Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis

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Nissen SE, et al. "Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis". New England Journal of Medicine. 2016. 375(26):2519-2529.
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Clinical Question

In patients taking NSAIDs for arthritis and at increased risk of cardiovascular disease, is Celecoxib non-inferior to conventional therapy of Naproxen or Ibuprofen to prevent hemorrhagic death, nonfatal myocardial infarction, or nonfatal stroke?

Bottom Line

Celecoxib is non-inferior to both Naproxen and Ibuprofen at preventing hemorrhagic death, nonfatal myocardial infarction, or nonfatal stroke.

Major Points

Nonsteroidal antiinflammatory drugs (NSAIDs) have been associated with cardiovascular risk. NSAIDs inhibit cyclooxygenase (COX) which reduces pain and inflammation by blocking the formation of prostaglandins. There are two isoforms of COX, COX-1 and COX-2. Inhibition of COX-1 is associated with gastrointestinal side effects, while inhibition of COX-2 limits the GI effects. In 2004, adverse cardiovascular events were shown in a COX-2 inhibitor, rofecoxib, and it was withdrawn from the market. The FDA allowed continuation of another selective COX-2 inhibitor, celecoxib. This study focuses on cardiovascular, gastrointestinal, renal, and other outcomes with celecoxib as compared with two nonselective COX inhibitors, naproxen and ibuprofen.

This trial was a randomized, double-blinded, noninferiority study. The patients selected had an increased risk of cardiovascular disease and also were diagnosed with rheumatoid arthritis or osteoarthritis. There was no statistically significant difference between naproxen, ibuprofen and celecoxib in regard to the primary cardiovascular outcome (HR: celecoxib vs. naproxen, 0.93; (95%CI, 0.76-1.13, P<0.001); HR: celecoxib vs. ibuprofen, 0.85; (95% CI, 0.70-1.04, P<0.001)). The COX-2 inhibitor, celecoxib, is not inferior to the COX-1 inhibitors, naproxen and ibuprofen. As NSAIDs are used widely in arthritis, evaluating the risks such as cardiovascular events is of major importance. In patients with a high risk of cardiovascular disease, this study was necessary to compare the safety of the NSAIDs, celecoxib, ibuprofen and naproxen.


  • 2012 ACR Recommendations for Management of Hand, Hip, and Knee OA (LOE=1a)
    • Recommends one or more of the following:
      • Topical capsaicin
      • Topical NSAIDs, including trolamine salicylate
      • Oral NSAIDs, including COX-2 selective inhibitors
      • Tramadol
  • OARSI guidelines for the non-surgical management of knee osteoarthritis
    • NSAIDs (oral COX-2 inhibitors) (LOE=1a)
      • Appropriate: individuals without comorbidities
      • Appropriate: multiple-joint OA with moderate co-morbidity risk
      • Uncertain: knee-only OA with moderate co-morbidity risk
      • Not appropriate: individuals with high co-morbidity risk
    • NSAIDs (oral non-selective NSAIDs) (LOE=1a)
      • Recommendations
      • Appropriate: individuals without comorbidities
      • Uncertain: individuals with moderate co-morbidity risk
      • Not appropriate: individuals with high co-morbidity risk


  • Trial Type: randomized, multicenter, double-blind, noninferiority trial
  • N=24,222
  • Celecoxib N=8072
  • Naproxen N=7969
  • Ibuprofen N=8040
  • Setting: 936 centers in 13 countries
  • Enrollment: October 23, 2006, and June 30, 2014
  • Mean Follow-Up: minimum follow-up time of 18 months, with censoring of data from event-free patients after 30 months in the intention-to-treat population and after 43 months in the on-treatment population
  • Analysis: intention-to-treat
  • Primary Outcome: Cardiovascular-related death (including hemorrhagic death), non-fatal myocardial infarction, and non-fatal stroke


Inclusion Criteria

  • Patients with osteoarthritis or rheumatoid arthritis with an increased cardiovascular risk (or already acquired cardiovascular disease)
    • Cardiovascular risk defined as established or high risk coronary disease, occlusive disease of noncoronary arteries, diabetes, and artherosclerotic disease.
  • Require daily treatment with NSAIDs for arthritis pain

