Critiquing Evidence About the Risky Arthritis and Pain Drug Celecoxib (CELEBREX, CONSENSI)

Celecoxib is a widely used selective COX-2 inhibitor that belongs to a drug class called nonsteroidal anti-inflammatory drugs (NSAIDs). It is available in two formulations. The first, CELEBREX — which is currently indicated to relieve symptoms associated with three arthritic conditions (ankylosing spondylitis, osteoarthritis and rheumatoid arthritis) and to relieve acute pain (such as pain due to a musculoskeletal injury) and menstrual pain — was approved by the Food and Drug Administration (FDA) in 1998.[1]

The second, CONSENSI — which is, in our opinion, a nonsensical combination product containing celecoxib and the hypertension (high blood pressure) drug amlodipine — is indicated for use in patients with hypertension and osteoarthritis only and was approved by the FDA in 2018.[2]

Public Citizen has classified both formulations of celecoxib as Do Not Use and petitioned the FDA to ban this drug in 2005.[3] This is because even early evidence had linked the drug to increased cardiovascular risks (including heart attacks) compared with traditional non-aspirin NSAIDs, such as ibuprofen (ADVIL, IBU-TAB, MIDOL LIQUID GELS, MOTRIN, TAB-PROFEN) and naproxen (ALEVE, ANAPROX DS, NAPRELAN, NAPROSYN).

Faulty initial evidence

When Pfizer launched celecoxib, it claimed that the drug was as effective as traditional non-aspirin NSAIDs but had fewer gastrointestinal adverse effects (including stomach ulcers and bleeding) than these other drugs.[4]

These claims were based on results from the Pfizer-funded CLASS trial that had been manipulated to favor celecoxib.[5] Specifically, an article from 2000 that was based on this trial showed that celecoxib decreased the annual rate of upper gastrointestinal ulcers and related complications (bleeding, perforation and obstruction) compared with ibuprofen and diclofenac (CAMBIA, ZIPSOR, ZORVOLEX).[6]

Controversially, these results were improperly combined and extrapolated by the authors of the 2000 article from two separate trials.[7] In fact, an analysis by FDA reviewers uncovered similar rates of upper gastrointestinal ulcer complications among subjects in the celecoxib, ibuprofen and diclofenac groups in the CLASS trial.[8] Additionally, the FDA reviewers showed a nonsignificant trend in favor of diclofenac when they used an alternative definition of upper gastrointestinal ulcer complications.

Cardiovascular risks

Two related selective COX-2 inhibitors — rofecoxib (VIOXX) and valdecoxib (BEXTRA) — were withdrawn from the global market in 2004 and 2005, respectively, because of their cardiovascular toxicity.[9] Celecoxib is the only drug from this class that remains on the U.S. market,[10] although evidence has linked this drug to higher cardiovascular risks than those associated with traditional non-aspirin NSAIDs.

As we pointed out in our FDA petition, an FDA reviewer of the CLASS trial observed a trend toward more cardiovascular adverse effects among subjects taking celecoxib compared with those taking traditional NSAIDs, although this trend did not reach statistical significance.[11]

A placebo-controlled trial, called the APC trial, showed a dose-related increase in a composite endpoint of cardiovascular death, heart attack or stroke among subjects in the celecoxib group compared with subjects in the placebo group after three years of follow-up.[12]

Subsequently, Pfizer conducted a postmarketing cardiovascular safety trial called PRECISION at the request of the FDA.[13] After enrolling more than 24,000 subjects with osteoarthritis or rheumatoid arthritis, the trial results published in 2016 showed that celecoxib was equivalent in cardiovascular risk (cardiovascular death, nonfatal heart attack and nonfatal stroke) to naproxen and that gastrointestinal adverse events were significantly less common with use of celecoxib than with use of ibuprofen and naproxen.

These findings were challenged by a group of scientists at the University of Pennsylvania, led by Dr. Garret A. FitzGerald, and elsewhere for several reasons.[14],[15]

First, although the PRECISION trial was designed to enroll subjects with established cardiovascular risk, it ended up enrolling subjects with low cardiovascular risk.

Second, the subjects in the celecoxib group on average received significantly lower dosages of the drug compared with the drug dosages given to subjects in the ibuprofen and naproxen groups in the PRECISION trial. This meant that the trial compared subjects taking low-dose celecoxib with those taking relatively higher doses of ibuprofen and naproxen, which clearly favored celecoxib because the cardiovascular risks of all non-aspirin NSAIDs are generally proportionate to their dosages.

Third, more than two-thirds of the subjects withdrew from the trial.

The University of Pennsylvania scientists had similar concerns about a 2017 Pfizer-funded trial, called the SCOT trial.[16] They concluded that both PRECISION and SCOT trials offered “no conclusive answer as to which of the compared NSAIDs have the most favorable safety profile for patients who require daily pain relief for arthritis, particularly when they also have cardiovascular risk factors or established cardiovascular disease.”

