Systematic Review With Meta-analysis

Association Between Acetaminophen and Nonsteroidal Anti–inflammatory Drugs (NSAIDs) and Risk of Crohn's Disease and Ulcerative Colitis Exacerbation

O. O. Moninuola; W. Milligan; P. Lochhead; H. Khalili

Disclosures

Aliment Pharmacol Ther. 2018;47(11):1428-1439. 

In This Article

Results

Literature Search

Our search strategy resulted in 8378 unique citations: 1412 from Medline, 6966 from Embase to 4 from in–article references (Figure 1). Of these, 552 and 7695 citations were excluded by review of titles and abstracts during the first screen on account of duplication and relevance respectively. After full text review of 135 articles, 111 articles were excluded including 1 abstract that examined the association between aspirin and not NSAIDs and risk of IBD exacerbation.[19] A total of 24 studies were included in the final systematic review. 18 of these studies examined NSAIDs use and IBD exacerbation including five studies that reported nonsuitable association measure for meta–analysis, eight studies looked at COX–2 inhibitor use, and six studies examined acetaminophen use and IBD exacerbation including 1 without suitable association measure for meta–analysis. There were multiple entries for studies that reported separate results for different exposure categories.

Figure 1.

Flow diagram of eligible studies. **Multiple entries

Study Characteristics and Quality

Studies undertaken to elucidate the relationship of NSAIDs use and IBD disease activity or complications are outlined in Table 1 and Table 2. There were a total of 18 studies, nine case–control, eight cohort studies and one nonrandomised clinical trial, published between years 1983 and 2016. Nine studies evaluated IBD complications in quiescent disease ranging from symptomatic relapses confirmed on sigmoidoscopy and disease flares requiring steroids to emergency admissions.[6,20–27] Nine studies examined worsening disease activity level using physician global assessment of disease activity or objective indices like Harvey–Bradshaw, Manitoba or Mayo scores.[8,9,28–34] The number of participants per study ranged from 60 to 1940 for a total of 6276 participants across studies pooled for the meta–analysis. Thirteen studies were included in the meta–analysis, five cohort[9,23,25,27,29] and 8 case–control studies.[6,8,20,21,26,28,31,32] Crude RRs were calculated for 3 studies that presented raw data.[20,21,26]Table 3 outlines studies evaluating COX–2 inhibitor use and IBD exacerbation. These include one case–control study,[8] two cohort studies,[35,36] three nonrandomised clinical trials[33,37,38] and two RCTs.[39,40] Similarly, Table 4 outlines characteristics of acetaminophen studies which included one nonrandomised clinical trial,[33] and two cohort[9,27] and three case–control studies.[8,21,26] Due to the inherent qualitative differences among studies, we conducted quality assessment using Newcastle–Ottawa scale (Table S1 and Table S2). Studies with a score ≥7 were considered to have low risk of bias, consistent with prior definitions.[6,8,9,25,27,29,31]

Meta–analysis of NSAIDs use and IBD Exacerbation

A total of 13 studies were included in the meta–analysis with multiple entries for studies with distinct CD and UC results (Figure 1 and Figure 2). The results of the meta–analysis are outlined in Figure 2. Among the five studies examining the association between NSAIDs use and risk of CD exacerbation, substantial heterogeneity was observed (I 2 = 60.3%). The pooled RR of CD exacerbation using the random–effect model was 1.42; 95% CI (0.65–3.09). We observed moderate heterogeneity across the 8 studies that examined the association between NSAIDs use and UC exacerbation (I 2 = 56.1%). The pooled RR of UC exacerbation was 1.52; 95% CI (0.87–2.63) using the random effect model. Last, we examined the association between NSAIDs use and IBD exacerbation among nine studies that reported effect estimates and observed a nonstatistically significant increase in risk (RR = 1.29; 95% CI 0.92–1.80). However, there was substantial heterogeneity across the studies (I 2 = 63.2%).

Figure 2.

Meta–analysis of NSAIDs use and risk of IBD Exacerbation

Systematic Review of NSAIDs use and IBD Exacerbation

We also performed a systematic review of studies not included in our meta–analysis (Table 2). Bonner et al[30] evaluated the influence of NSAIDs use on disease activity among 426 CD and 203 UC patients over a 5–year follow–up. Information on disease activity was collected using the modified Harvey Bradshaw score for CD and Lichtiger index for UC. NSAIDs use was defined as over the counter or prescription use within 3 days of every clinic visit, the time when information on disease activity was collected, and usage was categorised into non–users, low–dose and high–dose users. For CD, average MHB score was 4.07 for the non–user group, 4.24 for low–dose NSAIDs (P = 0.46) and 4.78 for high–dose group (P = 0.0072 vs no–NSAIDs) while for UC, corresponding scores were 5.64, 5.46 (P = 0.74), and 6.20 (P = 0.69) respectively.

