Effect of Aspirin Coadministration on the Safety of Celecoxib, Naproxen, or Ibuprofen - C5Research
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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 71, NO. 16, 2018 ª 2018 THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION. PUBLISHED BY ELSEVIER. ALL RIGHTS RESERVED. Effect of Aspirin Coadministration on the Safety of Celecoxib, Naproxen, or Ibuprofen Grant W. Reed, MD, MSC,a,b Mouin S. Abdallah, MD, MSC,a,b Mingyuan Shao, MS,a Kathy Wolski, MPH,a Lisa Wisniewski, RN,a Neville Yeomans, MD,c Thomas F. Lüscher, MD,d Jeffrey S. Borer, MD,e David Y. Graham, MD,f M. Elaine Husni, MD, MPH,g Daniel H. Solomon, MD, MPH,h Peter Libby, MD,h Venu Menon, MD,a,b A. Michael Lincoff, MD,a,b Steven E. Nissen, MDa,b ABSTRACT BACKGROUND The safety of nonsteroidal anti-inﬂammatory drug (NSAID) and aspirin coadministration is uncertain. OBJECTIVES The aim of this study was to compare the safety of combining NSAIDs with low-dose aspirin. METHODS This analysis of the PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen) trial included 23,953 patients with osteoarthritis or rheumatoid arthritis at increased cardio- vascular risk randomized to celecoxib, ibuprofen, or naproxen. The on-treatment population was used for this study. Outcomes included composite major adverse cardiovascular events, noncardiovascular death, gastrointestinal or renal events, and components of the composite. Cox proportional hazards models compared outcomes among NSAIDs strat- iﬁed by aspirin use following propensity score adjustment. Kaplan-Meier analysis was used to compare the cumulative probability of events. RESULTS When taken without aspirin, naproxen or ibuprofen had greater risk for the primary composite endpoint compared with celecoxib (hazard ratio [HR]: 1.52; 95% conﬁdence interval [CI]: 1.22 to 1.90, p
1742 Reed et al. JACC VOL. 71, NO. 16, 2018 Safety of Combined Aspirin and NSAID Use APRIL 24, 2018:1741–51 C ABBREVIATIONS oncomitant use of nonsteroidal Randomized Evaluation of Celecoxib Integrated AND ACRONYMS anti-inﬂammatory drugs (NSAIDs) Safety Versus Ibuprofen or Naproxen) trial to evaluate and aspirin is widespread. In 2010, the safety of combining aspirin (a selective COX-1 APTC = Antiplatelet Trialists’ Collaboration >43 million U.S. adults were regular aspirin inhibitor) with celecoxib (a selective COX-2 inhibi- users, and >28 million took NSAIDs regularly tor), naproxen (a nonselective COX-1 > COX-2 inhib- CAD = coronary artery disease (1,2). An estimated 20% to 50% of patients itor), or ibuprofen (a nonselective COX-2 > COX-1 CI = conﬁdence interval with osteoarthritis or rheumatoid arthritis inhibitor). COX = cyclooxygenase take aspirin daily (3,4). The coadministration GI = gastrointestinal of NSAIDs and aspirin has raised safety con- METHODS HR = hazard ratio cerns, because both inhibit synthesis of pros- IPTW = inverse probability of tanoids in tissues in which these lipid treatment weights STUDY POPULATION. This was a post hoc analysis of mediators may have protective effects. the PRECISION trial. The design, rationale, and pri- MACE = major adverse Furthermore, nonselective NSAIDs may mary results of PRECISION have been previously cardiovascular event(s) compete with aspirin for its binding site on published (3,21). Brieﬂy, PRECISION was a multi- NSAID = nonsteroidal anti- inﬂammatory drug cyclooxygenase (COX)–1 (5,6), blocking aspi- center, randomized controlled trial of patients with rin’s ability to acetylate a serine residue on osteoarthritis or rheumatoid arthritis on long-term COX-1 necessary for platelet inhibition (6,7). NSAIDs at increased cardiovascular risk that demon- SEE PAGE 1752 strated the noninferiority of moderate-dose celecoxib (100 to 200 mg twice daily) to naproxen (375 to Observational studies and meta-analyses suggest 500 mg twice daily) and