Elsevier

The Lancet

Volume 385, Issue 9976, 11–17 April 2015, Pages 1406-1417
The Lancet

Articles
Crohn's disease management after intestinal resection: a randomised trial

https://doi.org/10.1016/S0140-6736(14)61908-5Get rights and content

Summary

Background

Most patients with Crohn's disease need an intestinal resection, but a majority will subsequently experience disease recurrence and require further surgery. This study aimed to identify the optimal strategy to prevent postoperative disease recurrence.

Methods

In this randomised trial, consecutive patients from 17 centres in Australia and New Zealand undergoing intestinal resection of all macroscopic Crohn's disease, with an endoscopically accessible anastomosis, received 3 months of metronidazole therapy. Patients at high risk of recurrence also received a thiopurine, or adalimumab if they were intolerant to thiopurines. Patients were randomly assigned to parallel groups: colonoscopy at 6 months (active care) or no colonoscopy (standard care). We used computer-generated block randomisation to allocate patients in each centre to active or standard care in a 2:1 ratio. For endoscopic recurrence (Rutgeerts score ≥i2) at 6 months, patients stepped-up to thiopurine, fortnightly adalimumab with thiopurine, or weekly adalimumab. The primary endpoint was endoscopic recurrence at 18 months. Patients and treating physicians were aware of the patient's study group and treatment, but central reading of the endoscopic findings was undertaken blind to the study group and treatment. Analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00989560.

Findings

Between Oct 13, 2009, and Sept 28, 2011, 174 (83% high risk across both active and standard care groups) patients were enrolled and received at least one dose of study drug. Of 122 patients in the active care group, 47 (39%) stepped-up treatment. At 18 months, endoscopic recurrence occurred in 60 (49%) patients in the active care group and 35 (67%) patients in the standard care group (p=0·03). Complete mucosal normality was maintained in 27 (22%) of 122 patients in the active care group versus four (8%) in the standard care group (p=0·03). In the active care arm, of those with 6 months recurrence who stepped up treatment, 18 (38%) of 47 patients were in remission 12 months later; conversely, of those in remission at 6 months who did not change therapy recurrence occurred in 31 (41%) of 75 patients 12 months later. Smoking (odds ratio [OR] 2·4, 95% CI 1·2–4·8, p=0·02) and the presence of two or more clinical risk factors including smoking (OR 2·8, 95% CI 1·01–7·7, p=0·05) increased the risk of endoscopic recurrence. The incidence and type of adverse and severe adverse events did not differ significantly between patients in the active care and standard care groups (100 [82%] of 122 vs 45 [87%] of 52; p=0·51) and (33 [27%] of 122 vs 18 [35%] of 52; p=0·36), respectively.

Interpretation

Treatment according to clinical risk of recurrence, with early colonoscopy and treatment step-up for recurrence, is better than conventional drug therapy alone for prevention of postoperative Crohn's disease recurrence. Selective immune suppression, adjusted for early recurrence, rather than routine use, leads to disease control in most patients. Clinical risk factors predict recurrence, but patients at low risk also need monitoring. Early remission does not preclude the need for ongoing monitoring.

Funding

AbbVie, Gutsy Group, Gandel Philanthropy, Angior Foundation, Crohn's Colitis Australia, and the National Health and Medical Research Council.

Introduction

70% of patients with Crohn's disease need intestinal resection.1, 2, 3, 4, 5 Within 1 year of surgery, subclinical endoscopic recurrence occurs at the anastomosis in 90% of patients with Crohn's disease, symptomatic clinical recurrence occurs in 30%, and 5% of patients have undergone further surgical intervention.6, 7, 8 70% of patients who have had operations need further surgery.1, 9

Smoking, perforating disease, and previous resection have been identified individually from retrospective studies as risk factors for earlier postoperative recurrence.2, 10, 11, 12 These factors have neither been assessed prospectively nor have they been used to tailor postoperative therapy.

Recurrent mucosal disease after surgery precedes clinical symptoms, and its severity predicts subsequent clinical disease.8 Early endoscopy might therefore help to guide therapeutic decision making; however, such an approach has not been assessed prospectively.13, 14

Metronidazole is of modest benefit in reduction of postoperative recurrence,15 whereas metronidazole combined with a thiopurine is moderately effective.16 Anti-tumour necrosis factor (anti-TNF) therapy is the most effective therapy for post-operative Crohn's disease,17, 18, 19 but studies for this indication have had a small sample size, and its optimal method of use postoperatively is yet to be established.

This study compared strategies to prevent disease recurrence, taking into account risk of recurrence, efficacy of different drug regimens, and assessment of the benefit of endoscopic monitoring with treatment intensification for mucosal disease recurrence, and aimed to identify the optimal strategy to prevent disease recurrence. Mucosal endoscopic normality was the target in this treat-to-target study.

Section snippets

Study design and patients

In this randomised postoperative Crohn's endoscopic recurrence (POCER) trial, consecutive patients with Crohn's disease undergoing intestinal resection of all macroscopic disease, with an endoscopically accessible anastomosis, were included at 17 hospitals in Australia and New Zealand. The diagnosis of Crohn's disease was based on standard clinical, imaging, and laboratory criteria.20 Patients were excluded if they had an anastomosis that was endoscopically inaccessible by standard colonoscopy;

Results

Between Oct 13, 2009, and Sept 28, 2011, 128 patients were randomly assigned to active care and 56 to standard care (figure 2). 174 patients (122 active care, 52 standard care) received at least one study drug dose and were included in the analysis. 133 patients underwent ileocaecal resection, 15 simultaneous ileocaecal and proximal small intestinal resection, 12 ileal resection, 8 subtotal colectomy, and 6 simultaneous ileocaecal with sigmoid resection. 122 patients were randomly assigned to

Discussion

Postoperative drug therapy, according to clinical risk of recurrence, with colonoscopy at 6 months and treatment step-up for recurrence, is significantly better than standard care alone for prevention of Crohn's disease recurrence (panel). The study inclusion of low and high risk patients with a variety of previous treatments was intended to reflect real-life practice, and as such we randomly assigned 184 of 212 consecutive screened patients. Furthermore, this heterogeneous group of patients

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