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Hartmann's procedure versus sigmoidectomy with primary anastomosis for perforated diverticulitis with purulent or faecal peritonitis (LADIES): a multicentre, parallel-group, randomised, open-label, superiority trial

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Summary

Background

Previous studies have suggested that sigmoidectomy with primary anastomosis is superior to Hartmann's procedure. The likelihood of stoma reversal after primary anastomosis has been reported to be higher and reversal seems to be associated with lower morbidity and mortality. Although promising, results from these previous studies remain uncertain because of potential selection bias. Therefore, this study aimed to assess outcomes after Hartmann's procedure versus sigmoidectomy with primary anastomosis, with or without defunctioning ileostomy, for perforated diverticulitis with purulent or faecal peritonitis (Hinchey III or IV disease) in a randomised trial.

Methods

A multicentre, randomised, open-label, superiority trial was done in eight academic hospitals and 34 teaching hospitals in Belgium, Italy, and the Netherlands. Patients aged between 18 and 85 years who presented with clinical signs of general peritonitis and suspected perforated diverticulitis were eligible for inclusion if plain abdominal radiography or CT scan showed diffuse free air or fluid. Patients with Hinchey I or II diverticulitis were not eligible for inclusion. Patients were allocated (1:1) to Hartmann's procedure or sigmoidectomy with primary anastomosis, with or without defunctioning ileostomy. Patients were enrolled by the surgeon or surgical resident involved, and secure online randomisation software was used in the operating room or by the trial coordinator on the phone. Random and concealed block sizes of two, four, or six were used, and randomisation was stratified by age (<60 and ≥60 years). The primary endpoint was 12-month stoma-free survival. Patients were analysed according to a modified intention-to-treat principle. The trial is registered with the Netherlands Trial Register, number NTR2037, and ClinicalTrials.gov, number NCT01317485.

Findings

Between July 1, 2010, and Feb 22, 2013, and June 9, 2013, and trial termination on June 3, 2016, 133 patients (93 with Hinchey III disease and 40 with Hinchey IV disease) were randomly assigned to Hartmann's procedure (68 patients) or primary anastomosis (65 patients). Two patients in the Hartmann's group were excluded, as was one in the primary anastomosis group; the modified intention-to-treat population therefore consisted of 66 patients in the Hartmann's procedure group (46 with Hinchey III disease, 20 with Hinchey IV disease) and 64 in the primary anastomosis group (46 with Hinchey III disease, 18 with Hinchey IV disease). In 17 (27%) of 64 patients assigned to primary anastomosis, no stoma was constructed. 12-month stoma-free survival was significantly better for patients undergoing primary anastomosis compared with Hartmann's procedure (94·6% [95% CI 88·7–100] vs 71·7% [95% CI 60·1–83·3], hazard ratio 2·79 [95% CI 1·86–4·18]; log-rank p<0·0001). There were no significant differences in short-term morbidity and mortality after the index procedure for Hartmann's procedure compared with primary anastomosis (morbidity: 29 [44%] of 66 patients vs 25 [39%] of 64, p=0·60; mortality: two [3%] vs four [6%], p=0·44).

Interpretation

In haemodynamically stable, immunocompetent patients younger than 85 years, primary anastomosis is preferable to Hartmann's procedure as a treatment for perforated diverticulitis (Hinchey III or Hinchey IV disease).

Funding

Netherlands Organisation for Health Research and Development.

Introduction

Diverticular disease is the third most costly gastrointestinal disorder in developed countries, making it an important condition in terms of health-care utilisation.1 An estimated 8–35% of patients with acute diverticulitis present with complicated disease, including abscess formation (Hinchey classification Ib and II) or perforation with purulent or faecal peritonitis (Hinchey III or IV).2, 3

Research in context

Evidence before this study

We did a systematic literature search in PubMed for articles published from inception to Jan 17, 2019, with the keywords “diverticulitis”, “peritonitis”, “Hartmann*”, “primary”, and “anastomosis”, without language restrictions. We specifically included randomised controlled trials that compared Hartmann's procedure with sigmoidectomy with primary anastomosis for perforated diverticulitis with purulent or faecal peritonitis (Hinchey III or Hinchey IV); three of 127 articles identified by our search met this criterion. Quality assessment of these studies is given in the appendix (p 6). Overall, these trials randomly allocated 116 patients to primary anastomosis and 138 patients to Hartmann's procedure, of whom 204 (80%) had Hinchey III diverticulitis. All three studies were prematurely terminated, either because of slow patient accrual (two studies) or for safety reasons (one study). No significant differences in mortality or overall morbidity were reported after the index procedure or reversal procedure. Two studies found a significant difference in stoma reversal rates in favour of primary anastomosis.

