GI Safety of NSAIDs: The Latest

As far as I recall, whenever there are concerns over GI safety in a patient needing NSAIDs, cox-2 selective inhibitors (C2SIs or coxibs) were the appropriate medications to prescribe. In fact, coxibs were primarily developed to address serious GI adverse events (GI AEs)associated with traditional or non-selective NSAIDs (tNSAIDs). Later studies, however, showed that administering gastro-protective agents with NSAIDs were as effective as coxibs in minimizing serious upper GI AEs.

The latest recommendations1 identify the following as risk factors for serious GI AEs:

  • Age>65
  • Current / concomitant use of aspirin, steroids or warfarin
  • Other medical conditions (hypertension, diabetes, etc)
  • GI bleeding or peptic ulcer disease
  • Alcoholic beverage intake
  • Smoking

If a patient does not have any of the above risk factors, any NSAID – traditional or coxib – can be prescribed to the patient.

If a patient has a few risk factors or has a history of GI bleeding or peptic ulcer disease but >1 year ago, the patient should use either a coxib or an NSAID with a proton pump inhibitor.

But if a has multiple risk factors or has a recent history of GI bleeding or peptic ulcer disease <1 year ago then only a coxib with a proton pump inhibitor must be used.

But the CONDOR trial2 in 2010, introduced the concept of clinically significant upper and lower GI events (CSULGIEs) in NSAID safety. Aside from serious upper GI events, NSAIDs can also cause problems (perforation, bleeding and obstruction) in the distal GI tract (from the jejenum to the rectum). But unlike upper GI events which frequently produce symptoms, lower GI events often are asymptomatic – detectable as either occult drops in hemoglobin or via capsule endoscopy.

In the CONDOR trial, fewer patients on celecoxib (200 mg twice daily) had lower GI events compared to diclofenac (75mg twice daily) with omperazole (20mg twice daily) [RR 0.21 (95% confidence interval 0.11 – 0.39). Another study using a PROBE design (GI-REASONS3) comparing celecoxib 200 mg once-twice daily versus usual NSAID practice showed similar results [RR 0.58 (95% confidence interval 0.42 – 0.81).

Laine (2008)4, in his review of the MEDAL program, showed that etoricoxib 60-90mg/day produced comparable rates of lower GI events as diclofenac 150mg/day [RR 0.84 (95% confidence interval 0.63 – 1.13).

Harirforoosh (2013)5 observed that the risk of distal GI toxicity with NSAIDs appears to increase with formulations that are designed to release in the intestines (e.g. sustained release and enteric coated formulations).

Clearly, interventions designed to protect the upper GI tract, doesn’t protect the rest of the GI tract.

The coxib and traditional NSAID trialists’ meta-analysis (CNT MA, 2013)6 – the largest meta-analysis of RCTs on NSAID safety – now challenges even our long held concept about coxibs’ advantage in GI safety. Based on the 754 trials included, the following are the risks of patients having serious upper GI complications (compared to placebo):

  • Etoricoxib 5.70 (95% CI 1.12 – 28.99)
  • Naproxen 4.22 (95% CI 2.71 – 6.56)
  • Ibuprofen 3.97 (95% CI 2.22 – 7.10)
  • Lumiracoxib 2.62 (95% CI 0.61 – 11.26)
  • Rofecoxib 2.43 (95% CI 1.61 – 3.68)
  • Diclofenac 1.89 (95% CI 1.16 – 3.09)
  • Celecoxib 1.31 (95% CI 0.83 – 2.07)

It appears now that (upper) GI safety is not a monopoly of coxibs as both the highest and lowest risks for serious upper GI AEs were found in coxibs. Likewise, the second highest and the second lowest risks for serious upper GI AEs were found in tNSAIDs.

It would be interesting to follow how safety recommendations would change as a result of the CNT MA.

What do the above studies now tell us? That GI safety is not a benefit afforded by any particular class of NSAIDs – noting how individual members of each class performed differently in the meta-analysis. Likewise, GI safety is not only limited to events happening from the mouth to the duodenum but should also include those that happen in the distal GI tract. Risk mitigation strategies, so far, are only able to protect portions of the upper GI tract.


  1. Burmester G, et al. The appropriate use of non-steroidal anti-inflammatory drugs in rheumatic diseases: opinions of a multidisciplinary European expert panel. Ann Rheum Dis 2010; doi: 11.1136
  2. Chan FKL, et al. Celecoxib versus Omeprazole and Diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomized trial. Lancet 2010; 376: 173-79.
  3. Cryer B, et al. GI REASONS: A Novel 6-month Prospective Randomized Open-Label Blind Endpoint (PROBE) Trial. Am J Gastroenterol 2013; 108: 392-400.
  4. Laine L, Curtis SP, Langman M, et al. Lower GI events in a Double Blind Trial of the COX-2 Selective Inhibitor and the traditional NSAID Diclofenac. Gastroenterol 2008; 135: 1517-25.
  5. Harirforoosh S, Asghar W, Jamili F. Adverse effects of NSAIDs: An Update of Gastrointestinal, Cardiovascular and Renal Complications. J Pharm Pharma Scie 2013; 16 (5): 821-47
  6. Coxib and traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper GI adverse effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual patient data from randomized trials. Lancet 2013; 382: 769-79.

Author: Sids Manahan MD 🇵🇭

Rheumatology. Internal Medicine. Educating Patients and Colleagues. Curating Rheumatology. Bloggero-Wanabe.

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