differences were observed in secondary outcomes. Combination therapy was well tolerated. CONCLUSIONS: The combination of infliximab and methotrexate, although safe, was no more effective than infliximab alone in patients with CD receiving treatment with prednisone. ClincialTrials.gov number, NCT00132899.

Simplified therapeutic intervention to control hypertension and hypercholesterolemia: a cluster randomized controlled trial (STITCH2).

BACKGROUND: Notwithstanding improving rates of hypertension control in North America, management of patients with both hypertension and dyslipidemia remains problematic. Based on evidence of improved control utilizing a simplified algorithm for management of hypertension (STITCH), we questioned whether a simplified comprehensive treatment algorithm featuring initial use of single-pill combinations (SPCs) would improve management of participants with both hypertension and dyslipidemia. METHOD: We randomized 35 primary care practices in Ontario to either Guidelines-care (following current Canadian guidelines) or STITCH2-care (following a treatment algorithm featuring SPCs). Practices each enrolled up to 50 participants with at least one risk factor above target at entry based on Canadian guidelines for BP and LDL-cholesterol control. The primary endpoint was achieving targets for both hypertension and dyslipidemia control after 6 months, assessed at the practice level. RESULTS: The primary endpoint was achieved in 31.3% of participants in STITCH2-care practices, compared with 28.1% in Guidelines-care practices, yielding a difference of 3.2% (P = 0.63). Notably, STITCH2-care practices had a significantly greater reduction in SBP while LDL-cholesterol reduction was only marginally greater in STITCH2 practices. CONCLUSION: The STITCH2 algorithm resulted in significantly greater use of any SPC compared with Guidelines-care and greater use of the SPC of calcium channel blocker/statin. Unwillingness of the prescribing physician to advance treatment beyond a monotherapy threshold was found to be an important determinant for failing to achieve blood pressure control. In contrast, the more important determinant for failing to achieve LDL control appeared to be the unwillingness of the prescribing physician to initiate therapy with a statin.

The role of centralized reading of endoscopy in a randomized controlled trial of mesalamine for ulcerative colitis.

BACKGROUND & AIMS: Interobserver differences in endoscopic assessments contribute to variations in rates of response to placebo in ulcerative colitis (UC) trials. We investigated whether centralized review of images could reduce these variations. METHODS: We performed a 10-week, randomized, double-blind, placebo-controlled study of 281 patients with mildly to moderately active UC, defined by an Ulcerative Colitis Disease Activity Index (UCDAI) sigmoidoscopy score ≥2, that evaluated the efficacy of delayed-release mesalamine (Asacol 800-mg tablet) 4.8 g/day. Endoscopic images were reviewed by a single expert central reader. The primary outcome was clinical remission (UCDAI, stool frequency and bleeding scores of 0, and no fecal urgency) at week 6. RESULTS: The primary outcome was achieved by 30.0% of patients treated with mesalamine and 20.6% of those given placebo, a difference of 9.4% (95% confidence interval [CI], -0.7% to 19.4%; P = .069). Significant differences in results from secondary analyses indicated the efficacy of mesalamine. Thirty-one percent of participants, all of whom had a UCDAI sigmoidoscopy score ≥2 as read by the site investigator, were considered ineligible by the central reader. After exclusion of these patients, the remission rates were 29.0% and 13.8% in the mesalamine and placebo groups, respectively (difference of 15%; 95% CI, 3.5%-26.0%; P = .011). CONCLUSIONS: Although mesalamine 4.8 g/day was not statistically different from placebo for induction of remission in patients with mildly to moderately active UC, based on an intent-to-treat analysis, the totality of the data supports a benefit of treatment. Central review of endoscopic images is critical to the conduct of induction studies in UC; ClinicalTrials.gov Number, NCT01059344.

A randomised, double-blind, sham-controlled study of granulocyte/monocyte apheresis for moderate to severe Crohn's disease.