Added value of this study

To our knowledge, the LADIES trial is the largest study to date on primary anastomosis in Hinchey III and Hinchey IV diverticulitis and has several methodological differences compared with previous randomised trials. First, to our knowledge, this is the first trial to report on stoma-free survival as a primary endpoint and to incorporate patient-reported outcomes. Second, the decision to construct a defunctioning ileostomy was left to the discretion of the surgeon, whereas in previous studies, by design, a defunctioning ileostomy had to be constructed in all patients undergoing sigmoidectomy with primary anastomosis. However, in one previous trial, a third of patients underwent primary anastomosis without construction of an ileostomy, thereby deviating from the study protocol. Furthermore, patients in the present study were randomly assigned after diagnostic laparoscopy, allowing for a more accurate distinction between Hinchey III and Hinchey IV diverticulitis and, consequently, this is the first study to report on outcomes in Hinchey III and IV disease separately. Finally, although not all non-included patients could be registered during the trial period, baseline demographics and preoperative disease severity data for 235 eligible non-included patients were available to compare with included patients. This comparison improves the external generalisability of our study.

Implications of all the available evidence

The LADIES trial provides strong support in favour of sigmoidectomy with primary anastomosis as the most appropriate surgical treatment for diverticulitis with purulent or faecal peritonitis in patients who are haemodynamically stable and immunocompetent. This finding is important because, in combination with existing evidence, it has the potential to fundamentally change current practice and reduce both patient and socioeconomic burden.

In cases of perforated diverticulitis with purulent or faecal peritonitis, emergency operative treatment is standard practice.4, 5, 6, 7 Hartmann's procedure—resection with end colostomy construction—remains the favoured option for most surgeons and avoids the risk of anastomotic leakage.3, 8 However, several studies have suggested that sigmoidectomy with primary anastomosis is equal to Hartmann's procedure in terms of post-operative mortality and morbidity.5, 7, 9 Additionally, the likelihood of reversal of end colostomies after Hartmann's procedure has been reported to be lower (50–60%) than that of closure of defunctioning ileostomies after sigmoidectomy with primary anastomosis (85%), thereby increasing associated health-care costs and negatively affecting quality of life.10, 11, 12 Moreover, Hartmann's procedure reversal is associated with high mortality and morbidity,13, 14 whereas primary anastomosis allows for a safer, less challenging closure procedure.12, 13, 15 In selected cases of sigmoidectomy with primary anastomosis, a defunctioning ileostomy might even be avoided.8, 16

Despite increased interest in sigmoidectomy with primary anastomosis and its potential advantages, high-quality evidence from randomised studies comparing this procedure with Hartmann's procedure is scarce, particularly with regard to stoma-free survival, which, as a single outcome measure, reflects both the risk of mortality and the likelihood of stoma reversal. Therefore, the aim of the DIVA arm of the international, multicentre, randomised controlled LADIES trial17 was to compare Hartmann's procedure with primary anastomosis (with or without defunctioning ileostomy) to determine the optimal strategy for perforated diverticulitis with purulent or faecal peritonitis.

Section snippets

Study design and participants

The LADIES trial17 was a multicentre, randomised, open-label, superiority trial done at 34 teaching hospitals and eight academic hospitals in Belgium, Italy, and the Netherlands. Initially, the trial had a combined design to compare laparoscopic peritoneal lavage with sigmoidectomy for purulent perforated diverticulitis (LOLA arm) and Hartmann's procedure with sigmoidectomy with primary anastomosis in both purulent and faecal perforated diverticulitis (DIVA arm; appendix p 3).17 After

Results

Between July 1, 2010, and Feb 22, 2013, 90 patients (47 assigned to laparoscopic lavage and 43 to sigmoidectomy) were recruited and enrolled in the trial, after which recruitment was temporarily stopped, as advised by the data safety monitoring board, because of safety concerns in the LOLA arm at the third interim analysis. After IRB approval, randomisation (1:1) between Hartmann's procedure and sigmoidectomy with primary anastomosis continued in the DIVA arm, as safety concerns were limited to

Discussion

This randomised trial, comparing Hartmann's procedure to sigmoidectomy with primary anastomosis in patients with perforated diverticulitis and purulent or faecal peritonitis, showed significantly better 12-month stoma-free survival for patients in the primary anastomosis group, without significant differences in short-term morbidity and mortality. Furthermore, we found signi-ficantly lower short-term overall morbidity after stoma reversal for primary anastomosis, and a significantly shorter

Data sharing

If requested, deidentified data collected for the LADIES trial, the study protocol, and informed consent form can be made available. Please contact WAB ([email protected]) or JFL ([email protected]), who will review all requests with the members of the Dutch Diverticular Disease (3D) Collaborative Study Group and the LADIES trial investigators. Requests should fulfil the following access criteria: research can only be conducted in collaboration with and after approval of the

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