The general contraindications and adverse effects of NSAIDs are well established and have been documented in sources such as the NHG Guideline on Pain and the guideline on systemic NSAID use. There is a need to revise the current guideline module in response to clinical concerns regarding the use of NSAIDs in patients undergoing intestinal anastomosis, particularly with respect to their potential association with anastomotic leakage.

Summary of findings

Population: Patients undergoing an intestinal anastomosis

Intervention: NSAIDs

Comparator: no NSAIDs

_{^1. Systematic review [1] with included studies: Rutegard, 2016; Lai, 2013; Paulasir, 2015; Wu, 2022; Zittel, 2013; Gong, 2014; Gorrisen, 2012; Bakker, 201; Gessler, 2016, Klein, 2012; Klein, 2019; Sim, 2007; Wattchow, 2009; EuroSurg, 2020; Hultberg, 2017. Baseline/comparator Control arm of reference used for intervention .}

_{^2. Risk of Bias: serious. Inconsistency: serious. Imprecision: serious.}

Summary of findings – subgroup analyses

Population: Patients undergoing an intestinal anastomosis

Intervention: 1) COX-2 inhibitors or 2) nonselective NSAIDs

Comparator: no NSAIDs

Description of studies

A total of 4 studies were included in the analysis of the literature: one systematic review and three individual studies. Important study characteristics and results are summarized in table 2. The assessment of the risk of bias is summarized in the risk of bias tables (under the tab ‘Evidence tabellen’).

Table 2. Characteristics of included studies

_{M, men; f, female; N, number of participants; AL, anastomotic leak}

_{*For further details, see risk of bias table in the appendix}

_{^AAdequate follow-up was defined as >30 days in the quality assessment of the systematic review by Kastora (2021). Although follow-up duration was not always explicitly reported in the included studies, a low score on this item in the quality assessment indicates a follow-up shorter than 30 days.}

Results

A total of 4 studies were included, comprising 15 underlying primary studies (RCTs and observational studies) that compared NSAID use to no NSAIDs or placebo in the context of colorectal surgery. Of these, 12 primary studies were included in the SR by Kastora (2021), which specifically compared NSAIDs to no NSAIDs or placebo in colorectal cancer procedures. In addition, three further primary studies were included (Klein, 2012; Paulasir, 2025; Wu, 2022).

Anastomotic leakage

Across 15 studies involving 39,750 patients, 5.8% (745 out of 12,839) of those who received NSAIDs experienced an AL, compared to 4.5% (1,212 out of 26,911) in the non-NSAID group. The pooled risk ratio (RR) was 1.38 (95% CI: 0.93 to 2.06), indicating a clinically relevant difference.

_{Figure 1. Forest plot of functional status comparing NSAIDs versus no NSAIDs on AL for included RCTs and observational studies}

_{Risk Ratio, random effects model. Z: p-value of overall effect; df: degrees of freedom; I2; statistical heterogeneity; CI: confidence interval}

NSAID type

Subgroup analyses were performed to determine whether the effects varied depending on the type of NSAID administered.

1. COX-2 inhibitors: AL occurred in 4.5% (127 out of 2,807) of patients who received COX-2 inhibitors, compared to 3.9% (385 out of 9,989) in the non-NSAID group. The RR was 1.81 (95% CI: 0.80 to 4.06), suggesting a clinically relevant difference.
2. Non-selective NSAIDs: AL occurred in 7.1% (361 out of 5,103) of patients who received non-selective NSAIDs, compared to 4.1% (648 out of 15,911) in the non-NSAID group. The pooled RR was 1.69 (95% CI 0.90 to 3.18), indicating a clinically relevant difference.

A systematic review of the literature was performed to answer the following question(s):

What is the influence of postoperative use of NSAIDS to no NSAIDS in patients undergoing a colorectal anastomosis on anastomotic leakage (AL)?

Table 1. PICO

Relevant outcome measures

The guideline panel considered anastomotic leakage as a critical outcome measure for decision making.

A priori, the guideline panel did not define the outcome measures listed above but used the definitions used in the studies.

The guideline panel defined the following thresholds as a minimal clinically (patient) important difference.

• For continuous outcomes, a threshold of 10% for continuous outcomes.
• For dichotomous outcomes, a threshold of <0.80 and >1.25.

Search and select (Methods)

A systematic literature search was performed by a medical information specialist using the following bibliographic databases: Embase.com and Ovid/Medline. Both databases were searched from 2005 to 14 of May 2025 for systematic reviews, RCTs and observational studies. Systematic searches were completed using a combination of controlled vocabulary/subject headings (e.g., Emtree-terms, MeSH) wherever they were available and natural language keywords. The overall search strategy was derived from three primary search concepts: (1) intestinal surgery; (2) NSAIDs; (3) anastomotic leakage. Duplicates were removed using EndNote software. After deduplication a total of 193 records were imported for title/abstract screening. Inclusion criteria were conform the PICO, and in addition, only publications that reported on NSAIDs used in the Netherlands were relevant for inclusion, except metamizole was excluded since the registration of this NSAID is up for debate (EMA review).

Initially, 44 studies were selected based on title and abstract screening. After reading the full text, 40 studies were excluded (see the exclusion table under the tab ‘Evidence tabellen’), and 4 studies were included. Although initially no filter was used for the type of intestinal anastomosis, almost all articles exclusively described patients with a colon or colorectal anastomosis. We therefore limited the recommendations to patients undergoing colorectal surgery with a colon or colon-rectum anastomosis.

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2. Gessler B, Bock D, Pommergaard H, Burcharth J, Rosenberg J, Angenete E. Risk factors for anastomotic dehiscence in colon cancer surgery—a population-based registry study. Int J Colorectal Dis. 2016;31(4):895-902. doi:10.1007/s00384-016-2532-7.
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