OBJECTIVES: Activated granulocytes and monocytes may contribute to the pathogenesis of Crohn's disease (CD). In small, uncontrolled studies, granulocyte/monocyte apheresis (GMA) has shown promise in treating CD. We conducted a randomised, double-blind study to compare GMA with a sham procedure in patients with moderate to severe CD. DESIGN: Patients with active CD as defined by a Crohn's Disease Activity Index (CDAI) of 220-450 were randomly allocated in a 2:1 ratio to treatment with GMA using the Adacolumn Apheresis System (JIMRO, Takasaki, Japan) or sham apheresis. Ten apheresis sessions were scheduled over a 9-week period, and efficacy was evaluated at week 12. The primary end point was the proportion of patients achieving clinical remission (CDAI score ≤ 150 without use of prohibited drugs). RESULTS: Clinical remission was achieved by 17.8% of patients in the GMA group (n = 157) compared with 19.2% of those in the sham control group (n = 78) (absolute difference--1.4% (95% CI--12.8% to 8.5%), p = 0.858). Clinical response (defined as a ≥ 100-point decrease in CDAI) was achieved by 28.0% and 26.9% of patients in the GMA and sham groups, respectively (p = 1.000). The two treatments produced similar changes from baseline in CDAI and quality of life, as well as in disease severity assessed endoscopically. The incidence and types of adverse events did not differ between groups. CONCLUSIONS: GMA was well tolerated, but this study did not demonstrate its effectiveness over a sham procedure in inducing clinical remission or response in patients with moderate to severe CD.

Barriers to blood pressure control: a STITCH substudy.

Despite improvements in blood pressure (BP) control, a substantial percentage of patients do not achieve target. The relative importance of determinants of poor BP control is unclear. Therefore, the authors conducted a post hoc exploratory analysis to assess determinants of BP control. Data were collected in 45 general practices, which enrolled patients with uncontrolled hypertension. Antihypertensive medication changes throughout the 6-month follow-up period were documented. Baseline and 6-month BPs were recorded. Of the 2030 patients analyzed, 320 had diabetes. Overall, 42% of patients did not achieve BP control. In multivariate analysis, failure to intensify therapy was identified as a significant independent predictor of lesser BP reduction. Of patients unable to reach target after 6 months, only 25% were prescribed ≥ 3 drugs. Patients with diabetes were significantly less likely to reach target than those without (26% vs 64%, P<.001). Antihypertensive therapy prescribed to patients with diabetes was only marginally more intensive than to those without. In patients with hypertension, whether with or without coexisting diabetes, poor BP control appears to be at least partially due to failure to uptitrate antihypertensive therapy. Clinical inertia is likely an important barrier to BP control.

A simplified approach to the treatment of uncomplicated hypertension: a cluster randomized, controlled trial.

Notwithstanding the availability of antihypertensive drugs and practice guidelines, blood pressure control remains suboptimal. The complexity of current treatment guidelines may contribute to this problem. To determine whether a simplified treatment algorithm is more effective than guideline-based management, we studied 45 family practices in southwestern Ontario, Canada, using a cluster randomization trial comparing the simplified treatment algorithm with the Canadian Hypertension Education Program guidelines. The simplified treatment algorithm consisted of the following: (1) initial therapy with a low-dose angiotensin-converting enzyme inhibitor/diuretic or angiotensin receptor blocker/diuretic combination; (2) up-titration of combination therapy to the highest dose; (3) addition of a calcium channel blocker and up-titration; and (4) addition of a non-first-line antihypertensive agent. The proportion of patients treated to target blood pressure (systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg for patients without diabetes mellitus or systolic blood pressure <130 mm Hg and diastolic blood pressure <80 mm Hg for diabetic patients) at 6 months was analyzed at the practice level. The proportion of patients achieving target was significantly higher in the intervention group (64.7% versus 52.7%; absolute difference: 12.0%; 95% CI: 1.5% to 22.4%; P=0.026). Multivariate analysis of patient-level data showed that assignment to the intervention arm increased the chance of reaching the target by 20% (P=0.028), when adjusted for other covariates. In conclusion, the Simplified Treatment Intervention to Control Hypertension Study indicates that a simplified antihypertensive algorithm using initial low-dose fixed-dose combination therapy is superior to guideline-based practice for the management of hypertension.

Treatment of active Crohn's disease with MLN0002, a humanized antibody to the alpha4beta7 integrin.