ibuprofen (600 to 800 mg 3 that both NSAIDs nonselective for COX-1 or COX-2 times daily) with regard to cardiovascular safety. The and NSAIDs selective for COX-2 have adverse ef- PRECISION trial protocol pre-speciﬁed an analysis fects, including cardiovascular, gastrointestinal (GI), stratiﬁed by aspirin use a priori. However, the sta- and renal events, compared with placebo (8–13). tistical methodology used to accomplish this was Studies have reported conﬂicting results with regard established post hoc. to whether adding aspirin to an NSAID modiﬁes these As previously reported, in PRECISION, patients risks (14–19). Likewise, there have been reports of were randomized according to their primary diag- aspirin failure in patients with inﬂammatory disor- nosis (osteoarthritis or rheumatoid arthritis), and ders, particularly among patients on NSAIDs (20). The stratiﬁed by low-dose aspirin (#325 mg) use at base- relative safety of combining aspirin and NSAIDs with line to ensure equal distribution among NSAIDs. The various degrees of COX-1 and COX-2 inhibition is not study protocol did not permit doses of aspirin well understood, presenting challenges to providing >325 mg. All subjects were provided with once-daily patient recommendations on this subject. esomeprazole 20 to 40 mg as a gastroprotective Accordingly, we performed a propensity score– agent regardless of aspirin use. All patients gave adjusted substudy of the PRECISION (Prospective informed consent before enrollment in the study. membership on the adjudication committee in the ARIVE trial. Dr. Borer served as chair of a data and safety monitoring board for an unrelated product being developed by Pﬁzer; has served as a consultant, trial executive committee member, data and safety monitoring board member, or cardiac event adjudication committee member for unrelated products for Amgen, Novartis, AstraZeneca, Takeda, Biotronik, Servier, GlaxoSmithKline, Gilead, and ARMGO; and owns stock in BioMarin and ARMGO. Dr. Graham is a consultant for RedHill Biopharma regarding novel Helicobacter pylori therapies; has received research support from RedHill Biopharma for culture of H. pylori; is the principal investigator of an international study of the use of antimycobacterial therapy for Crohn’s disease; and is a consultant for BioGaia in relation to probiotic therapy for H. pylori infection and for Takeda in relation to H. pylori therapies. Dr. Husni has received an institution grant to perform the PRECISION trial; has received a Sanoﬁ Genzyme investigator grant; and has served on advisory boards for AbbVie, Bristol-Myers Squibb, Amgen, UCB, Regeneron, and Janssen. Dr. Solomon has received a research grant from Pﬁzer for unrelated work; and has received royalties from UpToDate for a chapter about NSAIDs. Dr. Libby has been an unpaid consultant to or has been involved in clinical trials for Amgen, AstraZeneca, Esperion Therapeutics, Ionis Pharmaceuticals, Kowa Pharmaceuticals, Merck, Novartis, Pﬁzer, Sanoﬁ-Regeneron, Takeda Phar- maceuticals, and XBiotech; has served as a member of scientiﬁc advisory boards for Amgen, Corvidia Therapeutics, DalCor Pharmaceuticals, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, and Novartis; and his laboratory has received research funding in the past 2 years from Novartis. Dr. Menon has received grant support to the institution to perform the PRECISION trial. Dr. Lincoff has received grant support to the institution to perform the PRECISION trial; is a consultant for Amgen, Novo, Nordisk, Sanoﬁ, Abbott, Sarpeta, and Sermonix; and has received research grants to his institution from Pﬁzer, AstraZeneca, Esperion, AbbVie, Eli Lilly, and Roche. Dr. Nissen has received grant support to the institution to perform the PRECISION trial. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received January 15, 2018; accepted February 6, 2018.
