Gastrointestinal Safety of Celecoxib Versus Naproxen Systematic Review and Meta Analysis
Original Commodity
Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis
Listing of authors.Abstract
Background
The cardiovascular safety of celecoxib, equally compared with nonselective nonsteroidal antiinflammatory drugs (NSAIDs), remains uncertain.
Methods
Patients who required NSAIDs for osteoarthritis or rheumatoid arthritis and were at increased cardiovascular take chances were randomly assigned to receive celecoxib, ibuprofen, or naproxen. The goal of the trial was to assess the noninferiority of celecoxib with regard to the primary composite result of cardiovascular death (including hemorrhagic decease), nonfatal myocardial infarction, or nonfatal stroke. Noninferiority required a gamble ratio of 1.12 or lower, likewise equally an upper 97.5% confidence limit of ane.33 or lower in the intention-to-treat population and of 1.forty or lower in the on-treatment population. Gastrointestinal and renal outcomes were as well adjudicated.
Results
A total of 24,081 patients were randomly assigned to the celecoxib group (hateful [±SD] daily dose, 209±37 mg), the naproxen grouping (852±103 mg), or the ibuprofen group (2045±246 mg) for a mean treatment duration of 20.3±16.0 months and a mean follow-up period of 34.1±13.4 months. During the trial, 68.8% of the patients stopped taking the written report drug, and 27.four% of the patients discontinued follow-upwardly. In the intention-to-care for analyses, a main outcome event occurred in 188 patients in the celecoxib group (2.iii%), 201 patients in the naproxen grouping (ii.five%), and 218 patients in the ibuprofen group (2.7%) (hazard ratio for celecoxib vs. naproxen, 0.93; 95% conviction interval [CI], 0.76 to 1.13; hazard ratio for celecoxib vs. ibuprofen, 0.85; 95% CI, 0.70 to 1.04; P<0.001 for noninferiority in both comparisons). In the on-treatment analysis, a main effect event occurred in 134 patients in the celecoxib group (1.7%), 144 patients in the naproxen grouping (1.8%), and 155 patients in the ibuprofen group (1.ix%) (hazard ratio for celecoxib vs. naproxen, 0.90; 95% CI, 0.71 to 1.15; take chances ratio for celecoxib vs. ibuprofen, 0.81; 95% CI, 0.65 to 1.02; P<0.001 for noninferiority in both comparisons). The risk of gastrointestinal events was significantly lower with celecoxib than with naproxen (P=0.01) or ibuprofen (P=0.002); the take chances of renal events was significantly lower with celecoxib than with ibuprofen (P=0.004) but was not significantly lower with celecoxib than with naproxen (P=0.19).
Conclusions
At moderate doses, celecoxib was plant to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety. (Funded by Pfizer; ClinicalTrials.gov number, NCT00346216.)
Methods
Trial Pattern and Oversight
PRECISION was a randomized, multicenter, double-bullheaded, noninferiority trial involving patients who were at increased cardiovascular risk and had rheumatoid arthritis or osteoarthritis. Randomization was stratified according to the primary diagnosis (osteoarthritis or rheumatoid arthritis), aspirin use, and geographic region. Detailed methods for the trial take been published previously,five and both the protocol and the statistical assay plan are bachelor with the total text of this article at NEJM.org. At each center, either a key institutional review lath (Schulman IRB) or the local institutional review board approved the trial, and the patients provided written informed consent. A multidisciplinary executive committee supervised the trial, and an independent information and safe monitoring commission reviewed unblinded information to assess safety. The members of the committees are listed in Supplementary Appendix, bachelor at NEJM.org. The members of the executive committee agreed not to accept any financial payments from any maker of NSAIDs for the duration of the trial. The trial sponsor (Pfizer) participated in the design of the trial and in the writing of the protocol in collaboration with the executive committee and in consultation with the FDA; the sponsor also assisted with data drove and maintained the trial database. The sponsor shared operational roles with the Cleveland Clinic Coordinating Center for Clinical Inquiry (C5Research) and several contract research organizations. After the conclusion of the trial, the database was transferred to C5Research for statistical analyses. The academic authors wrote the manuscript. The sponsor was immune to review and comment on the manuscript, but the conclusion to publish and the final contents were determined by the bookish authors, with no contractual limits on the correct to publish. All the authors had access to the final results, canonical the manuscript, and assume responsibility for its accuracy and completeness and for the adherence of the trial and this report to the protocol.
