The Potential Risks and Benefits Associated With the Use of Celecoxib and Other NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of mild to moderate pain. Ibuprofen and naproxen are available over-the-counter (OTC) and are commonly used by patients; as such, patients may not report their use of these NSAIDs to their physician. The OTC status of ibuprofen and naproxen may convey to patients an element of safety. However, these and other NSAIDs are associated with renal and cardiovascular (CV) toxicity in addition to an increased risk of bleeding, most notably in the gastrointestinal (GI) tract.

In an effort to limit GI bleeding, selective cyclooxygenase 2 (COX-2) inhibitors, such as celecoxib, etoricoxib, rofecoxib, and valdecoxib, have been developed. However, in the United States rofecoxib and valdecoxib have been taken off the market, and etoricoxib has not been approved by the US Food and Drug Administration, as a result of unacceptably high rates of adverse CV events (myocardial infarction and stroke) associated with their use. Celecoxib is still available by prescription, and while it is a selective COX-2 inhibitor NSAID, its relative COX-2 selectivity is dramatically lower than that of etoricoxib and rofecoxib. Nevertheless, concern remains about the potential elevated risk of CV events associated with the use celecoxib.

Patient Case

JG is a 67-year-old man who presents to the clinic for his annual physical examination. He reports that he is doing well overall with the exception of aching knee pain, which appears to be osteoarthritis (OA). JG is currently taking chlorthalidone, 12.5 mg daily, and lisinopril, 20 mg daily, for his blood pressure, which is well controlled. He would like to begin treatment for his knee pain, and he notes that he recently heard on the news that based on new information, a medication named celecoxib has been determined to be a safe NSAID. Is celecoxib now considered safe?

The Evidence

In November 2016, the New England Journal of Medicine published the results of the PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen) trial,¹ which evaluated the safety of celecoxib in patients with rheumatoid arthritis or OA. More than 24,000 patients were randomly assigned to receive celecoxib at 100 mg twice daily, ibuprofen at 600 mg 3 times a day, or naproxen at 375 mg twice a day. Daily dosages could be increased to a total of 400 mg of celecoxib, 2400 mg of ibuprofen, or 1000 mg of naproxen for pain that was not adequately controlled. The primary outcome was time to first CV death, nonfatal myocardial infarction or stroke, or hemorrhagic death; GI bleeding was considered a secondary outcome. The safety of celecoxib was compared with that of naproxen as the primary comparator; celecoxib also was compared with ibuprofen, and ibuprofen with naproxen.

After an average treatment duration of 20 months, celecoxib was found to be noninferior to naproxen (the event rate for the primary outcome in the intention-to-treat population was 2.3% for those receiving celecoxib, 2.5% for those receiving naproxen, and 2.7% for those receiving ibuprofen). Furthermore, there was not an increased risk of CV events with celecoxib compared with naproxen, and there were fewer adverse serious GI events with celecoxib than with naproxen, although the absolute difference was small (0.4% difference). The incidence of clinically significant GI events was the same with celecoxib and naproxen (0.7%).

While the results of the PRECISION trial confirm the relative safety of celecoxib, they should not be taken to suggest that celecoxib or any NSAID is particularly safe. Overall, NSAIDs are well known for causing fluid retention and blood pressure elevation.² Compared with placebo, agents such as naproxen and ibuprofen are associated with a 4-fold increase in the risk of GI bleeding events.² While the selectivity of agents such as celecoxib and diclofenac reduces the risk of adverse GI events compared with nonselective NSAIDs, the risk remains significant (a 1.8-fold increase in relative risk for celecoxib, and a 1.9-fold increase for diclofenac).²

Lastly and most notably, all NSAIDs, whether selective or not, are associated with an increase in the risk of adverse CV events. One meta-analysis³ found that celecoxib and diclofenac increased the risk of major CV events by roughly one-third. Such risk is independent of baseline CV risk and is increased only when other risk factors are present. The nonselective NSAID ibuprofen is associated with a similar risk; however, the naproxen may not share such properties.³

While celecoxib is a COX-2 selective NSAID, it is worth noting that the relative selectivity of celecoxib for COX-2 pales in comparison with that of rofecoxib and is similar to that of diclofenac, meloxicam, and etodolac (ibuprofen is nonselective, while naproxen is slightly more COX-1 selective). Given that CV risk is associated with the degree of COX-2 selectivity, it is not surprising that the CV risks associated with celecoxib are closer to those of traditional nonselective NSAIDs than to the agents with a much higher selectivity for COX-2 that were removed from the market.

