Diclofenac gastrointestinal bleeding

The risk of serious upper gastrointestinal bleeding was inereased by the use of more than one NSAID in a meta-analysis of data from three ease-eontrolled studies (odds ratio 4.9 with one NSAID and 10.7 with two). Another study provided similar findings the odds ratio was 7.1 with one NSAID and 12.3 with two or more NSAIDs. Similar findings have been reported with aspirin and NSAIDs, see NSAIDs + Aspirin Anti-inflammatory dose , p.l42. Analysis of yellow eard reports to the CSM in the UK, of gastrointestinal perforation, obstruetion, uleeration or bleeding with diclofenac, naproxen, and ibuprofen, revealed that 6% of the patients were reeeiving another non-aspirin NSAID. ... 

Studies surest that diclofenac does not alter the anticoagulant effect of acenocoumarol, phenprocoumon or warfarin, su esting dose adjustments are unlikely to be needed. Isolated cases of raised INRs have been described. Note that all NSAIDs increase the risk of gastrointestinal bleeding, and an increased risk is seen when they are combined with anticoagulants. 

Celecoxib, which has a low selectivity for COX-2 compared to COX-1, is still available, although its more selective successor, valdecoxib has been withdrawn. Etoricoxib, the successor to rofecoxib, is marketed in Europe but not in the USA. In a large multinational clinical trial, etoricoxib caused no more thromboembolic events than diclofenac, but after 18 months the incidence of gastrointestinal ulcers and bleeding was the same for both drugs [4]. 

Gastrointestinal ulceration may occur less frequently than with some other NSAIDs. A preparation combining diclofenac and misoprostol decreases upper gastrointestinal ulceration but may result in diarrhea. Another combination of diclofenac and omeprazole was also effective with respect to the prevention of recurrent bleeding, but renal adverse effects were common in high-risk patients. Diclofenac, 150 mg/d, appears to impair renal blood flow and glomerular filtration rate. Elevation of serum aminotransferases occurs more commonly with this drug than with other NSAIDs. 

Clinical trial evidence in general appears to support the theory that COX-2 selective inhibitors are as effective as, but have fewer adverse effects than, non-COX-2 selective compounds for example meloxicam is better tolerated than diclofenac or piroxicam. The relative risk of serious gastrointestinal effects (bleeding peptic ulcers) due to rofecoxib (COX-2 selective) was 0.51 compared with conventional NSAIDs. COX-2 selective drugs are yet associated with significant dyspeptic symptoms (indigestion, heartburn), and these effects may result from inhibition of the (protective) constitutively expressed COX-2 in the stomach. 

Gastrointestinal adverse effects are particularly frequent, and affect some 14-25% of patients the incidence of the most serious, peptic ulcer and bleeding were 0.16-0.34% and 0.16-0.17%, respectively (1). A prospective 12-week endoscopic study documented better gastrointestinal tolerability with diclofenac than naproxen (SEDA-20, 92). Upper gastrointestinal hemorrhage has been associated with transdermal application of diclofenac, with massive bleeding in two of four patients (SEDA-21, 104). 

A lower gastrointestinal risk with coxibs was confirmed in a retrospective case-control study of the incidence of peptic ulcer bleeding and perforation in users of COX-2 selective and non-selective NSAIDs [3 ]. The study was based on 2.2 million adults taking celecoxib, diclofenac, ibuprofen, naproxen, rofecoxib, or valdecoxib. Adjusted odds ratios (OR) compared with naproxen were ibuprofen 0.86 (95% Cl = 0.68, 1.09), rofecoxib 0.79 (0.62, 1.02), diclofenac 0.66 (0.47, 0.94), valdecoxib 0.50 (0.26, 0.97), and celecoxib 0.45 (0.35, 0.58). The overall... 

Musculoskeletal Bleeding outside the gastrointestinal tract due to diclofenac, a rare event, has been reported [40 ]. 

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