BACKGROUND & AIMS: Selective blockade of lymphocyte-vascular endothelium interactions in the gastrointestinal tract is a promising therapeutic strategy for inflammatory bowel disease. This randomized, double-blind, controlled trial assessed the efficacy and safety of MLN0002, a monoclonal antibody targeting the alpha4beta7 integrin, in patients with active Crohn's disease. METHODS: Patients were randomized to receive MLN0002 2.0 mg/kg (n = 65), MLN0002 0.5 mg/kg (n = 62), or placebo (n = 58) by intravenous infusion on days 1 and 29. The primary efficacy end point was clinical response (>or=70-point decrement in the Crohn's Disease Activity Index [CDAI] score) on day 57. Secondary end points were the proportions of patients with clinical remission (CDAI score or=100-point decrement in CDAI). Human anti-human antibody levels were measured. RESULTS: Clinical response rates at day 57 were 53%, 49%, and 41% in the MLN0002 2.0 mg/kg, MLN0002 0.5 mg/kg, and placebo groups. Clinical remission rates at day 57 were 37%, 30%, and 21%, respectively (P = .04 for the 2.0 mg/kg vs placebo comparison). At day 57, 12% and 34% of patients in the 2.0- and 0.5-mg/kg groups had clinically significant human anti-human antibody levels (titers > 1:125). There was one infusion-related hypersensitivity reaction. The most common serious adverse event was worsening of Crohn's disease. CONCLUSIONS: This phase 2 study was suggestive of a dose-dependent beneficial effect of MLN0002 therapy on clinical remission. MLN0002 was well tolerated in patients with active Crohn's disease.

A randomized, double-blind, sham-controlled study of granulocyte/monocyte apheresis for active ulcerative colitis.

BACKGROUND & AIMS: Activated granulocytes and monocytes/macrophages are implicated in the pathogenesis of ulcerative colitis. Open-label studies and clinical experience in Japan and Europe have suggested that granulocyte/monocyte apheresis is safe and effective in treating ulcerative colitis. METHODS: We evaluated the efficacy of granulocyte/monocyte apheresis in a randomized, double-blind, sham-controlled trial in patients with active moderate-to-severe ulcerative colitis (Mayo score 6-11) in community-based and tertiary care centers. As intervention, we used granulocyte/monocyte apheresis with the Adacolumn Apheresis System (JIMRO, Ltd, Takasaki, Japan) or sham apheresis in a 2:1 ratio for 9 weeks of treatment in a North American pivotal study (N = 168) and in a smaller, companion study of identical design conducted in Europe and Japan (N = 47). RESULTS: In the pivotal study, clinical remission rates (Mayo score 0-2, with scores of 0 on rectal bleeding and 0 or 1 on endoscopic examination) were 17% and 11% for the granulocyte/monocyte apheresis (n = 112)- and sham-treatment groups, respectively (n = 56; P = .361). Clinical response (Mayo score reduction of >/=3 points from baseline) was observed in 44% and 39% of patients, respectively (P = .620). Similar changes were observed for the apheresis- and sham-treatment groups for endoscopic remission and response, and changes in Mayo and quality-of-life scores. The companion study and pooled data from both studies also yielded similar results. CONCLUSIONS: In this study, granulocyte/monocyte apheresis was well tolerated but did not demonstrate efficacy for induction of clinical remission or response in patients with moderate-to-severe ulcerative colitis.

Omega-3 free fatty acids for the maintenance of remission in Crohn disease: the EPIC Randomized Controlled Trials.

CONTEXT: Maintenance therapy for Crohn disease features the use of immunosuppressive drugs, which are associated with an increased risk of infection. Identification of safe and effective maintenance strategies is a priority. OBJECTIVE: To determine whether the oral administration of omega-3 free fatty acids is more effective than placebo for prevention of relapse of Crohn disease. DESIGN, SETTING, AND PATIENTS: Two randomized, double-blind, placebo-controlled studies (Epanova Program in Crohn's Study 1 [EPIC-1] and EPIC-2) conducted between January 2003 and February 2007 at 98 centers in Canada, Europe, Israel, and the United States. Data from 363 and 375 patients with quiescent Crohn disease were evaluated in EPIC-1 and EPIC-2, respectively. INTERVENTIONS: Patients with a Crohn's Disease Activity Index (CDAI) score of less than 150 were randomly assigned to receive either 4 g/d of omega-3 free fatty acids or placebo for up to 58 weeks. No other treatments for Crohn disease were permitted. MAIN OUTCOME MEASURE: Clinical relapse, as defined by a CDAI score of 150 points or greater and an increase of more than 70 points from the baseline value, or initiation of treatment for active Crohn disease. RESULTS: For EPIC-1, 188 patients were assigned to receive omega-3 free fatty acids and 186 patients to receive placebo. Corresponding numbers for EPIC-2 were 189 and 190 patients, respectively. The rate of relapse at 1 year in EPIC-1 was 31.6% in patients who received omega-3 free fatty acids and 35.7% in those who received placebo (hazard ratio, 0.82; 95% confidence interval, 0.51-1.19; P = .30). Corresponding values for EPIC-2 were 47.8% and 48.8% (hazard ratio, 0.90; 95% confidence interval, 0.67-1.21; P = .48). Serious adverse events were uncommon and mostly related to Crohn disease. CONCLUSION: In these trials, treatment with omega-3 free fatty acids was not effective for the prevention of relapse in Crohn disease. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: EPIC-1: NCT00613197, EPIC-2: NCT00074542.