JACC VOL. 71, NO. 16, 2018 Reed et al. 1743 APRIL 24, 2018:1741–51 Safety of Combined Aspirin and NSAID Use myocardial infarction, nonfatal stroke, coronary T A B L E 1 Patient Characteristics Stratiﬁed by Aspirin Use at Randomization revascularization, or hospitalization for unstable angina or transient ischemic attack. Clinically signif- No Aspirin Aspirin (n ¼ 12,935) (n ¼ 11,018) p Value icant GI events included acute gastric or intestinal Age, yrs 61.6 9.6 65.1 8.8
1744 Reed et al. JACC VOL. 71, NO. 16, 2018 Safety of Combined Aspirin and NSAID Use APRIL 24, 2018:1741–51 from the imputed and nonimputed datasets were package in R version 3.4.0 (R Foundation for Statis- very similar. tical Computing, Vienna, Austria). The plot of abso- To adjust for differences between patients taking lute standardized differences was made using aspirin and not, propensity scores for aspirin treat- SigmaPlot version 11.0 (Systat, San Jose, California). ment and corresponding stabilized inverse probabil- RESULTS ity of treatment weights (IPTWs) were calculated using a universal binary logistic regression model PATIENT CHARACTERISTICS. This study included including all of the baseline characteristics as cova- 23,953 patients (24,222 patients were randomized in riates (23), in each of the imputed datasets for each PRECISION, but 141 patients were excluded because endpoint. Improvement in the balance of baseline of enrollment errors and 128 patients did not have characteristics was assessed by evaluating a plot of data on aspirin use); 8,030 were assigned to celecoxib, the absolute standardized differences with and 7,933 to naproxen, and 7,990 to ibuprofen. Aspirin was without IPTW (Online Figure 1). An absolute value in used by 11,018 patients (46.0%) at randomization; standardized differences of
JACC VOL. 71, NO. 16, 2018 Reed et al. 1745 APRIL 24, 2018:1741–51 Safety of Combined Aspirin and NSAID Use F I G U R E 1 Outcomes in Non–Aspirin Users on Naproxen or Ibuprofen Compared With Celecoxib Naproxen (N = 4,239) Celecoxib Ibuprofen Endpoints Adjusted HR (95% CI) (N = 4,347) (N = 4,295) Composite Safety Endpoint Naproxen vs. Celecoxib 1.52 (1.22, 1.90) 132 (3.0) 195 (4.5) Ibuprofen vs. Celecoxib 1.81 (1.46, 2.26) 132 (3.0) 213 (5.0) Extended MACE Naproxen vs. Celecoxib 1.11 (0.83, 1.49) 90 (2.1) 96 (2.2) Ibuprofen vs. Celecoxib 1.35 (1.02, 1.78) 90 (2.1) 109 (2.5) APTC MACE Naproxen vs. Celecoxib 1.20 (0.84, 1.72) 57 (1.3) 67 (1.6) Ibuprofen vs. Celecoxib 1.47 (1.04, 2.08) 57 (1.3) 74 (1.7) GI Events Naproxen vs. Celecoxib 2.60 (1.59, 4.27) 22 (0.5) 56 (1.3) Ibuprofen vs. Celecoxib 3.20 (1.97, 5.22) 22 (0.5) 64 (1.5) Renal Events Naproxen vs. Celecoxib 2.09 (1.10, 3.96) 19 (0.4) 33 (0.8) Ibuprofen vs. Celecoxib 1.93 (1.00, 3.73) 19 (0.4) 28 (0.7) 0.71 1.0 1.41 