Inclusion and Exclusion Criteria
We enrolled patients who were xviii years of age or older and who, every bit adamant past the patient and physician, required daily treatment with NSAIDs for arthritis pain; patients whose arthritis hurting was managed adequately with acetaminophen were not eligible. A key inclusion criterion was established cardiovascular disease or an increased take a chance of the development of cardiovascular disease (defined in the Supplementary Appendix). Other inclusion criteria and the exclusion criteria are provided in the protocol and in a previous publication.v
Treatment
Patients were randomly assigned, in a 1:i:1 ratio, to receive celecoxib (100 mg twice a day), ibuprofen (600 mg three times a day), or naproxen (375 mg twice a day) with matching placebo. At subsequent visits, for patients with rheumatoid arthritis, investigators could increase the dose of celecoxib to 200 mg twice a solar day, the dose of ibuprofen to 800 mg three times a day, or the dose of naproxen to 500 mg twice a twenty-four hours for the treatment of symptoms. For patients with osteoarthritis, increases in the doses of ibuprofen and naproxen were permitted; however, regulatory dosing restrictions precluded dose escalation for celecoxib in these patients. Esomeprazole (xx to 40 mg) was provided to all patients for gastric protection. Investigators were encouraged to provide cardiovascular preventive management in accordance with local standards and guidelines. Patients who were taking low-dose aspirin (≤325 mg daily) were permitted to continue this therapy.
Adjudicated and Other Outcomes
The primary blended outcome, in a time-to-consequence analysis, was the first occurrence of an adverse outcome that met Antiplatelet Trialists Collaboration (APTC) criteria (i.e., death from cardiovascular causes, including hemorrhagic death; nonfatal myocardial infarction; or nonfatal stroke). 6 A secondary blended effect, major adverse cardiovascular events, included the components of the primary effect plus coronary revascularization or hospitalization for unstable angina or transient ischemic attack. Secondary outcomes also included clinically pregnant gastrointestinal events. Third outcomes included clinically meaning renal events, fe deficiency anemia of gastrointestinal origin, and hospitalization for eye failure or hypertension. (Definitions are provided in the Supplementary Appendix.) Although it is non described in the protocol, the composite outcome of clinically pregnant gastrointestinal events or iron deficiency anemia of gastrointestinal origin was designated as the key gastrointestinal safe outcome before the trial data were unblinded. An independent commission of multidisciplinary specialists at C5Research who were unaware of the treatment assignments reviewed and adjudicated events. An cess of the intensity of arthritis pain with the use of the Visual Counterpart Scale for Hurting (VAS) (scores range from 0 to 100 mm, with higher scores indicating worse pain) was a nonadjudicated secondary issue; differences greater than 13.7 mm are considered to exist clinically meaningful.7 The incidence of decease from any cause was a prespecified tertiary outcome. Other prespecified outcomes are listed in the protocol and statistical analysis programme.
Statistical Analysis
Naproxen was designated as the primary comparator for the assessment of the noninferiority of celecoxib. Noninferiority comparisons of celecoxib versus ibuprofen and of ibuprofen versus naproxen were also prespecified. Noninferiority required four criteria to exist met; in the original design, a hazard ratio not exceeding 1.12 was required, with an upper limit of the one-sided 97.5% conviction interval of less than ane.33 in both the intention-to-care for population and the on-treatment population. The assessment of the on-treatment population included events that occurred while patients were taking the written report drug and during the 30 days after discontinuation. The trial was result-driven, requiring 762 events to provide 90% power to make up one's mind noninferiority. Under the supposition of an annual consequence rate of two% and a treatment discontinuation rate of 40%, the required sample size was estimated to be twenty,000 patients. The observed event rate was lower, the discontinuation rate higher, and the enrollment rate slower than anticipated. At the recommendation of the data and safe monitoring committee and after consultation with the FDA, the protocol was amended to accept the study provide eighty% power, and the upper 97.v% conviction limit for noninferiority in the on-treatment population was modified to i.40, which required 580 events in the intention-to-care for population and 420 events in the on-treatment population. The protocol prespecified a minimum follow-up time of 18 months, with censoring of data from event-gratis patients after 30 months in the intention-to-care for population and afterwards 43 months in the on-treatment population.
A Cox proportional-hazards model with adjustment for stratification factors was used to calculate the adventure ratios and conviction intervals. A one-sided noninferiority P value of less than 0.025 was considered to indicate statistical significance for the primary cease point, with no adjustment for multiple comparisons. P values for secondary analyses in the intention-to-treat population are reported for descriptive purposes; a two-sided P value of less than 0.05 was considered to point statistical significance, with no adjustment for multiple comparisons. For the on-handling analyses, P values for noninferiority are reported for the primary APTC outcome, just P values are not reported for superiority comparisons. Additional details regarding the statistical analyses are provided in the Supplementary Appendix.