Takeuchi et al[33] conducted 2 nonrandomised clinical trials examining the risk of IBD relapse following administration of nonselective NSAIDs compared to acetaminophen in patients with quiescent disease. In the first trial, use of NSAIDs was associated with frequent early clinical relapse in IBD. Specifically, disease exacerbations occurred in nine (28%) of those receiving naproxen, five (24%) of those receiving indomethacin and five (17%) patients receiving diclofenac. These numbers were significantly different than the rate of relapse in the acetaminophen group (zero of 26 patients). In the second trial, four (20%) patients each in the naproxen and nabumetone treated groups experienced disease exacerbation compared to only one (5%) in acetaminophen group.

Feagins et al.[24] conducted a case–control study in 33 IBD patients with symptom flares and 23 IBD patients in clinical remission as controls, no statistically significant difference in the frequency of NSAIDs use was observed between cases and controls. Similarly, Riley et al[22] and Jejuna et al[34] in their respective cohort studies on UC and CD did not find significant difference in NSAIDs use among patients with active disease and those in remission.

Systematic Review of COX–2 Inhibitors use and IBD Exacerbation

Our study captured eight articles evaluating selective COX–2 inhibitor use and IBD exacerbation (Table 3). We did not conduct a meta–analysis because of insufficient data. Specifically, three of the studies had no comparator group,[35,36,38] one study utilised patients with dyspepsia as controls[37] while another study used acetaminophen exposure as control.[33] Studies by Mahadevan et al,[35] Reinisch et al[38] and Takeuchi et al[33] showed that only two of 27, zero of 32 and one of 20 IBD patients experienced exacerbation with use of celecoxib, rofecoxib and nimesulide respectively. Similarly, Hensley et al[8] study showed that only one of seven patients experienced IBD relapse with use of celecoxib or etoricoxib. In contrast, a retrospective cohort study by Matuk and colleagues[36] and an open–label trial by Biancone et al,[37] demonstrated that IBD patients had high rate of disease exacerbation (39% and 20% respectively) with use of celecoxib or rofecoxib. El Miedany et al[39] reported a multicentre, double–blinded, placebo–controlled study of the safety of etoricoxib among 146 patients with rheumatological manifestations of IBD. Participants, who were aged 18–65 years with varying degrees of disease activity, were given 60–120 mg/d of etoricoxib or placebo. At 3 months, there were no significant changes in disease activity index between the treatment and control groups, (RR = 0.92; 95% CI 0.37–2.32). Lastly, Sandborn and colleagues conducted a multicentre, randomised, double–blinded, controlled trial involving 222 UC patients who were in clinical remission and were given 200 mg of oral celecoxib, a selective COX–2 inhibitor, or placebo twice daily for 14 days. The study found no association between use of celecoxib and risk of disease exacerbation (RR = 0.73, 95% CI 0.17–3.18).[40]

Meta–analysis of Acetaminophen use and IBD Exacerbation

A total of five studies were included in the meta–analysis as shown in Figure 3. Moderate heterogeneity was observed (I2 = 45.6%) among the three studies that examined the association between acetaminophen use and risk of UC exacerbation. The pooled RR of UC exacerbation using the random–effect model was 1.40; 95% CI (0.96–2.04). We observed no heterogeneity among the two studies that examined the association between acetaminophen use and IBD exacerbation (I2 = 0.0%). The pooled RR of IBD exacerbation showed a statistically significant increase in risk 1.56; 95% CI (1.22–1.99) using the random effect model. Only one study, Long et al.[9] reported a separate result for acetaminophen use and CD exacerbation (RR = 1.72, 95% CI 1.11–2.68).

Figure 3.

Meta–analysis of acetaminophen use and risk of IBD exacerbation

Systematic Review of Acetaminophen use and IBD Exacerbation

Results of two nonrandomised clinical trials by Takeuchi et al[33] examining the risk of IBD relapse following administration of acetaminophen demonstrated only one disease exacerbation in the 46 patients with quiescent IBD, which was lower than the rate observed in the NSAIDs group (27 of 143 patients).

Sensitivity Analyses

We considered the possibility that quality of studies may have been a major source of substantial heterogeneity observed across the studies and therefore performed sensitivity analysis limiting our studies to those with a score of ≥7 on the Newcastle–Ottawa scale (Figure 4). The risk of CD exacerbation was increased and statistically significant with NSAIDs use (RR = 1.53, 95% CI 1.08–2.16 and I2 = 0.0%). In contrast, we did not observe an association between NSAIDs use and risk of UC exacerbation (RR = 0.94, 95% CI 0.36–2.42 and I2 = 64.7%) or risk of IBD exacerbation (RR = 1.15, 95% CI 0.89–1.49 and I2 = 44.9%). We also performed sensitivity analysis limiting our population to cohort studies and observed similar results (Figure 5). The pooled RR of IBD exacerbation with NSAIDs use was 1.22, 95% CI 0.90–1.66 with moderate heterogeneity (I2 = 58.1%). There were insufficient data for separate analyses on CD and UC as only two cohort studies reported separate results for UC[9,23] and one study for CD.[9]

Figure 4.

Meta–analysis of NSAIDs use and risk of IBD exacerbation among studies with low risk of bias

Figure 5.

Meta–analysis of NSAIDs use and risk of IBD exacerbation among cohort studies

Publication Bias

We assessed for presence of publication bias using Egger's test and found no evidence for publication bias (P values of Egger's test = 0.952 for CD, 0.699 for UC and 0.239 for IBD).

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