2.0 6.0 Favors Favors Naproxen/Ibuprofen Celecoxib The number of events (percentage of total) is reported. APTC ¼ Antiplatelet Trialists’ Collaboration; CI ¼ conﬁdence interval; GI ¼ gastrointestinal; HR ¼ hazard ratio; MACE ¼ major adverse cardiovascular event. and 5.0% vs. 3.0%, respectively; naproxen vs. cele- common with celecoxib compared with the other coxib adjusted HR: 1.52; 95% CI: 1.22 to 1.90; NSAIDs (Figures 2A and 2C). p < 0.001; ibuprofen vs. celecoxib HR: 1.81; 95% CI: OUTCOMES OF CELECOXIB, NAPROXEN, AND 1.46 to 2.26; p < 0.001) (Figure 1). These results IBUPROFEN COMBINED WITH ASPIRIN. Patients derived primarily from a greater risk for GI events taking ibuprofen plus aspirin had greater risk for the with either naproxen compared with celecoxib composite safety endpoint compared with celecoxib (1.3% vs. 0.5%; adjusted HR: 2.60; 95% CI: 1.59 to plus aspirin (7.1% vs. 6.0%; adjusted HR: 1.27; 95% CI: 4.27; p < 0.001) and ibuprofen compared with cele- 1.06 to 1.51; p ¼ 0.01) (Figure 3). However, there was coxib (1.5% vs. 0.5%; adjusted HR: 3.20; 95% CI: 1.97 no difference in extended MACE or APTC-deﬁned to 5.22; p < 0.001). However, when comparing MACE between NSAIDs with the addition of aspirin. ibuprofen with celecoxib, there was also slightly The difference in the composite safety endpoint was higher risk for extended MACE (adjusted HR: 1.35; driven by an increased risk for GI events with 95% CI: 1.02 to 1.78; p ¼ 0.039) and APTC-deﬁned ibuprofen plus aspirin compared with celecoxib plus MACE (adjusted HR: 1.47; 95% CI: 1.04 to 2.08; aspirin (1.4% vs. 0.9%; adjusted HR: 1.71; 95% CI: 1.10 p ¼ 0.031), and compared with celecoxib, naproxen to 2.67; p ¼ 0.017), which was also observed with was associated with a greater risk for renal events naproxen plus aspirin compared with celecoxib plus (adjusted HR: 2.09; 95% CI: 1.10 to 3.96; p ¼ 0.024), aspirin (1.6% vs. 0.9%; adjusted HR: 1.91; 95% CI: 1.24 while excess risk with ibuprofen was borderline sig- to 2.94; p ¼ 0.003). Likewise, the hazard of renal niﬁcant (adjusted HR: 1.93; 95% CI: 1.00 to 3.73; events was greater with ibuprofen plus aspirin p ¼ 0.052). compared with celecoxib plus aspirin (1.2% vs. 0.6%; On adjusted Kaplan-Meier analysis, the composite adjusted HR: 2.01; 95% CI: 1.23 to 3.30; p ¼ 0.005), but safety endpoint and extended MACEs occurred least there was no difference with naproxen plus aspirin frequently with celecoxib compared with naproxen or compared with celecoxib plus aspirin. Event rates ibuprofen (Central Illustration) (log-rank p < 0.0001 tended to be higher for all endpoints with aspirin and p ¼ 0.0012, respectively). Similarly, GI events addition, regardless of which NSAID was used (p < 0.0001) and renal events (p ¼ 0.0005) were least (Figures 1 and 3).