Exclusion Criteria

  • Age <18 YOA
  • Pain is adequately managed with acetaminophen

Baseline Characteristics

  • Groups were similar except when specified
  • Demographics
    • Age 63 YOA, female 64%,
    • Race: white 75%, black 14%, other 9%, asian 2%
  • BMI: 32
  • PMH: hypertension 78%, dyslipidemia 63%, diabetes 35%, current smoker 21%
  • Current Medications: Aspirin 45%, statin 54%, DMARD 7%
  • Primary arthritis diagnosis: OA 90%, RA 10%
  • Cardiovascular risk category: primary prevention 77%, secondary prevention 23%


  • Patients were randomly assigned to a group
    • Celecoxib 100mg twice a day
    • Naproxen 375mg twice a day
    • Ibuprofen 600mg three times a day
  • After follow up with each patient, the celecoxib dose could be increased to a max of 200 mg twice a day, the naproxen dose could be increased to a max of 500 mg, and the ibuprofen dose could be increased to a max of 800 mg three times a day.
  • Drugs were taken by mouth
  • Esomeprazole was given to all patients for gastric protection


Primary Outcomes

  • Cardiovascular-related death (including hemorrhagic death), non-fatal myocardial infarction, and non-fatal stroke.
    • Intention-to-treat: Occurred in 188 patients administered celecoxib (2.3%), 201 patients administered naproxen (2.5%), and 218 patients administered ibuprofen (2.7%). (HR: celecoxib vs. naproxen, 0.93; (95%CI, 0.76-1.13, P=0.45); HR: celecoxib vs. ibuprofen, 0.85; (95% CI, 0.70-1.04, P=0.12).

Secondary Outcomes

  • Death from any cause: Celecoxib when compared to naproxen was just outside the margins for significantly reducing all-cause mortality (1.6% vs. 2% HR: 0.80; 95% CI, 0.63-1.00, P=0.052)
  • Hospitalization for Hypertension: Celecoxib treatment resulted in fewer hospital admissions for hypertension when compared to ibuprofen. (0.3% vs. 0.5% HR: 0.60, 95% CI, 0.36-0.99, P=0.04)

Adverse Events

  • Gastrointestinal and Renal Events:
    • Rate of composite gastrointestinal events (clinically significant GI events and iron-deficiency anemia)
      • celecoxib vs naproxen (1.1% vs. 1.5% HR: 0.71; 95% CI, 0.54-0.93, P = 0.01)
      • celecoxib vs ibuprofen (1.1% vs 1.6% HR: 0.65; 95% CI, 0.50-0.85; P = 0.002)
    • Rate of severe renal events
      • celecoxib vs naproxen (0.7% vs 0.9% HR: 0.79; 95% CI, 0.56-1.12; P = 0.19)
      • celecoxib vs ibuprofen (0.7% vs 1.1% HR: 0.61; 95% CI, 0.44-0.85; P = 0.004)


  • The celecoxib dosing was more restricted in the celecoxib treatment group, and the outcomes of the research study could have falsely portrayed that celecoxib is noninferior in respect to rate of cardiovascular events in comparison to naproxen or ibuprofen. Celecoxib could have been associated with more cardiovascular and gastrointestinal events if patients were given higher doses.
  • The study did not selectively assess celecoxib, naproxen, or ibuprofen use only in patients with preexisting heart disease1. Assessment of outcomes exclusively in individuals with preexisting heart disease would have a more meaningful study purpose.


The research study was funded Pfizer in collaboration with the Cleveland Clinic. Pfizer is a major pharmaceutical manufacturer of Celebrex (celecoxib) and Advil (ibuprofen).

Further Reading

1. Wood, Shelley. Tctmd [Internet]. 2016 Nov 13. No cv safety differences for cox-2 inhibitor vs other nsaids in precision [2017 Apr 13]. Available from: