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N Engl J Med. 2016 Dec 29;375(26):2519-29. doi: 10.1056/NEJMoa1611593. Epub 2016 Nov 13.
Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis.
Nissen SE1, Yeomans ND1, Solomon DH1, Lüscher TF1, Libby P1, Husni ME1, Graham DY1, Borer JS1, Wisniewski LM1, Wolski KE1, Wang Q1, Menon V1, Ruschitzka F1, Gaffney M1, Beckerman B1, Berger MF1, Bao W1, Lincoff AM1; PRECISION Trial Investigators.
Full Text for NephJC/RheumJC readers: NEJM Article
Pain management in patients with osteoarthritis or rheumatoid arthritis often requires long-term use of nonsteroidal antiinflammatory drugs (NSAIDs). However, the relative cardiovascular safety of these therapies remains uncertain. The cardiovascular (CV) risks of nonsteroidal antiinflammatory drugs (NSAIDs) have received intense scientific and public attention after the withdrawal of rofecoxib from the market in September of 2004 and the mandatory class label changes including boxed warnings in the United States.
In medical school during an elective in Rheumatology I expressed interest in this topic and conducted some basic science research.
The Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION) trial in evaluating the cardiovascular safety of celecoxib, ibuprofen, and naproxen was to provide data to help guide NSAID use for pain management.
Investigation on the overall risks/benefits of non-selective NSAIDs and COX-2 selective inhibitors is of great public health significance, since a large number of patients using these drugs are elderly and have cardiovascular risk factors.
Aim of the Study: assess the noninferiority of celecoxib with regard to the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke.
Study design and Methods: PRECISION was a randomized, multicenter, double-blind, noninferiority trial involving patients who were at increased cardiovascular risk and had rheumatoid arthritis or osteoarthritis. Randomization was stratified according to the primary diagnosis, aspirin use, and geographic region.
Primary Endpoints: first occurrence of an Antiplatelet Trialists Collaboration (APTC) end point, including CV death (including hemorrhagic death), nonfatal MI, or nonfatal stroke. Myocardial infarction is defined according to the ACC/AHA guidelines. Stroke is defined as an acute neurologic cerebral vascular event with focal neurologic signs lasting >24 hours.
Secondary Endpoints: first occurrence of a major adverse CV event defined as a composite of CV death (including hemorrhagic death), nonfatal MI, nonfatal stroke, hospitalization for unstable angina, revascularization, or hospitalization for a transient ischemic attack. Clinically significant GI events and arthritis pain are evaluated as secondary endpoints.
Inclusion Criteria: patients ≥18 years of age with a clinical diagnosis of OA or RA who, as determined by the individual patient and physician, require daily treatment with NSAIDs to maintain their quality of life. A key inclusion requirement is presence of, or high risk for, CV disease.
Sample Size: Approximately 20,000 patients with symptomatic osteoarthritis or rheumatoid arthritis at high risk for, or with, established cardiovascular disease were randomized. The goal of the study 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. It was decided that noninferiority of any of the regimens will require a 97.5% upper CI of the hazard ratio (HR) ≤1.33 and point estimate ≤1.12 for both intent-to-treat (ITT) and modified ITT populations.
Funding: Supported by Pfizer. ClinicalTrials.gov number, NCT00346216.
Of the 31,857 patients screened, 24,222 underwent randomization at 926 centers in 13 countries between October 23, 2006, and June 30, 2014. 24,081 participants were included in the analysis as 141 were excluded (106 were determined to be fraudulently enrolled, and 35 enrolled more than once).
Figure 1 Time-to-Event Analysis for Primary and Secondary Outcomes.
Noninferiority Analysis for Primary APTC End Point
Box A and B of Figure 1
- Analysis of secondary outcomes showed the time to a major adverse CV event (C) was 15% higher with ibuprofen than celecoxib in the ITT group but fell just short of statistical significance (P=0.06)
- Death from cardiovascular causes was lowest with celecoxib, while all-cause mortality(D) was 25% higher with naproxen than celecoxib, which was right on the borderline of significance (P= 0.052)
- The risk of gastrointestinal events (E) was significantly lower with celecoxib than with naproxen (P = 0.01) or ibuprofen (P = 0.002)
- Compared with celecoxib, major GI event (E) rates were 54% higher with ibuprofen and 41% higher with naproxen than celecoxib in the ITT group (P =0.002; P=0.01, respectively) and at least twice as high for ibuprofen and naproxen in the on-treatment group
- The risk of renal events (F) was significantly lower with celecoxib than with ibuprofen (P = 0.004) but was not significantly lower with celecoxib than with naproxen (P = 0.19).
Table 3 shows that the primary APTC outcome occurred in 134 patients in the celecoxib group (1.7%), 144 in the naproxen group (1.8%), and 155 in the ibuprofen group (1.9%).
Celecoxib, as compared with either naproxen or ibuprofen, met all four prespecified noninferiority requirements (P<0.001 for noninferiority in both comparisons). Ibuprofen, as compared with naproxen, just met the noninferiority criteria (P = 0.025) (Table S2).
Conclusion: “the PRECISION trial showed the noninferiority of moderate doses of celecoxib, as compared with naproxen or ibuprofen, with regard to the primary APTC cardiovascular outcome. Celecoxib treatment also resulted in lower rates of gastrointestinal events than did either comparator drug and in lower rates of renal adverse events than did ibuprofen.”
Limitations: The authors acknowledged that adherence and retention were lower than in most trials that assess cardiovascular outcomes, possibility of informative censoring (i.e., the bias that is created when participants drop out of a study because of factors related to the study itself), and since the dose of celecoxib was limited this may have provided a potential safety advantage for celecoxib. Thus these results provide reassurance regarding the safety of moderate doses of celecoxib but not the safety of high doses of celecoxib.