1746 Reed et al. JACC VOL. 71, NO. 16, 2018 Safety of Combined Aspirin and NSAID Use APRIL 24, 2018:1741–51 C E NT R AL IL L U STR AT IO N Safety of Combined Aspirin and Nonsteroidal Anti-Inﬂammatory Drug Use No Aspirin Aspirin A B 1.00 1.00 Log rank p < 0.0001 Log rank p < 0.0001 0.98 0.98 Event-Free Survival Event-Free Survival 0.96 0.96 Composite 0.94 0.94 Safety 0.92 0.92 Endpoint 0.90 0.90 0.88 0.88 0.86 0.86 0.84 0.84 0 250 500 750 1000 1250 0 250 500 750 1000 1250 Time to Event (Days) Time to Event (Days) C D 1.00 1.00 Log rank p = 0.0012 Log rank p = 0.5506 0.98 0.98 Event-Free Survival Event-Free Survival 0.96 0.96 Extended MACE 0.94 0.94 0.92 0.92 0.90 0.90 0 250 500 750 1000 1250 0 250 500 750 1000 1250 Time to Event (Days) Time to Event (Days) Celecoxib Naproxen Ibuprofen Reed, G.W. et al. J Am Coll Cardiol. 2018;71(16):1741–51. Adjusted Kaplan-Meier curves for the composite safety endpoint and extended major adverse cardiovascular event (MACE), stratiﬁed by aspirin use. Among patients not on aspirin, celecoxib had the lowest incidence of composite safety events and extended MACE. The addition of aspirin attenuated the relative safety beneﬁt of celecoxib. Furthermore, adjusted Kaplan-Meier analysis CAD AND ASPIRIN COMPLIANCE SENSITIVITY ANALYSES. demonstrated that the addition of aspirin attenuated In a pre-speciﬁed sensitivity analysis, comparing pa- the beneﬁt of celecoxib compared with naproxen and tients with CAD with those without, the relative ibuprofen with regard to the composite safety hazard of the composite safety endpoint was endpoint and extended MACE (Central Illustration). approximately the same whether aspirin was also Likewise, in the presence of aspirin, there was less used (adjusted HR: 2.23; 95% CI: 1.90 to 2.60; differentiation in renal events among NSAIDs p < 0.001) or aspirin was not used (adjusted HR: 2.01; (Figure 2D). However, GI events remained least 95% CI: 1.56 to 2.59; p < 0.001), demonstrating no frequent with celecoxib (log-rank p ¼ 0.004) signiﬁcant interaction between CAD and aspirin use (Figure 2B). (Online Figure 3) (interaction p ¼ 0.35).
JACC VOL. 71, NO. 16, 2018 Reed et al. 1747 APRIL 24, 2018:1741–51 Safety of Combined Aspirin and NSAID Use F I G U R E 2 Adjusted Kaplan-Meier Curves for the Cumulative Incidence of Gastrointestinal and Renal Events, Stratiﬁed by Aspirin Use A No Aspirin B Aspirin 1.00 1.00 Log rank p < 0.0001 Log rank p = 0.0040 0.99 0.99 Event-Free Survival Event-Free Survival 0.98 0.98 GI Events 0.97 0.97 0.96 0.96 0.95 0.95 0 250 500 750 1000 1250 0 250 500 750 1000 1250 Time to Event (Days) Time to Event (Days) Celecoxib 4410 3075 2336 1794 1299 997 Celecoxib 3670 2561 1993 1529 1139 872 Ibuprofen 4283 2830 2081 1573 1187 906 Ibuprofen 3674 2492 1853 1406 1049 795 Naproxen 4312 2972 2208 1681 1279 971 Naproxen 3623 2542 1956 1453 1059 819 C D 1.00 1.00 Log rank p = 0.0005 Log rank p = 0.0546 Event-Free Survival Event-Free Survival 0.99 0.99 Renal Events 0.98 0.98 0.97 0.97 0 250 500 750 1000 1250 0 250 500 750 1000 1250 Time to Event (Days) Time to Event (Days) Celecoxib 4410 3077 2345 1799 1302 1000 Celecoxib 3670 2561 1993 1528 1142 875 Ibuprofen 4283 2830 2087 1586 1195 907 Ibuprofen 3674 2491 1858 1410 1057 804 Naproxen 4312 2933 2212 1685 1282 974 Naproxen 3623 2547 1963 1463 1065 826 Celecoxib Naproxen Ibuprofen The addition of aspirin attenuated the gastrointestinal (GI) and renal safety of celecoxib, although GI events were still less frequent with celecoxib than ibuprofen or naproxen. Only 304 patients (1.3%) discontinued aspirin after modiﬁed by concomitant aspirin use. Speciﬁcally, randomization, and 964 patients (4.0%) who were not celecoxib was associated with a more favorable on aspirin started aspirin during the study (this was overall safety proﬁle than naproxen or ibuprofen equally