A cluster-randomized controlled trial of a blood conservation algorithm in patients undergoing total hip joint arthroplasty.

BACKGROUND: The optimum strategy for reducing allogeneic blood transfusion in patients undergoing total hip joint arthroplasty (THJA) is unknown. STUDY DESIGN AND METHODS: The effectiveness of a comprehensive blood conservation algorithm (BCA) was evaluated by means of a cluster randomization trial. Thirty hospitals performing primary THJA were randomly assigned to implement the algorithm or to continue with usual care (UC). Subsequently, the institutional rate of allogeneic transfusion was determined for 60 consecutive patients who underwent surgery at each site. The BCA consisted of patient and provider education, hemoglobin-based recommendations for specific blood conservation strategies (recombinant human erythropoietin [rHuEPO] or autologous blood donation [ABD]) and transfusion guidelines. The main outcome measure was the institutional allogeneic transfusion rate. RESULTS: One hospital withdrew consent after randomization, resulting in 14 hospitals assigned to BCA and 15 to UC. In the BCA arm, the institutional rates of rHuEPO use and ABD participation were 20.1 and 27.1 percent compared to 0.6 and 25.8 percent, respectively, in the UC arm. The allogeneic transfusion rate was substantially reduced in hospitals assigned to the BCA group (p = 0.02; absolute risk reduction, 9.6% [26.1% UC vs. 16.5% BCA]). Multivariate analysis of patient-level data showed that assignment to the UC arm was an independent risk factor for allogeneic transfusion (p = 0.037; odds ratio, 1.8; 95% confidence interval, 1.0-3.1) when adjusted for other prognostic factors. No differences were observed in the use of autologous blood. CONCLUSION: A comprehensive approach to blood conservation was superior to UC for reducing allogeneic transfusion in patients undergoing THJA.

Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin.

BACKGROUND: Selective blockade of interactions between leukocytes and vascular endothelium in the gut is a promising strategy for the treatment of inflammatory bowel diseases. METHODS: We conducted a multicenter, double-blind, placebo-controlled trial of MLN02, a humanized antibody to the alpha4beta7 integrin, in patients with active ulcerative colitis. We randomly assigned 181 patients to receive 0.5 mg of MLN02 per kilogram of body weight, 2.0 mg per kilogram, or an identical-appearing placebo intravenously on day 1 and day 29. Eligible patients also received concomitant mesalamine or no other treatment for colitis. Ulcerative colitis clinical scores and sigmoidoscopic assessments were evaluated six weeks after randomization. RESULTS: Clinical remission rates at week 6 were 33 percent, 32 percent, and 14 percent for the group receiving 0.5 mg of MLN02 per kilogram, the group receiving 2.0 mg per kilogram, and the placebo group, respectively (P=0.03). The corresponding proportions of patients who improved by at least 3 points on the ulcerative colitis clinical score were 66 percent, 53 percent, and 33 percent (P=0.002). Twenty-eight percent of patients receiving 0.5 mg per kilogram and 12 percent of those receiving 2.0 mg per kilogram had endoscopically evident remission, as compared with 8 percent of those receiving placebo (P=0.007). For the minority of patients in whom an MLN02 antibody titer greater than 1:125 developed, incomplete saturation of the alpha4beta7 receptor on circulating lymphocytes was observed and no benefit of treatment was identifiable. CONCLUSIONS: In this short-term study, MLN02 was more effective than placebo for the induction of clinical and endoscopic remission in patients with active ulcerative colitis.