PracticeUpdate: Dermatology - Vol 1 - No.1 - 2017

RHEUMATOLOGY 24

Celecoxib noninferior to ibuprofen and naproxen for cardiovascular safety The New England Journal of Medicine Take-home message

Abstract BACKGROUND The cardiovascular safety of celecoxib, as compared with nonselective nonsteroidal antiinflammatory drugs (NSAIDs), remains uncertain. METHODS Patients who required NSAIDs for osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk were randomly assigned to receive celecoxib, ibuprofen, or naproxen. The goal of the trial was to assess the noninferiority of celecoxib with regard to the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke. Nonin- feriority required a hazard ratio of 1.12 or lower, as well as an upper 97.5% confidence limit of 1.33 or lower in the intention-to-treat population and of 1.40 or lower in the on-treatment popula- tion. Gastrointestinal and renal outcomes were also adjudicated.

• The authors assessed the noninferiority of celecoxib compared with ibuprofen and naproxen in 24,081 patients who required NSAIDs due to osteo- or rheuma- toid arthritis and so were at higher cardiovascular risk. Gastrointestinal and renal adverse events were also evaluated. Median follow-up was 34 months. During the study, 68.8% of the patients stopped taking their medication and 27.4% discon- tinued follow-up. In the intention-to-treat analysis, the primary composite outcome (cardiovascular death [including hemorrhagic death], nonfatal myocardial infarction, and nonfatal stroke) was met by 2.3% of the celecoxib group compared with 2.5% of the naproxen group and 2.7% of the ibuprofen group (celecoxib noninferior to naproxen and ibuprofen; P < 0.001 for both comparisons). Additionally, celecoxib was associated with a lower risk of gastrointestinal side effects than naproxen (P = 0.01) and ibuprofen (P = 0.002). The risk of kidney events was lower with celecoxib than ibuprofen (P = 0.004) but not naproxen. • Relative to cardiac safety, celecoxib at moderate doses was found to be noninferior to ibuprofen and naproxen.

COMMENT COX-2 inhibitors: safe or not? By Peter Lin MD, CCFP

them to receive celecoxib, naproxen, or ibuprofen. Over 90% were osteoarthritis patients, with 10% having rheumatoid arthri- tis. The mean follow up was 34 months. Unfortunately, 68% of the patients stopped their therapy and 27% of the patients dropped out of the study. This is terrible for the study, but it reflects what our patients do in real life. They take their anti-inflammatories when they need to and they do not take them on a regular basis. Despite these drop outs there were still large amounts of use data. From the remaining patients, there was no difference in the primary cardiovascular outcomes among any of the ther- apies. Interestingly, despite the use of PPIs in the study, there were still less gastrointestinal events in the celecoxib group. Below are some of the significant findings of the on-treatment patients in this study.

T he basis of this question comes from the cyclooxygenase (COX) enzyme system, which creates prostaglandins that have many different physiologic effects. For example, the COX-1 enzyme in the stomach provides protection from acidity. On the other hand, the COX-2 enzyme in joints creates prosta- glandins that cause inflammation and pain. The original NSAIDs inhibited both COX-1 and COX-2 and hence, they were good for joint pain but bad on the stomach lining, resulting in ulcer development. This led to the development of selective COX-2 inhibitors, which did not affect the stomach but still had good anti-inflammatory effects. The only problem was that the COX enzymes are also found elsewhere in the body, not only in the stomach and joints. In the endothelium coating of blood vessels, the COX-2 enzymes produce prostaglandins that prevent platelets from sticking and clotting. So, a COX-2 inhibitor would block that process and platelets would be more likely to stick and form clots. Perhaps this is the explanation of why rofecoxib had increased cardiac events compared with naproxen. Interestingly, in the platelets, COX-1 makes prostaglandins that promote clot formation, so the theory is that an NSAID that blocks both COX-1 and COX-2 equally would still maintain balance – COX-2 is blocked in the endothelium but COX-1 is blocked in the platelet. Hence, balance is maintained and there is no increase in clot formation. That is the simple explanation of why naproxen does not seem to increase CV risk. However, because naproxen blocks COX-1 in the stomach, GI complications are still there. The PRECISION trial was designed to see if celecoxib blocks enough COX-2 to have the same CV risk issues as rofecoxib. This was funded by Pfizer but was done with the advice of the FDA. This study enrolled over 24,000 patients and randomly assigned

Outcome for on treatment patients

Celecoxib vs naproxen 0.90 (0.71–1.15) 0.45 (0.33–0.63) 0.66 (0.44–0.97) 0.65 (0.46–0.92)

Celecoxib vs ibuprofen 0.81 (0.65–1.02) 0.44 (0.32–0.61) 0.54 (0.37–0.80)

Primary APTC outcome

Serious gastrointestinal events

Renal events

Death from any cause 0.68 (0.48–0.97) It would seem that celecoxib is as safe as naproxen or ibuprofen for CV events, but definitely celecoxib had fewer gastrointestinal complications. And thankfully, most of our patients do not take these agents continuously. They tend to stop and start in real life, which, in fact, may reduce their exposure and hence reduce their potential risks.

Dr Lin is Director of Primary Care Initiatives, Canadian Heart Research Centre, and Medical Director at LinCorp Medical Inc, Canada.

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