NSAIDs Not Always Interchangeable

May 8, 2017

Celecoxib is preferred over naproxen for arthritis patients at high risk for cardiovascular and gastrointestinal events, researchers report.

Celecoxib is preferred over naproxen for patients with chronic arthritis and cardiothrombotic diseases who are also taking aspirin, researchers in China report. 

In the study, published online April 11 in The Lancet, researchers address the lack of treatment guidelines for patients at high risk for cardiovascular and gastrointestinal events, but who still require aspirin and non-steroidal anti-inflammatory drugs (NSAIDS) for anti-inflammatory and cardiovascular therapies. Approximately 30 billion doses of NSAIDS are consumed annually in the United States and in China, an estimated 3.6% of adults take NSAIDS regularly. 

Led by Francis Chan, M.D., of the Chinese University of Hong Kong in China, the primary goal of the study was to evaluate the incidence of upper gastrointestinal bleeding in concomitant aspirin using patients on celecoxib, a cyclooxygenase (COX)-2-selective NSAID, and those on naproxen, a non-selective NSAID.

“In the present study, although a combination of celecoxib, aspirin, and a proton-pump inhibitor could not completely eliminate the risk of recurrent upper gastrointestinal bleeding, this treatment strategy still probably offers the best upper gastrointestinal protection for patients with arthritis and cardiothrombotic diseases who are at high risk of upper gastrointestinal bleeding,” wrote Chan and colleagues.

It is well established that upper gastrointestinal bleeding is associated with NSAIDS. Moreover, concomitant use of NSAIDS and aspirin greatly increases a patient’s risk of developing upper gastrointestinal bleeding. Approximately seven national and international guidelines exist on the use of NSAIDs. However, these guidelines provide conflicting recommendations for patients at high risk of both cardiovascular and gastrointestinal events who continue to require NSAIDs.

More than a decade ago, (COX)-2-selective NSAIDs were introduced as gastric-sparing anti-inflammatory analgesics that could reduce NSAIDS-related gastrointestinal complications. However, concerns with this treatment emerged. Prior studies suggested that COX-2-selective NSAIDs could increase the risk of myocardial infarction. Additionally, the gastric safety benefits of COX-2-selective NSAIDs as compared with non-selective NSAIDs, seemed to disappear with the concomitant use of aspirin.

The study

This was a double-blind, randomized trial conducted between 2005-2012 with 514 patients who had arthritis and cardiothrombotic diseases. 257 patients were randomized to each of two groups. The first received an oral dose of celecoxib 100 mg twice per day plus esomeprazole 20 mg once per day. The second received an oral dose of naproxen 500 mg twice per day plus esomeprazole 20 mg once per day for 18 months. Patients in both groups took 80 mg of aspirin of once per day.

Recurrent upper gastrointestinal bleeding occurred in 14 patients in the celecoxib group (nine gastric ulcers and five duodenal ulcers) and 31 patients in the naproxen group (25 gastric ulcers, three duodenal ulcers, one gastric ulcer and duodenal ulcer, and two bleeding erosions). Specifically, the cumulative incidence of recurrent bleeding at 18 months was significantly lower in the celecoxib group at 5.6% compared with the naproxen group at 12.3% (log-rank test p=0·008; crude HR 0·44, 95% CI 0·23–0·82; p=0·010). The primary endpoint was recurrent upper gastrointestinal bleeding within 18 months.

"Our findings address the major unmet need in the present guidelines on the management of patients at high risk of both cardiovascular and astrointestinal events who continue to require antiinflammatory analgesics. These patients have been largely neglected because none of the published studies sought to identify treatments to reduce the risk of life-threatening complications in these patients," the authors wrote.

Takeaways

In the present study, although a combination of celecoxib, aspirin, and a proton-pump inhibitor could not completely eliminate the risk of recurrent upper gastrointestinal bleeding, this treatment strategy still probably offers the best upper gastrointestinal protection for patients with arthritis and cardiothrombotic diseases who are at high risk of upper gastrointestinal bleeding. "Avoidance of all NSAIDs will be the safest approach in these high-risk patients, but in patients who continue to require concomitant NSAIDs and aspirin, celecoxib plus a proton-pump inhibitor encompass the least risk of recurrent upper gastrointestinal bleeding," the authors wrote. 

PRECISION trial

 The PRECISION trial, published in the New England Journal of Medicine in December, found that at moderate doses, celecoxib was non-inferior to naproxen with regard to cardiovascular safety. The trial primarily designed to compare the cardiovascular safety of celecoxib with two non-selective NSAIDs, but it also found superior gastrointestinal safety with celecoxib than with nonselective NSAIDs. By contrast, the current study is designed to assess the gastrointestinal safety. It did not find any meaningful difference in cardiovascular events in aspirin users between celecoxib and naproxen. 

Disclosures:

Funding:  This research was supported by the Research Grant Council of Hong Kong

Disclosures:  FKLC has served as a consultant to Eisai, Pfizer, Takeda, and Otsuka, and has been paid lecture fees by Eisai, Pfizer, AstraZeneca, and Takeda. SCN has been paid lecture fees by Ferring and Takeda. JCYW has received grant support from the US National Institute of Health and hasbeen paid lecture fees by AstraZeneca and Takeda.

 

References:

Chan F, Ching J, Tse Y, et al. "Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independent, double-blind, double-dummy, randomised trial," The Lancet. Published online April 11, 2017. DOI: 10.1016/S0140-6736(17)30981-9.