Results
Patient Population
Table 1.
Table 1. Baseline Characteristics of Patients in the Intention-to-Care for Population. We screened 31,857 patients; a total of 24,222 patients underwent randomization at 926 centers in 13 countries between October 23, 2006, and June 30, 2014, and 141 were excluded from the assay (106 were determined to be fraudulently enrolled, and 35 enrolled more than in one case), leaving 24,081 participants who could be included in the analysis. There were 8072 patients assigned to the celecoxib group (hateful [±SD] daily dose, 209±37 mg), 7969 assigned to the naproxen group (852±103 mg), and 8040 assigned to the ibuprofen group (2045±246 mg). The characteristics of the patients at baseline were similar among the treatment groups (Table 1). The hateful durations of treatment and follow-up, respectively, were 20.three±16.0 and 34.1±13.4 months for all patients: 20.8±16.0 and 34.2±thirteen.4 months in the celecoxib grouping, 20.5±15.ix and 34.2±xiii.3 months in the naproxen group, and xix.6±xvi.0 and 33.eight±13.6 months in the ibuprofen group. During this 10-year trial, 68.8% of patients stopped taking the study drug, and 27.4% of patients discontinued follow-up; 2.5% of patients died, 8.iii% withdrew consent in writing, 7.4% verbally expressed unwillingness to continue participation, and seven.ii% were lost to follow-upward before a concluding follow-up visit. Details regarding patient disposition, fourth dimension to study-drug discontinuation, and time to nonretention in the trial are provided in Figs. S1, S2, and S3 in the Supplementary Appendix.
Primary APTC Upshot
Table 2.
Tabular array 2. Adjudicated Outcomes in the Intention-to-Treat Population. Figure ane. 
Figure ane. Time-to-Outcome Analysis for Chief and Secondary Outcomes. The primary blended outcome in the time-to-event analysis was the first occurrence of an adverse consequence that met Antiplatelet Trialists Collaboration (APTC) criteria (expiry from cardiovascular causes, including hemorrhagic death; nonfatal myocardial infarction; or nonfatal stroke). The definitions for all outcomes are provided in the Supplementary Appendix. The cumulative incidences were estimated with the Kaplan–Meier method, and the hazard ratios were calculated with the Cox proportional-hazards regression model with aligning for stratification factors. The intention-to-treat information analyses were truncated at 30 months, and the on-treatment analyses were truncated at 43 months. The insets show the same data on an enlarged y axis.
In the intention-to-treat population (Tabular array 2 and Figure 1), the primary APTC result occurred in 188 patients in the celecoxib group (ii.3%), 201 in the naproxen group (2.5%), and 218 in the ibuprofen group (2.7%). The take chances ratio for this issue in the celecoxib grouping, equally compared with the naproxen group, was 0.93 (95% confidence interval [CI], 0.76 to i.13; P<0.001 for noninferiority). The hazard ratio for celecoxib versus ibuprofen was 0.85 (95% CI, 0.70 to 1.04; P<0.001 for noninferiority), and the hazard ratio for ibuprofen versus naproxen was ane.08 (95% CI, 0.xc to one.31; P=0.02 for noninferiority) (Table S1 in the Supplementary Appendix).
Table 3.
Table 3. Adjudicated Outcomes in the On-Treatment Population. In the on-treatment population (Table 3 and Effigy one), the principal APTC effect occurred in 134 patients in the celecoxib group (1.7%), 144 in the naproxen grouping (one.viii%), and 155 in the ibuprofen group (ane.9%). The take a chance ratio in the celecoxib group, as compared with the naproxen grouping, was 0.xc (95% CI, 0.71 to 1.15; P<0.001 for noninferiority); for celecoxib versus ibuprofen, the hazard ratio was 0.81 (95% CI, 0.65 to 1.02; P<0.001 for noninferiority), and for ibuprofen versus naproxen, the run a risk ratio was 1.12 (95% CI, 0.89 to ane.40; P=0.025 for noninferiority) (Tabular array S2 in the Supplementary Appendix).
Celecoxib, as compared with either naproxen or ibuprofen, met all four prespecified noninferiority requirements (P<0.001 for noninferiority in both comparisons). Ibuprofen, equally compared with naproxen, just met the noninferiority criteria (P=0.025).
