Safety of Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A Swedish National Population-Based Cohort Study.

Arthritis Care & Research DOI 10.1002/acr.22555

Original Article

Safety of etoricoxib, celecoxib and non-selective NSAIDs in Ankylosing spondylitis and other Spondyloarthritis patients: a Swedish national population based cohort study L E Kristensen* (1,2), A K Jakobsen* (3), J Askling (4), F X Nielsson (1), L T H Jacobsson(5)

1: The Parker Institute, Department of Rheumatology; Copenhagen University Hospital, Frederiksberg, Denmark. 2: Department of Rheumatology Skåne University Hospital, Lund University, Sweden 3: Department of Urology Malmö University Hospital of Skåne 4: Clinical Epidemiology Unit Department of Medicine, Karolinska Institutet 5: Department of Rheumatology and Inflammation Research Sahlgrenska Academy at University of Gothenburg

Corresponding author Lars Erik Kristensen The Parker Institute Department of Rheumatology University hospital of Copenhagen Fasanvej 57 2000 Fredriksberg, Denmark E-mail: [email protected] Running header: Safety of selective and non-selective COX-inhibitors in spondyloathritis

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/acr.22555 © 2015 American College of Rheumatology Received: Aug 31, 2014; Revised: Jan 13, 2015; Accepted: Jan 20, 2015 This article is protected by copyright. All rights reserved.

Arthritis Care & Research

Competing interests LEK and LTHJ have received consultancy fees and fees for speaking from Pfizer, AbbVie, and MSD. JA has received consultancy fees from BMS and MSD. AKJ and FXN have declared no conflicting interests. Author contributions: *LEK (guarantor) and AKJ participated equally in acquisition of data, draft and revision of the manuscript, analysis and interpretation of data. LTHJ and JA participated in study design, acquisition of data, revision of the manuscript, and interpretation of data. FXN participated in study design, data analysis and revision of the manuscript. All authors read and approved the final manuscript. Funding: This study was partly funded by Merck Sharpe & Dohme Corp, a subsidiary of Merck & Co Inc, Whitehouse Station, New Jersey. Employees at MSD contributed to the design of the study and were allowed to comment on the draft manuscript; however, all final decisions regarding content were made by the authors. Further unrestricted grants from Lund University hospital, The Oak Fundation, Reumatikerförbundet, Swedish Research Council, Swedish Foundation for Strategic Research, and King Gustav V 80-year fund. Keywords: NSAID, etoricoxib, celecoxib, safety, spondyloarthritis, serious adverse event, ankylosing spondylitis, epidemiology, cohort study, register

John Wiley & Sons, Inc. This article is protected by copyright. All rights reserved.

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Abstract Objective: Safety data regarding the usage of etoricoxib and other nonsteroidal anti-inflammatory drugs (NSAIDs) in ankylosing spondylitis (AS) and other spondyloarthritis (SpA) patients are rather limited. To estimate and compare rates of gastrointestinal, renovascular, and cardiovascular adverse events in patients exposed to etoricoxib, celecoxib, non-selective NSAIDs (nsNSAIDs) or totally unexposed to NSAIDs. Methods: This is a national register-based cohort study on patients with AS or SpA (N=21,872) identified in the Swedish national patient register (NPR) 1987 – 2009. Treatment exposure was assessed time-dependently based on the prescription drugs register from 2006 – 2009 adjusting for socio-demography, and comorbidities derived from national population-based registers. Results: Exposure to etoricoxib, celecoxib and nsNSAID were 7.6%, 3.9% and 71.2%, respectively. No major risk differences for serious cardiovascular, gastrointestinal or renal adverse events were seen among the three exposure groups. Patients unexposed to NSAIDs had more baseline co-morbidities and an increased relative risk for congestive heart failure events during the study period 2.0 (95% 1.3 to 3.2). The relative risk for atherosclerotic events was non-significant when compared to the nsNSAID group 1.0 (95% CI: 0.7 to 1.5), while the risk for gastrointestinal events was lower for unexposed patients 0.5 (0.4 to 0.7). Conclusion: Overall, serious adverse events related to nsNSAID, etoricoxib and celecoxib were similar and in the range of what would be expected in a group of SpA patients. Patients unexposed to NSAIDs had considerable more baseline co-morbidities and increased risk for congestive heart failure, reflecting a selection of patients being prescribed NSAID in clinical practice. Word count: 249



