“Noninferiority” was determined by the Antiplatelet Trialists Collaboration (APTC) composite outcome of CV death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke at 18 months post-stratification. A one-sided 97.5% confidence interval (CI) of the hazard ratio (HR) for each of the 3 comparisons (celecoxib:naproxen, ibuprofen:naproxen, and celecoxib:ibuprofen) was specified by the researchers. The study also investigated gastrointestinal and renal outcomes.

Study Findings

“The most important finding was that celecoxib unequivocally met its primary end point of noninferiority,” Dr Nissen stated.


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In intent-to-treat (ITT) analyses, a primary outcome event occurred in 188 patients (2.3%) in the celecoxib group, 201 patients (2.5%) in the naproxen group, and 218 (2.7%) patients in the ibuprofen group; (HR for celecoxib vs naproxen: 0.93; 95% CI, 0.76-1.13; HR for celecoxib vs ibuprofen: 0.85; 95% CI, 0.70-1.04; P <.001 for noninferiority in both comparisons). The HR for the non-selective NSAIDs—ibuprofen vs naproxen—was 1.08 (95% CI, 0.90-1.31; P =.02 for noninferiority).4

In the on-treatment analysis, a primary outcome event occurred in 134 patients (1.7%) in the celecoxib group, 144 patients (1.8%) in the naproxen group, and 155 patients (1.9%) in the ibuprofen group; (HR for celecoxib vs naproxen: 0.90; 95% CI, 0.71-1.15; HR for celecoxib vs ibuprofen: 0.81; 95% CI, 0.65-1.02; P <.001 for noninferiority in both comparisons). Finally, ibuprofen vs naproxen had an HR of 1.12 (95% CI, 0.89-1.40; P =.025 for noninferiority). 4

“Numerically fewer APTC events occurred with celecoxib than naproxen, and fewer APTC events occurred with celecoxib than ibuprofen,” Dr Nissen said, adding that celecoxib met all 4 noninferiority criteria for both NSAIDs (P <.001).

Comparitive safety analysis showed that the risk of gastrointestinal events was significantly lower with celecoxib than with naproxen (P =.01) or ibuprofen (P =.002); the risk of renal events was significantly lower with celecoxib than with ibuprofen (P =.004) but was not significantly lower with celecoxib than with naproxen (P =.19). 4

“Celecoxib also seemed safer, in terms of gastrointestinal and renal adverse effects, although we were cautious in interpreting these findings,” Dr Nissen commented.

He added, “We were surprised. We expected the drug to have the same risks as rofecoxib, but, if anything, the trend went in the opposite direction.”

Study Limitations

During the trial, 68.8% of patients discontinued taking the study agent, and 27.4% of patients were lost to follow-up. “The principal limitation was the low retention and nonadherence rates,” Nissen said. “This is more typical in pain trials than in CV outcome trials.”

A second limitation he noted was that, due to regulatory restrictions on the doses of celecoxib, “we used doses considered to be moderate—100 mg twice a day, which could be increased to 200 mg twice a day for those with RA. But patients with RA were only 10% of the total number of participants.” By contrast, those taking naproxen or ibuprofen were allowed to escalate doses without restriction.

In an interview with Cardiology Advisor, Elliot Antman, MD, professor of medicine, Cardiovascular Division, Brigham and Women’s Hospital and associate dean for Clinical and Translational Research at Harvard Medical School in Boston concurred that these were important limitations.

“Poor adherence and low retention challenge the claim of noninferiority, since the proportion of individuals who discontinued the drug was significantly higher in celecoxib, as compared to ibuprofen or naproxen, suggesting that the dose of celecoxib was too low to achieve pain reduction,” Dr Antman said. By contrast, “those who discontinued ibuprofen or naproxen did so because of adverse reactions, and were receiving comparatively higher doses.”

He expressed additional concerns: “Previous data9 showed that high doses of celecoxib were associated with risk of [CV] events, and this study utilized relatively low doses.”

“Moreover, since a relatively small percentage of participants had known heart disease, the population can be considered low-risk. The low dose of celecoxib administered to a low-risk population, calls into question the statement of noninferiority,” Dr Antman said.

Additionally, “there was no reported analysis of the presence or absence of aspirin or aspirin dose used by patients during the study.” This is important, Dr Antman explained, “because ibuprofen and naproxen can interfere with the benefits of aspirin.” So if the patient was receiving aspirin and then randomized to ibuprofen or naproxen, “it is possible that the cardioprotective benefit of aspirin was neutralized.” 

Take-Home Messages for Clinicians

“Celecoxib is not worse than NSAIDs, with regard to [CV] risk,” Dr Nissen stated. Patients with high risk of gastrointestinal bleeding, such as those on anticoagulants, as well as patients with abnormal kidney function may actually experience advantages with celecoxib.

Regarding practical applications of the study, Dr Nissen said, “I am going to let the guideline writers and the FDA look at our trial and make recommendations for clinical practice.”

Dr Antman cautioned, “We need to resort to the totality of the literature, including consensus statements of major societies.10,11 While they were written before the PRECISION results were released, it does not appear that PRECISION would change the guidance.”

He added, “It seems best to avoid using NSAIDS in patients with known heart disease, restrict their use to the lowest risk patients, and select the lowest risk drug in the lowest dose needed to control the symptoms, and for the shortest period of time.”

References

  1. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005 Mar 17;352(11):1092-1102.
  2. US Food and Drug Administration. Postmarket drug safety information for patients and providers. Vioxx (rofecoxib): questions and answers. http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformation
    forpatientsandproviders/ucm106290.htm
    . Updated April 6, 2016. Accessed December 6, 2016.
  3. Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005;352:1071-1080.
  4. Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016. doi:10.1056/NeJMoa1611593 [Epub ahead of print].
  5. Nissen SE. LBCT.01: Big Trials for Big Ideas. Cardiovascular outcomes with celecoxib vs ibuprofen or naproxen: the PRECISION trial. Presented at: the 2016 American Heart Association Scientific Sessions. November 12-16, 
  6. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286(8):954-959.
  7. Martínez-González J, Badimon L. Mechanisms underlying the cardiovascular effects of COX-inhibition: benefits and risks. Curr Pharm Des. 2007;13(22):2215-2227.
  8. Blankfield RP, Iftikhar IH. Food and drug administration regulation of drugs that raise blood pressure. J Cardiovasc Pharmacol Ther. 2015;20(1):5-8.
  9. Solomon SD, Wittes J, Finn PV, et al. Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis. Circulation. 2008;117(16):2104-2113.
  10. Antman EM, Bennett JS, Daugherty A, et al. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation. 2007;115(12):1634-1642.
  11. 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. 2016;37(13):1015-1023.