Dear Editor

We read with interest the recent article by Klein et al highlighting the negative impact of diclofenac on anastomotic leakage after colorectal resection with primary anastomosis across several Danish centres [1]. The authors are to be congratulated on the rigorous approach to data collection, analysis, and insightful reflection on the potential limitations of the study design while providing interesting data relevant to a large proportion of colorectal surgical practice.

In particular we focus on the issue of cofounding association as particularly relevant and suggest that it has an important role in considering the study results implicating diclofenac. While the decision to treat with NSAID is made preoperatively, the vast majority (>75%) receive ibuprofen instead of diclofenac. Is this arbitrary or indeed a centre specific decision? This has relevance if the proportion of the patients receiving diclofenac (226/2756 [8%]) are from one or only a few centres and perhaps the link with diclofenac and leak more likely to reflect local surgical practices (laparoscopic learning curve, proportion of rectal cancers, bowel preparation protocols, use of covering defunctioning stomas etc) and indeed patients factors (BMI, nutritional factors etc.) peculiar to that centre(s).

The authors report an increased use of blood transfusion (a recognised risk factor for anastomotic leak) in the cohort given ibuprofen compared to diclofenac and controls and conclude that this “strengthens the results of increased risk of anastomotic leakage among patients treated with diclofenac”. Does the data really support this statement as if we look at the operative variables we find that despite a statistically significant greater blood loss in the diclofenac group the use of intraoperative blood transfusion is more in the ibuprofen and control groups ? Again are the criteria for blood transfusion uniform across the centres or is there variation potentially creating relevant cofounding factor(s)? Indeed the authors go onto describe the negative impact of blood transfusion on immune function and as a surrogate marker for extent of surgery and “...perhaps insufficient anastomotic perfusion caused by anaemia or hypotension”. We propose this to be more relevant in the diclofenac group as they have greater blood loss and potential for perfusion insufficiency [2].

The authors have incorporated both colon and rectal cancer surgery as one group when considering anastomotic leakage and could present a challenge to the results as the reported factors for leakage vary in importance from right sided colonic resections to low rectal tumours and even hand vs. stapled anastomosis. It would be of interest to note the results when excluded for the rectal cancers thus providing more ‘homogenised’ data relevant to colonic and/or rectal cancer surgery. Furthermore we are not provided with information regarding the use of neoadjuvant chemo/radiotherapies, corticosteroids, the protocols for the use of defunctioning ‘protective’ stomas, or the use of low molecular weight heparin postoperatively (which may help in management of “microthomboses or micro emboli” and the “possible important mechanism behind the adverse effect of [cyclo-oxygenase -2 (COX-2) selective NSAIDS)”. We acknowledge the recent laboratory work suggesting a putative link between cyclo-oxygenase – 2 selective NSAIDs and await further in vivo studies that may indeed add weight to the authors’ conclusions. However data from a recent clinical study in 795 patients indicated that non-selective NSAIDs and not COX-2 inhibitors are associated with anastomotic leakage [3].

The univariate analysis of the risk of anastomotic leak by centre does highlight statistical significant variation. Taking this and all of the above into consideration in a study population using diclofenac of only 8%, the results of the study must be interpreted with significant weight given to the effect of cofounding by indication. Finally we view the recruitment of patients with informed consent into a randomised controlled trial in light of these finding to present a considerable challenge (n=2100 α=0.05, β=0.20).

References:
[1] Klein M, Gögenur I, Rosenberg J. Postoperative use of non-steroidal anti-inflammatory drugs in patients with anastomotic leakage requiring reoperation after colorectal resection: cohort study based on prospective data. BMJ. 2012 Sep 26;345.

[2] Iancu C, Mocan LC, Todea-Iancu D et al. Host-related predictive factors for anastomotic leakage following large bowel resections for colorectal cancer. J Gastrointestin Liver Dis. 2008 Sep;17(3):299-303.

[3] Gorissen KJ, Benning D, Berghmans T et al. Risk of anastomotic leakage with non-steroidal anti-inflammatory drugs in colorectal surgery. Br J Surg. 2012 May;99(5):721-7.

Competing interests: None declared