Significance and Innovation

No unexpected or severely increased risks were identified in SpA patients treated with either etoricoxib, celecoxib or non-specific NSAIDs Serious adverse events related to non-specific NSAID, etoricoxib and celecoxib were similar In clinical practice patients non-exposed to NSAIDs had considerable more baseline co-morbidities than patients receiving NSAIDs


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Introduction Traditional non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs) are known to be associated with an increased risk of upper GI adverse events (AEs) (1). Selective COX-2 inhibitors (coxibs) were developed in order to reduce upper GI toxicity. Several RCTs have demonstrated comparable efficacy but improved GI tolerability with long-term use of COX-2-inhibitors compared to nsNSAIDs (2-10). However placebo-controlled RCTs have indicated an increased risk of thrombotic cardiovascular events in patients treated with coxibs (9, 11). Subsequent RCTs comparing coxibs with nsNSAIDs have demonstrated comparable risk of cardiovascular events (4, 6) and thus it seems that not only coxibs, but NSAIDs as a group may have a higher risk of thrombotic cardiovascular adverse events. Regarding renovascular AEs, congestive heart failure, oedema and hypertension, both nsNSAIDS and coxibs seem to impose an increased risk, but whether differences between the two groups exist remains unsettled (2,4,12,13). Previous studies on the safety of coxibs have primarily been conducted in patients with osteoarthritis (OA), rheumatoid arthritis (RA) and in chemoprevention of colorectal adenomas. To our knowledge, studies on the safety of coxibs in patients with Ankylosing Spondylitis (AS) and other Spondyloarthritis (SpA) are scarce (14). Nevertheless the safety of coxibs is highly relevant in this group of patients, which is characterized by chronic inflammation, extra-articular manifestations, increased cardiovascular morbidity and high use of nsNSAIDs and selective COX-2 inhibitors. Objectives The purpose of this study was therefor to describe incidence rates and relative risks of clinical safety outcomes of interest, including upper gastrointestinal events, thrombotic cardiovascular and cerebrovascular events and renovascular events (renal impairment, hypertension and/or congestive heart failure), in Swedish patients with ankylosing spondylitis or spondyloarthritis (AS/SpA) exposed to etoricoxib, celecoxib, nonselective NSAIDs as well as SpA/AS patients not exposed to NSAIDs, with adjustment for potential confounders.

Methods



This is a population- and register-based nationwide cohort study using register data from AS and/or SpA patients in Swedish inpatient and outpatient specialist care (15). Ethical approval for the study was granted by the Regional Ethics Committee, Karolinska Institutet, Stockholm, Sweden (ethical number: 2011/29-31/1). Data Sources On 31 December 2009, Sweden had a population of about 9.2 million. The Swedish healthcare system is tax funded and offers universal access. Prescription drugs are provided free of charge above a threshold of SEK 1800 annually (≈€180). The vast majority of patients with AS and SpA are diagnosed and treated by rheumatologists at public outpatient and inpatient facilities. Health- and demographic information, including data on inpatient and outpatient visits at public specialist facilities, is registered in a series of national registers with a high degree of completeness (15). Data from the following registers are utilized: The Swedish Patient Register (of Hospital Discharges and Outpatients Visits) which prospectively records ICD-codes for all surgical and medical contacts with the hospital care system (not including visits to primary or private caregivers); Swedish Register of Total Population and Population Changes which prospectively records all citizens and their residence in Sweden; The Swedish Cancer Register which records all diagnosed malignancies; The Swedish Cause of Death Register which records the cause of all register deaths; The Swedish Biologics Register which records all antirheumatic biological treatment; and The Swedish Prescription Drug Register which records all collected pharmacological prescriptions. Patients and study period Patients were eligible for study entry on the first date at which all of the following criteria were met: Attended an outpatient clinic for specialized care 2001-2009, age >=16 years on the date at which they attended the outpatient clinic and received an ICD-code for SpA/AS, registered with at least one ICD-code corresponding to SpA (i.e. ICD10: M46.1, M46.8, M46.9, and ICD9: 720B, 720C or 720X for the appropriate periods) or AS (i.e. ICD10: M459 and ICD9: 720A for the appropriate periods). 78% of the patients have been diagnosed at a department of rheumatology or internal medicine (16), and more than 90% of these fulfilled any of the commonly used classification criteria for AS or SpA according to a large validation study of the included patients (17). Patients with psoriatic arthritis were not actively enrolled, however 5.4% of the AS patients and 6.4% of the SpA patients had received diagnosis codes forpsoriatic arthritis either prior to or during the study period.Patients were excluded if: the medical record indicated a previous/concomitant diagnosis of systemic lupus erythematosus (SLE) or juvenile inflammatory arthritis (JIA). Figure 1 illustrates the flow of patients and relevant time periods for the study. The study period, and consequently the ability to accumulate “time at risk”, ranged from January 1, 2006 (onset date of quantitative reliable Swedish Prescription Drug Registry recordings) through December 31, 2009. Patients with a first time diagnosis in the medical record on or after January 1, 2006 were defined as “registry incident” cases. Patients with “registry incident” AS/SpA were less likely to have been extensively exposed to NSAIDs or coxibs prior to study entry, and therefore data on exposure to NSAIDs and coxibs from first diagnosis is expected to be close to complete for this group.