distributed among the NSAIDs). When among regular NSAID users not taking aspirin. excluding these patients, the results for the primary However, the addition of aspirin attenuated the endpoint were not signiﬁcantly different. relatively favorable safety proﬁle of celecoxib, and although there was still a slight advantage of cele- DISCUSSION coxib over ibuprofen with regard to composite safety events, there were no longer differences in This study demonstrates that the relative cardio- extended MACE or APTC-deﬁned MACE. However, vascular and overall safety of NSAID therapy is celecoxib was still associated with fewer GI events
1748 Reed et al. JACC VOL. 71, NO. 16, 2018 Safety of Combined Aspirin and NSAID Use APRIL 24, 2018:1741–51 F I G U R E 3 Outcomes in Patients on Naproxen or Ibuprofen Compared With Celecoxib, With Combined Aspirin Naproxen (N = 3,640) Celecoxib Ibuprofen Endpoints Adjusted HR (95% CI) (N = 3,683) (N = 3,695) Composite Safety Endpoint Naproxen vs. Celecoxib 1.18 (0.98, 1.41) 222 (6.0) 249 (6.8) Ibuprofen vs. Celecoxib 1.27 (1.06, 1.51) 222 (6.0) 264 (7.1) Extended MACE Naproxen vs. Celecoxib 1.05 (0.84, 1.31) 157 (4.3) 157 (4.3) Ibuprofen vs. Celecoxib 1.19 (0.96, 1.47) 157 (4.3) 175 (4.7) APTC MACE Naproxen vs. Celecoxib 1.04 (0.76, 1.43) 77 (2.1) 77 (2.1) Ibuprofen vs. Celecoxib 1.10 (0.81, 1.51) 77 (2.1) 81 (2.2) GI Events Naproxen vs. Celecoxib 1.91 (1.24, 2.94) 32 (0.9) 59 (1.6) Ibuprofen vs. Celecoxib 1.71 (1.10, 2.67) 32 (0.9) 51 (1.4) Renal Events Naproxen vs. Celecoxib 1.30 (0.76, 2.23) 23 (0.6) 29 (0.8) Ibuprofen vs. Celecoxib 2.01 (1.23, 3.30) 23 (0.6) 45 (1.2) 0.71 1.0 1.41 3.5 Favors Favors Naproxen/Ibuprofen Celecoxib The number of events (percentage of total) is reported. Abbreviations as in Figure 1. than ibuprofen or naproxen and fewer renal events by aspirin use, that analysis was in the intention-to- than ibuprofen. treat population. The present study was better The primary ﬁndings of PRECISION were reported equipped to assess the effect of aspirin on outcomes, in the intention-to-treat population, in which pa- as it was a propensity score–adjusted analysis of tients were grouped on the basis of the study drug to overall harms in the on-treatment population and which they were assigned at randomization. In that thus more relevant for the reasons described. analysis, events were counted regardless of whether Our ﬁndings do not support the premise that se- the study drug was stopped during the study. How- lective COX-2 inhibitors as a class increase cardio- ever, in studies of drug safety, the on-treatment vascular risk compared with nonselective COX-1 and population can be more informative, as it considers COX-2 inhibitors (27). On the contrary, in the pri- events only while patients are actually taking the mary results from the PRECISION trial, selective COX-2 drug, and patients are censored a period of time after inhibition with celecoxib was noninferior for the study drug is stopped (30 days in the present cardiovascular safety to nonselective COX-2 > COX-1 analysis). This consideration has particular relevance inhibition with ibuprofen or COX-1 > COX-2 inhibi- to studies of patients with pain, as these patients tion with naproxen in the intention-to-treat popula- discontinue medications frequently in favor of trying tion. The present analysis of the on-treatment other analgesic drugs. In this case, the intention-to- population is clinically more relevant with regard to treat analysis actually reﬂects the effects of these safety endpoints and showed the most favorable car- other medications, while effects of the study drug are diovascular safety proﬁle in patients with the selective better reﬂected in an on-treatment analysis. Indeed, COX-2 inhibitor celecoxib alone. Adding COX-1 inhi- in PRECISION, study drug discontinuation was more bition with aspirin attenuated the cardiovascular common than expected, as previously reported (see safety advantage of celecoxib and rendered the rela- PRECISION Trial Supplemental Appendix Figure S2) tive cardiovascular safety proﬁles of the NSAIDs (3). Furthermore, although the main ﬁndings of approximately equivalent. These ﬁndings support the PRECISION did contain a subgroup analysis stratiﬁed hypothesis and main ﬁndings of the PRECISION trial