Clinical Application

While the PRECISION trial does provide some reassurance regarding the potential CV toxicity of celecoxib, the use of the  drug still has significant concerns for CV events, renal events, and bleeding (namely GI bleeding). While the incidence of serious GI events was slightly lower compared with naproxen, celecoxib still carried a risk for these events. The European Society of Cardiology and other expert groups strongly warn against the frequent use of these medications, and the results of PRECISION confirm this recommendation. Based on PRECISION results, celecoxib can be used almost interchangeably with other NSAIDs, but the significant risk for toxicity of any NSAID must be carefully weighed against the potential benefits prior to use.

Patients should be warned about the possible harms of the use of any NSAID, and otherwise healthy patients should be counseled to use OTC NSAIDs only sparingly. Patients taking prescription medications and especially patients with CV or renal disease, a history of GI bleeding, or concomitant use of aspirin should be discouraged from using OTC NSAIDs without first consulting their physician. Patients taking angiotensin-converting enzyme (ACE) inhibitors and diuretics should be strongly cautioned against using NSAIDs, given the very high risk of adverse renal events. Prescription treatment with NSAIDs should be monitored closely and initiated only after safer alternatives, if they represent viable treatment options, are trialed first. In certain patients, the risks of NSAIDs may always outweigh the benefits.

Outcome of the Case

JG should be counseled that the recent study results he heard about do indicate that celecoxib is as safe as any other NSAID, but that all NSAIDs carry a risk of GI, renal, and CV adverse events, in addition to an increased risk of bleeding.

Control of JG’s blood pressure is being maintained with an ACE inhibitor and a diuretic; if an NSAID were to be added to the regimen, he would be at a significantly increased risk for an adverse renal event. Furthermore, JG’s age puts him at higher risk for CV events and adverse GI events, both of which would be further elevated by NSAID use. While the PRECISION trial indicates that celecoxib is roughly as safe as other NSAIDs, at this time NSAID therapy may not be warranted for JG in light of the significant risks and the availability of viable alternative treatment options (eg, acetaminophen) for his presumed OA of the knee.

JG instead can be started on acetaminophen, 1000 mg every 8 hours, for his knee pain, given the more favorable safety profile of acetaminophen. While controversy exists about the clinical efficacy of acetaminophen, given that JG’s symptoms appear to be mild, acetaminophen represents a viable option as recommended by the American Academy of Rheumatology.⁴

Eric A. Dietrich, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy and completed a 2-year fellowship in family medicine where he was in charge of an anticoagulation clinic. He works for the College of Pharmacy and the College of Medicine at the University of Florida in Gainesville.

Kyle Davis, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy in Gainesville and completed a 2-year residency in internal medicine at Indiana University in Indianapolis. He is an internal medicine specialist at Ochsner Medical Center in Jefferson, Louisiana.

References:

1. Nissen SE, Yeomans ND, Solomon DH, et al; PRECISION Trial Investigators. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016;375(26):2519-2529.
2. Schmidt M, Lamberts M, Olsen AM, et al. Cardiovascular safety of non-aspirin non-steroidal anti-inflammatory drugs: review and position paper by the working group for Cardiovascular Pharmacotherapy of the European Society of Cardiology. Eur Heart J Cardiovasc Pharmacother. 2016;2(2):108-118.
3. Coxib and traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;​382(9894):​769-779.
4. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2012;64(4):465-474.