Practice Update: Cardiology

EDITOR’S PICKS 5

GI safety of celecoxib vs naproxen in patients with cardiothrombotic diseases and arthritis after upper GI bleeding The Lancet Take-home message

in the naproxen group (p=0.008; crude hazard ratio 0.44, 95% CI 0.23–0.82; p=0.010). Exclud- ing patients who reached study endpoints, 21 (8%) patients in the celecoxib group and 17 (7%) patients in the naproxen group had adverse events leading to discontinuation of treatment. No treatment-related deaths occurred during the study. INTERPRETATION In patients at high risk of both cardiovascular and gastrointestinal events who require concomitant aspirin and NSAID, celecoxib plus proton-pump inhibitor is the preferred treatment to reduce the risk of recur- rent upper gastrointestinal bleeding. Naproxen should be avoided despite its perceived cardi- ovascular safety. Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic dis- eases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independ- ent, double-blind, double-dummy, randomised trial. Lancet 2017 Apr 11;[EPub Ahead of Print], FKL Chan, JYL Ching, YK Tse, et al.

• In this double-blind trial, 514 patients with arthritis and cardiothrombotic diseases who presented with upper gastrointestinal bleeding were randomized (1:1) to treat- ment with a proton-pump inhibitor plus naproxen or celecoxib. In the celecoxib group, recurrent upper gastrointestinal bleeding occurred in 14 patients compared with 31 patients in the naproxen group. At 18 months of follow-up, the cumulative incidence of recurrent bleeding was significantly lower in the celecoxib group compared with the naproxen group (5.5% vs 12.3%; P =0.008). Discontinuation of treatment led to adverse events in 8% of patients in the celecoxib group and 7% in the naproxen group. There were no treatment-related deaths during the study. • The results suggest that, to reduce the risk of recurrent upper gastrointestinal bleeding, patients at high risk of both cardiovascular and gastrointestinal events should be treated with celecoxib plus a proton-pump inhibitor; naproxen should be avoided.

ulcer and duodenal ulcer, and two bleeding ero- sions). The cumulative incidence of recurrent bleeding in 18 months was 5.6% (95% CI 3.3– 9.2) in the celecoxib group and 12.3% (8.8–17.1)

Abstract BACKGROUND Present guidelines are conflicting for patients at high risk of both cardiovascular and gastrointestinal events who continue to require non-steroidal anti-inflammatory drugs (NSAIDs). We hypothesised that a cyclooxy- genase-2-selective NSAID plus proton-pump inhibitor is superior to a non-selective NSAID plus proton-pump inhibitor for prevention of recurrent ulcer bleeding in concomitant users of aspirin with previous ulcer bleeding. METHODS For this industry-independent, dou- ble-blind, double-dummy, randomised trial done in one academic hospital in Hong Kong, we screened patients with arthritis and cardiothrom- botic diseases who were presenting with upper gastrointestinal bleeding, were on NSAIDs, and require concomitant aspirin. After ulcer heal- ing, an independent staff member randomly assigned (1:1) patients who were negative for Helicobacter pylori with a computer-generated list of random numbers to receive oral admin- istrations of either celecoxib 100 mg twice per day plus esomeprazole 20 mg once per day or naproxen 500 mg twice per day plus esome- prazole 20 mg once per day for 18 months. All patients resumed aspirin 80 mg once per day. Both patients and investigators were masked to their treatments. The primary endpoint was recurrent upper gastrointestinal bleeding within 18 months. The primary endpoint and secondary safety endpoints were analysed in the modified intention-to-treat population. FINDINGS Between May 24, 2005, and Nov 28, 2012, we enrolled 514 patients, assigning 257 patients to each study group, all of whom were included in the intention-to-treat popula- tion. 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 gas- tric ulcers, three duodenal ulcers, one gastric

COMMENT By Jay L. Goldstein MD

T he hypothetical question of whether the use of aspirin negates the clinical benefit of a coxib is tested in a population of patients at high risk for recurrent upper GI bleeding who are H. pylori negative, have had upper gastrointestinal bleeding, and who have the ongoing need for non-steroidal therapy for arthritis as well as the need for low-dose aspirin for cardiovascular prophylaxis. This randomized prospec- tive trial compared rates of recurrent bleeding in patients who were being treated with 20 mg of esomeprazole and 80 mg of aspirin who additionally received either 200 mg daily of celecoxib or 1 g of naproxen per day. The results of the trial demon- strate that a COX-2-selective NSAID is still associated with a finite but significantly reduced risk of recurrent upper GI bleeding over the duration of the study (18 months). What does this mean to clinicians? In patients who are at high risk and require non-steroidals and aspirin therapy, the ques- tion goes beyond the simple need of a PPI for acid reduction and risk reduction. This study extends the question to the appropriateness of a coxib vs a non-selective NSAID. As this study demonstrates, use of a coxib has a clear benefit with a ≥50% reduction in the rate in recurrent upper GI bleeding; use of aspirin does not necessarily negate the benefit of a coxib in this population. However, the reduced risk does not equate to no risk. The bleeding rate in the coxib arm was approximately 1 in 20; this rate of approxi- mately 5% reminds the clinician that, despite the advantages of using a coxib with acid reduction, the risk of recurrent bleeding is still significant. Given the age/risk of the pop- ulation and associated morbidity and mortality associated with upper GI bleeding, one should always avoid use of any anti-inflammatory unless there is a stronger anticipation of a significantly greater benefit than risk. The conclusion of this study takes us one step closer to greater safety, but still reminds us that nothing is absolute.

Dr Goldstein is Vice Chairman of the Department of Medicine, and Head, Division of Gastroenterology at Northshore University HealthSystem, Illinois.

VOL. 2 • NO. 1 • 2017