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, p1742 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 8.81744 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 ofJACC 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 events1748 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 trialJACC 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: nissens@ccf.org.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.
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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.You can also read
