title: Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial.
abstract: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  Medical Research Council.
authors.affiliation: Gastrointestinal Unit, Ninewells Hospital, Dundee, UK.
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authors.lastname: Mowat
authors.affiliation: Gastrointestinal Unit, Western General Hospital, Edinburgh, UK.
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authors.affiliation: Gastrointestinal Unit, Glasgow Royal Infirmary, Glasgow, UK.
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authors.affiliation: Department of Gastroenterology, Royal Liverpool University Hospital, Liverpool, UK.
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authors.affiliation: Department of Gastroenterology, Darlington Memorial Hospital, Darlington, UK.
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authors.affiliation: Department of Gastroenterology, Torbay Hospital, South Devon Healthcare NHS Foundation Trust, Torbay, Devon, UK.
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authors.affiliation: Department of Gastroenterology, Bristol Royal Infirmary, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
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authors.affiliation: Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK.
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authors.affiliation: Department of Gastroenterology, Rotherham NHS Foundation Trust Hospital, Rotherham, UK.
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authors.affiliation: Department of Gastroenterology, Singleton Hospital, Abertawe Bro Morgannwg University Health Board, Swansea, UK.
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authors.affiliation: Department of Gastroenterology, Manchester Royal Infirmary, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
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authors.affiliation: Department of Gastroenterology, Derriford Hospital, Plymouth Hospitals NHS Trust, Plymouth, UK.
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authors.affiliation: Department of Gastroenterology, Hull Royal Infirmary, Hull and East Yorkshire Hospitals NHS Trust, Hull, UK.
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authors.affiliation: Department of Gastroenterology, Royal Stoke University Hospital, University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, UK.
authors.forename: Sandip
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authors.affiliation: Department of Gastroenterology, Salford Royal NHS Foundation Trust Hospital, Salford, UK.
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authors.affiliation: Department of Gastroenterology, Nottingham University Hospitals NHS Trust, Nottingham, UK.
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authors.affiliation: Department of Gastroenterology, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
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authors.affiliation: Department of Gastroenterology, Barts Health NHS Trust, Barts and the London School of Medicine, London, UK.
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authors.affiliation: Inflammatory Bowel Disease Unit, St Mark's Hospital, North West London Hospitals NHS Trust, London, UK.
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authors.lastname: Arebi
authors.affiliation: Gastrointestinal Unit, Raigmore Hospital, Inverness, UK.
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authors.affiliation: Department of Surgery, Aberdeen Royal Infirmary, Aberdeen, UK.
authors.forename: Aileen J
authors.initials: AJ
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authors.affiliation: Gastrointestinal Unit, Aberdeen Royal Infirmary, Aberdeen, UK.
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authors.initials: JM
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authors.affiliation: Gastrointestinal Unit, Ninewells Hospital, Dundee, UK.
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authors.affiliation: Colorectal Surgery, Western General Hospital, Edinburgh, UK.
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authors.affiliation: Gastrointestinal Unit, Glasgow Royal Infirmary, Glasgow, UK.
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authors.affiliation: Gastrointestinal Unit, Glasgow Royal Infirmary, Glasgow, UK.
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authors.initials: GD
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authors.affiliation: Edinburgh Clinical Trials Unit, University of Edinburgh, Edinburgh, UK.
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authors.initials: H
authors.lastname: Ennis
authors.affiliation: Edinburgh Clinical Trials Unit, University of Edinburgh, Edinburgh, UK.
authors.forename: Catriona
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authors.lastname: Keerie
authors.affiliation: Edinburgh Clinical Trials Unit, University of Edinburgh, Edinburgh, UK.
authors.forename: Steff
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authors.lastname: Lewis
authors.affiliation: Usher Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Prescott
authors.affiliation: Gastrointestinal Unit, Western General Hospital, Edinburgh, UK; IBD Pharmacogenetics Unit, University of Exeter, Exeter, UK.
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authors.initials: NA
authors.lastname: Kennedy
authors.affiliation: Gastrointestinal Unit, Western General Hospital, Edinburgh, UK. Electronic address: jack.satsangi@igmm.ed.ac.uk.
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authors.lastname: Satsangi
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D003424:Crohn Disease / Q000175:diagnosis / Q000517:prevention & control* / Q000601:surgery*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D015122:Mercaptopurine / Q000627:therapeutic use*; D008875:Middle Aged; D012008:Recurrence; D055502:Secondary Prevention / Q000379:methods*; D012907:Smoking / Q000009:adverse effects; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D015122:Mercaptopurine