JACC VOL. 71, NO. 16, 2018 Reed et al. 1749 APRIL 24, 2018:1741–51 Safety of Combined Aspirin and NSAID Use that the increased cardiovascular risk observed with adjust for baseline characteristics (Online Figure 1). rofecoxib is not a COX-2 inhibition class effect. Our use of this technique allowed adjustment for Furthermore, our results suggest that celecoxib has a baseline characteristics, creating a “pseudo-random- more favorable cardiovascular safety proﬁle than ization” result, increasing the validity to our results. ibuprofen or naproxen among patients not on aspirin To the best of our knowledge, ours is the only study and that the cardiovascular safety proﬁle of celecoxib on this topic to use such a technique. We further is noninferior to ibuprofen or naproxen among aspirin incorporated multivariate adjustment into propensity users. score–weighted survival regression analysis, a so- Our ﬁndings underscore the importance of appro- called doubly robust adjustment, to reduce residual priate patient counseling on the relative safety proﬁle confounding as much as possible (33). of NSAIDs when initiating therapy. Although short- STUDY LIMITATIONS. The strengths and limitations term NSAID use is likely safe (28), long-term use of of the PRECISION trial have been previously dis- any NSAID has been associated with increased car- cussed (3). Although the analysis was pre-speciﬁed in diovascular, GI, and renal risk compared with placebo the trial protocol, the study was not designed to in observational studies (9,29,30). However, if an detect an interaction between the study NSAIDs and NSAID is required, the relative safety of the various aspirin. Accordingly, the present analysis should be NSAIDs appears to be modiﬁed by concomitant considered hypothesis generating and needs to be aspirin use. Physicians administering any NSAID conﬁrmed by other studies. There were no compari- should consider the potential GI and renal hazards of sons of ibuprofen and naproxen in this study, though using combined NSAID and aspirin therapy. It would the relative safety of these agents to each other can be be reasonable to consider gastric protection with an inferred via the Kaplan-Meier curves. In the present H2 blocker or proton pump inhibitor if aspirin is also study we did not evaluate outcomes stratiﬁed by used (29). NSAID dose, given power limitations. Furthermore, Most studies on the comparative safety of NSAIDs the NSAID doses in our study were moderate, in have not investigated a possible interaction between accordance with approved labeling in the countries aspirin and NSAID use and have revealed conﬂicting where the trial was conducted. In addition, data on results, likely because of their heterogeneous study erythrocyte sedimentation rate was not collected, and designs and potential selection bias (16,17,31). A key although baseline levels of C-reactive protein were meta-analysis of 39 trials including more than 41,000 reported, this variable was included post hoc and not patients prior to PRECISION suggested that the inci- adjusted for. The present study was not designed to dence of APTC-deﬁned MACE did not differ in pa- evaluate outcomes on the basis of arthritis type tients treated with celecoxib compared with (osteoarthritis or rheumatoid arthritis), though a nonselective NSAIDs regardless of aspirin use. How- separate analysis of PRECISION