Major Agin Cardiovascular Events and Bloodshed Outcomes
The results of the intention-to-care for analyses for the blended outcome of major agin cardiovascular events and for the components of the issue are reported in Table two and Figure ane. The gamble ratio for celecoxib versus naproxen was 0.97 (95% CI, 0.83 to ane.12; P=0.64), and the hazard ratio for celecoxib versus ibuprofen was 0.87 (95% CI, 0.75 to 1.01; P=0.06). In pairwise comparisons for the components of the primary upshot, the differences between celecoxib and naproxen and between celecoxib and ibuprofen were not meaning. The adventure ratio for death from any cause was 0.fourscore for celecoxib versus naproxen (95% CI, 0.63 to ane.00; P=0.052) (Table 2 and Figure 1). The charge per unit of nonfatal myocardial infarction was higher in the ibuprofen grouping than in the naproxen grouping (gamble ratio, 1.39; 95% CI, ane.01 to ane.91; P=0.04) (Tabular array S1 in the Supplementary Appendix).
Gastrointestinal and Renal Outcomes
The results of the intention-to-treat analyses of gastrointestinal and renal outcomes are provided in Table 2 and Figure 1. The effect charge per unit for the composite outcome of serious gastrointestinal events was lower in the celecoxib group than in the naproxen group (hazard ratio, 0.71; 95% CI, 0.54 to 0.93; P=0.01) and was lower in the celecoxib group than in the ibuprofen group (hazard ratio, 0.65; 95% CI, 0.50 to 0.85; P=0.002). The take chances ratio for gastrointestinal events in the ibuprofen group versus the naproxen group was 1.08 (95% CI, 0.85 to one.39; P=0.53). Serious renal events occurred at a significantly lower charge per unit in the celecoxib group than in the ibuprofen group (take chances ratio, 0.61; 95% CI, 0.44 to 0.85; P=0.004), but the divergence in the charge per unit of this outcome in the celecoxib group versus the naproxen grouping was not pregnant (hazard ratio, 0.79; 95% CI, 0.56 to 1.12; P=0.19).
Other Outcomes
The rate of hospitalization for hypertension was significantly lower in the celecoxib group than in the ibuprofen group (chance ratio, 0.60; 95% CI, 0.36 to 0.99; P=0.04) only was not significantly lower in the celecoxib group than in the naproxen grouping (Table 2). The results of analyses of quality of life and efficacy for the relief of arthritis symptoms are reported in Table S3 in the Supplementary Appendix. In the assessment of pain with the apply of the VAS calibration, a meaning just pocket-size do good was found for naproxen relative to celecoxib or ibuprofen; the change in VAS score from baseline was −9.iii±0.26 mm for celecoxib, −9.5±0.26 for ibuprofen, and −10.ii±0.26 for naproxen (P<0.001 for naproxen versus celecoxib, P=0.01 for naproxen versus ibuprofen). The analyses of the primary blended outcome amongst prespecified subgroups showed no significant interactions for any pairwise comparison, including among the subgroups that were defined by aspirin apply at baseline (Fig. S5 in the Supplementary Appendix). Investigator-reported adverse furnishings that occurred in three% or more than of the patients in any handling group are reported in Tabular array S4 in the Supplementary Appendix.
Word
The PRECISION trial was designed in the aftermath of the withdrawal of rofecoxib during a flow of considerable scientific and public controversy most the cardiovascular safety of selective COX-ii inhibitors. Previous knowledge about the relative safety of selective or nonselective COX inhibitors was express, because NSAIDs received initial approval on the basis of relatively small, brusk-term studies that typically had been designed to appraise hurting relief and general safety. The master clinical concern was that celecoxib might exist associated with agin cardiovascular effects similar to those associated with rofecoxib. The PRECISION trial provides statistically strong show that the cardiovascular risk associated with moderate doses of celecoxib is non greater than that associated with nonselective NSAIDs. Every bit compared with two widely used nonselective NSAIDs — naproxen and ibuprofen — celecoxib was associated with numerically fewer cardiovascular events, which resulted in noninferiority P values of less than 0.001. The trial results practise not support the widely advocated belief that naproxen treatment, equally compared with treatment with other NSAIDs, results in meliorate cardiovascular outcomes.8
To found noninferiority, the trial design required that prespecified criteria be met in both the intention-to-care for population and the on-handling population. We selected this approach because these two alternative analyses provide complementary insights into drug safety. The intention-to-treat assay is the simply analysis that preserves the integrity of randomization, but information technology tends to dilute safe signals when patients do non adhere to the written report treatment. The on-treatment analysis considers events that occur only while patients are really taking the study drug, which can strengthen safe signals. Although both the intention-to-treat and the on-treatment analyses were used to assess noninferiority, superiority comparisons were performed with the intention-to-treat population. The on-handling analyses are included to provide a complete accounting of outcomes, but the results in this population may accept been influenced by between-group differences in rates of treatment discontinuation; therefore, these results are reported without P values and should exist considered exploratory (Table 3).