Minimal benefits

A 2017 review published by researchers from the Cochrane Collaboration, an independent nonprofit organization, analyzed evidence from 36 peer-reviewed randomized clinical trials that compared celecoxib with a placebo, traditional NSAIDs or no intervention in more than 17,200 adult subjects with hip or knee osteoarthritis or both.[17] Although these researchers found that celecoxib reduced pain by the same amount as traditional NSAIDs and improved physical function only slightly more than these drugs, they were “highly reserved” about these small benefits. This is because 34 (94%) of the reviewed trials were funded by the drug industry and each trial had at least one industry-employee author.

The Cochrane researchers could not reliably compare cardiovascular or gastrointestinal adverse effects in the reviewed trials because these data were “of low quality” and Pfizer and the authors of three trials — which collectively included 15,539 subjects — refused to provide their safety data to these researchers.

What You Can Do

Tell your doctor if you have a history of any cardiovascular disease or gastrointestinal bleeding or ulcers before taking any non-aspirin NSAIDs because all these medications increase the risk of developing a heart attack or stroke, which may occur anytime during treatment.[18],[19] Avoid celecoxib and opt for ibuprofen or naproxen at the lowest effective dose and for the shortest possible time if you and your doctor decide that you need to take one of these medications.

If you are pregnant, do not use any NSAIDs at 20 weeks of gestation or later unless specifically advised to do so by your doctor.[20]

Talk to your doctor before taking any over-the-counter NSAIDs for more than 10 days.
 

References

[1] Pfizer. Label: celecoxib (CELEBREX). April 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020998s056lbl.pdf. Accessed June 8, 2021.

[2] Burke Therapeutics, LLC. Label: amlodipine and celecoxib (CONSENSI). April 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/210045s009lbl.pdf. Accessed June 8, 2021.

[3] Public Citizen. Petition to withdraw celecoxib & valdecoxib. January 25, 2005. https://www.citizen.org/article/petition-to-withdraw-celecoxib-valdecoxib/. Accessed June 8, 2021.

[4] Celecoxib and the CLASS trial: data massaging by industry. Prescrire Int. 2002;11(62):190-191.

[5] Ibid.

[6] Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA. 2000;284(10):1247-1255.

[7] Taking stock of coxibs. Drug Ther Bull. 2005;43(1):1-6.

[8] Jüni P, Rutjes AW, Dieppe PA. Are selective COX 2 inhibitors superior to traditional non steroidal anti-inflammatory drugs? BMJ. 2002;324(7349):1287-1288.

[9] Prescrire R. Celecoxib still on the market: But for whose benefit? Prescrire Int. 2005;14(79):177-178.

[10] Food and Drug Administration. The benefits and risks of pain relievers: Q & A on NSAIDs with Sharon Hertz, M.D. September 24, 2015. https://www.fda.gov/consumers/consumer-updates/benefits-and-risks-pain-relievers-q-nsaids-sharon-hertz-md. Accessed June 8, 2021.

[11] Public Citizen. Petition to withdraw celecoxib & valdecoxib. January 25, 2005. https://www.citizen.org/article/petition-to-withdraw-celecoxib-valdecoxib/. Accessed June 8, 2021.

[12] Pfizer. Label: celecoxib (CELEBREX). April 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020998s056lbl.pdf. Accessed June 8, 2021.

[13] Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016;375(26):2519-2529.

[14] Fitzgerald GA. Imprecision: Limitations to interpretation of a large randomized clinical trial. Circulation. 2017;135(2):113-115.

[15] Grosser T, Ricciotti E, Fitzgerald GA. The cardiovascular pharmacology of nonsteroidal anti-inflammatory drugs. Trends Pharmacol Sci. 2017;38(8):733-748.

[16] Macdonald TM, Hawkey CJ, Ford I, et al. Randomized trial of switching from prescribed non-selective non-steroidal anti-inflammatory drugs to prescribed celecoxib: the Standard care vs. Celecoxib Outcome Trial (SCOT). Eur Hear J. 2017;38(23):1843-1850.

[17] Puljak L, Marin A, Vrdoljak D, et al. Celecoxib for osteoarthritis (review). Cochrane Database Syst Rev. 2017;5(5):CD009865.

[18] Food and Drug Administration. The benefits and risks of pain relievers: Q & A on NSAIDs with Sharon Hertz, M.D. September 24, 2015. https://www.fda.gov/consumers/consumer-updates/benefits-and-risks-pain-relievers-q-nsaids-sharon-hertz-md. Accessed June 9, 2021.

[19] Food and Drug Administration. Drug safety communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. July 9, 2015. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-strengthens-warning-non-aspirin-nonsteroidal-anti-inflammatory. Accessed June 9, 2021.

[20] FDA warns against using NSAIDs in pregnancy at 20 weeks or later. Worst Pills, Best Pills News. March 2021. https://www.worstpills.org/newsletters/view/1389. Accessed June 9, 2021.