was recently pub- ever, this analysis did ﬁnd a lower cardiovascular lished addressing this (34). death rate with celecoxib compared with nonselective NSAIDs (relative risk: 0.43; 95% CI: 0.19 to 0.95; CONCLUSIONS p ¼ 0.04) (14). Other observational studies have revealed increased cardiovascular risk with ibuprofen Among patients not taking aspirin, moderate-dose plus aspirin compared with ibuprofen alone (15,16), celecoxib is associated with a more favorable overall while others have shown reduced risk (18) or no safety proﬁle compared with naproxen or ibuprofen. change at all (17,32). Our study aimed to illuminate Combination with aspirin attenuates the safety these differences. Results of our study support the advantage of celecoxib, although celecoxib is relative safety of celecoxib compared with naproxen still associated with fewer GI events than ibuprofen or ibuprofen with regard to cardiovascular, GI, and or naproxen and fewer renal events than ibuprofen. renal events. These results suggest that in many cases, celecoxib The present study is a post hoc analysis of a ran- would be preferred to naproxen or ibuprofen, domized controlled trial, and as such there were dif- especially if the patient is not required to take ferences in patient characteristics when stratiﬁed by aspirin. aspirin use (Table 1). This is a common issue seen in most other observational studies of NSAID and aspirin ADDRESS FOR CORRESPONDENCE: Dr. Steven E. use and introduces bias that can be addressed only by Nissen, Department of Cardiovascular Medicine, a properly designed trial. A strength of the present Cleveland Clinic, 9500 Euclid Avenue, Desk J2-3, study is the use of propensity score weighting to Cleveland, Ohio 44195. E-mail: email@example.com.
1750 Reed et al. JACC VOL. 71, NO. 16, 2018 Safety of Combined Aspirin and NSAID Use APRIL 24, 2018:1741–51 PERSPECTIVES COMPETENCY IN PATIENT CARE AND PROCEDURAL TRANSLATIONAL OUTLOOK: The mechanisms by SKILLS: All NSAIDs increase cardiovascular, GI, and renal which aspirin and NSAIDs interact with respect to safety risk, but the risk proﬁles of the various NSAIDs differ and and efﬁcacy are complex and probably not conﬁned to are modiﬁed by concomitant aspirin use. Celecoxib ex- COX speciﬁcity. Additional research is needed to elucidate hibits a more favorable overall safety proﬁle than these other contributing factors and delineate pharma- ibuprofen or naproxen and is not associated with cological strategies that maximize analgesic and cardio- increased cardiovascular risk, whether or not patients vascular beneﬁt while minimizing risk. take aspirin concurrently. REFERENCES 1. 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JACC VOL. 71, NO. 16, 2018 Reed et al. 1751 APRIL 24, 2018:1741–51 Safety of Combined Aspirin and NSAID Use nonsteroidal anti-inﬂammatory drugs for osteoar- 33. Funk MJ, Westreich D, Wiesen C, Sturmer T, thritis and rheumatoid arthritis: the CLASS study: a Brookhart MA, Davidian M. Doubly robust estimation KEY WORDS aspirin, celecoxib, ibuprofen, randomized controlled trial. Celecoxib Long-Term of causal effects. Am J Epidemiol 2011;173:761–7. naproxen, nonsteroidal anti-inﬂammatory Arthritis Safety Study. JAMA 2000;284:1247–55. drugs 34. Solomon DH, Husni ME, Wolski KE, et al. Dif- 32. Garcia Rodriguez LA, Varas-Lorenzo C, ferences in safety of non-steroidal anti-inﬂam- Maguire A, Gonzalez-Perez A. Nonsteroidal anti- matory drugs in patients with osteoarthritis and inﬂammatory drugs and the risk of myocardial rheumatoid arthritis: a randomized clinical trial. A PP END IX For a supplemental table and infarction in the general population. Circulation Arthritis Rheumatol 2017 Dec 20 [E-pub ahead of ﬁgures, please see the online version of this 2004;109:3000–6. print]. paper.
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