We likewise included a broader result — major adverse cardiovascular events — as a secondary composite outcome to provide greater power to detect differences among the three treatments. Fewer major agin cardiovascular events occurred in the celecoxib group than in the ibuprofen group, but the departure did not reach significance in the intention-to-treat population (P=0.06). The rate of death from any cause was lower in the celecoxib group than in the naproxen group, although the difference did not reach significance (P=0.052). Nosotros urge caution in interpreting these findings, because major adverse cardiovascular events was a secondary issue and death from whatever cause a tertiary effect, and these outcomes were not adjusted for end-point multiplicity; in addition, major adverse cardiovascular events included more subjective components than did the APTC event.
Although the primary purpose of the trial was to appraise cardiovascular outcomes, nosotros as well adjudicated gastrointestinal and renal outcomes to provide a comprehensive safety evaluation. To compare the three drugs, we constructed a two-component blended of two adjudicated outcomes — clinically significant gastrointestinal events and iron-deficiency anemia of gastrointestinal origin. For this outcome, significantly fewer events occurred in the celecoxib group than in either the naproxen group or the ibuprofen group. These findings were expected on the ground of the theoretical gastrointestinal advantages of selective COX-two inhibition. The differences were found despite esomeprazole, a proton-pump inhibitor, beingness provided for all patients, although we practise not have information on adherence to this therapy. The rates of renal adverse events and hospitalization for hypertension were also significantly lower in the celecoxib group than in the ibuprofen group, although they did non differ significantly between the celecoxib grouping and the naproxen group. The pattern nosotros institute for investigator-reported agin effects was like to that for centrally adjudicated events, with a higher reported incidence of increased creatinine levels in the ibuprofen grouping than in the celecoxib group and a higher incidence of hypertension in both the naproxen group and the ibuprofen group, every bit compared with the celecoxib group (Table S4 in the Supplementary Appendix). Although naproxen-treated patients had a slightly greater reduction in pain, as assessed with the use of VAS scores, than did patients treated with celecoxib or ibuprofen, the differences were smaller than the 13.7-mm departure that is considered to be clinically meaningful.
The PRECISION trial had limitations. Adherence and retention were lower than in well-nigh trials that assess cardiovascular outcomes, which reflects the challenges of long-term handling of a painful status in patients who often experience frustration with unrelieved symptoms and switch therapies or exit the trial. Low levels of adherence and retention have too been institute in previous pain studies.9 Although the similarity in the results for the intention-to-treat and on-treatment populations suggests that low adherence was unlikely to have influenced the primary conclusions, the high levels of nonretention make estimation of the findings challenging. Although the rates of nonretention were similar for all iii treatments, the 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) cannot be ruled out. The big number of comparisons without adjustment for multiplicity increases the possibility of false positive findings.
The dose of celecoxib was express by regulatory restrictions to 200 mg daily for most patients, which may take provided a potential safety advantage for celecoxib, although the mean doses for both nonselective NSAIDs were likewise submaximal. Three previous trials assessed higher doses of celecoxib (400 to 800 mg per day),4,10,11 one of which showed a significantly higher adventure of cardiovascular events in clan with the unapproved 800-mg dose than with placebo, although the trial included but a small number of events. Our results provide reassurance regarding the safety of moderate doses of celecoxib but not the safe of high doses of celecoxib. Although ibuprofen and naproxen have been reported to potentially interfere with the antiplatelet effects of aspirin,12 we institute no statistical interaction for aspirin use (Fig. S4 in the Supplementary Appendix). Nonetheless, the trial was non specifically designed to assess the furnishings of aspirin on the relative safety of NSAIDs. Although enrollment was stratified according to aspirin use to ensure equal distribution of aspirin utilize among the treatment groups, patients were non randomly assigned to receive or non receive aspirin.
The current results reverberate the relative safety of only these 3 drugs and cannot provide insight into the effects of the more than than 2 dozen other marketed NSAIDs, specially because each of these drugs may have a unique condom profile. No inferences are possible regarding the effects of NSAIDs as compared with placebo or regarding the safety of intermittent treatment with low-dose over-the-counter preparations. For ethical reasons, a placebo comparison group was not viable, since we required all patients and physicians to document that participants had required NSAID handling for at least half dozen months for adequate symptom relief. Acetaminophen was not selected as a comparator because previous studies had shown this drug to be ineffective for the handling of patients with NSAID-dependent arthritis.thirteen
In summary, the PRECISION trial showed the noninferiority of moderate doses of celecoxib, equally 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 agin events than did ibuprofen.
Supplementary Material
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