Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Up to 60% of patients with Crohn's disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohn's disease. METHODS: We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohn's disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohn's disease (Crohn's Disease Activity Index >150 plus 100-point increase in score) and the need for anti-inflammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15). FINDINGS: Between June 6, 2008, and April 23, 2012, 240 patients with Crohn's disease were randomly assigned: 128 to mercaptopurine and 112 to placebo. All patients received at least one dose of study drug, and no randomly assigned patients were excluded from the analysis. 16 (13%) of patients in the mercaptopurine group versus 26 (23%) patients in the placebo group had a clinical recurrence of Crohn's disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95% CI 0·27-1·06; p=0·07; unadjusted HR 0·53, 95% CI 0·28-0·99; p=0·046). In a subgroup analysis, three (10%) of 29 smokers in the mercaptopurine group and 12 (46%) of 26 in the placebo group had a clinical recurrence that needed treatment (HR 0·13, 95% CI 0·04-0·46), compared with 13 (13%) of 99 non-smokers in the mercaptopurine group and 14 (16%) of 86 in the placebo group (0·90, 0·42-1·94; pinteraction=0·018). The effect of mercaptopurine did not significantly differ from placebo for any of the other planned subgroup analyses (previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis). The incidence and types of adverse events were similar in the mercaptopurine and placebo groups. One patient on placebo died of ischaemic heart disease. Adverse events caused discontinuation of treatment in 39 (30%) of 128 patients in the mercaptopurine group versus 41 (37%) of 112 in the placebo group. INTERPRETATION: Mercaptopurine is effective in preventing postoperative clinical recurrence of Crohn's disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence. FUNDING: Medical Research Council.

Is the Glasgow Blatchford score useful in the risk assessment of patients presenting with variceal haemorrhage?

BACKGROUND: The Glasgow Blatchford score (GBS) is a pre-endoscopic risk assessment tool for patients presenting with upper gastrointestinal haemorrhage. There are few data regarding use in patients with variceal bleeding, who are generally accepted as being at high risk. AIM: The aim of the study was to assess GBS in correctly identifying patients with subsequently proven variceal bleeding as 'high risk' and to compare GBS, admission and full Rockall scores in predicting clinical endpoints in this group. PATIENTS AND METHODS: Data on consecutive patients with upper gastrointestinal haemorrhage presenting to four UK hospitals were collected. The GBS, admission and full Rockall scores were calculated and compared for the subgroup subsequently shown to have variceal bleeding. Area under the receiver operating curve (AUROC) was used to assess the scores ability to predict clinical endpoints within this variceal bleeding subgroup. RESULTS: A total of 1432 patients presented during the study period. Seventy-one (5%) had a final diagnosis of variceal bleeding. At presentation, none of this group had GBS less than 2, but six had an admission Rockall score of 0. In predicting need for blood transfusion, AUROC scores for GBS, full and admission Rockall scores were 0.68, 0.65 and 0.68, respectively. For endoscopic/surgical intervention the scores were 0.34, 0.51 and 0.55, respectively, and for predicting death the scores were 0.56, 0.72 and 0.70, respectively. None of these AUROC score comparisons were significant. CONCLUSION: At presentation, GBS correctly identifies patients with variceal bleeding as high risk and appears superior to the admission Rockall score. However, GBS and both Rockall scores are poor at predicting clinical outcome within this group.