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Patients were followed from the date of study entry until the earliest of emigration, death (based on data from The Swedish Cause of Death Register and The Swedish Register of Total Population and Population Changes), or until the end of the Study Period. Baseline medications Data on prior medication at the start of the study period were retrieved in order to describe baseline characteristics of patients and for adjustment of potential confounders during analyses of clinical outcomes. Data on all dispensing of drugs of interest were available from The Swedish Prescription Drug Register, including substance (ATC-coding), amount dispensed, and date of dispensing. Drugs of interest included: Treatments for rheumatic conditions, gastro-protective medications, cardiovascular / lipid-lowering medications, diabetes medications, anticoagulants / antiplatelet therapy, prescription aspirin or narcotic and non-narcotic analgesics. Information on dispensing of biologic DMARDs was retrieved from the Swedish Biologics Register and was available for approximately 2500 patients with SpA/AS (in 2010). The individual ATC-codes used for the different drug categories are listed in the supplementary table series S1. Comorbidities Baseline comorbid conditions of interest were identified through linkage to the Swedish Patient Register, giving access to information on all outpatient visits and all hospital stays (date, ICD-code, duration of hospital stay, hospital and medical specialty/department type). Comorbidities of interest included: cardiovascular (cardiac valvular disease, arrhythmia); peripheral vascular (deep venous thrombosis, pulmonary embolism); endocrine / metabolic (diabetes mellitus, hyperlipidemia); renal (hypertension, nephritis); gastrointestinal (colorectal cancer, dyspeptic and other abdominal pain) and hepatic (alcoholism, liver failure). ICD codes for the various comorbidities are presented in supplementary table series S1. Primary exposure Data on all dispensing of etoricoxib, celecoxib (the only other selective COX-2 inhibitor available on the Swedish market), and nsNSAID treatments ranging from Q3 2005 through 2009, including substance (ATC-coding), amount dispensed, and date of dispensing, were identified through linkage to the Swedish Prescription Drug Register. The number of days exposed were standardized according to official Defined Daily Doses (DDD's), defined by WHO standard of exposure as the assumed average maintenance dose per day for a drug used for its main indication in adults (18). Exposure to etoricoxib or nsNSAID treatment was analyzed in a time-dependent manner, i.e. from the first date of dispensing during the study period and for periods determined by the calculated DDD's for the specific prescription, respectively. If exposure periods overlapped,



the first period was censored at a new dispensing. Overlapping prescriptions between the three exposure types was seen in 0.4% (nsNSAIDs to celecoxib) to 8.4% (etoricoxib to nsNSAIDs). The group of subjects totally unexposed to any of the three types of NSAIDs under study was defined as the unexposed group. Clinical outcome The first occurrence of each clinical outcome in a given patient was identified based on ICD-codes for the following diagnoses of interest (by body system): Atherosclerotic / thrombotic cardiovascular, i.e. angina pectoris, acute myocardial infarction (MI), percutaneous transluminal coronary angioplasty (PTCA), coronary artery bypass grafting, death from acute MI, sudden death presumed to be of cardiac origin, atherosclerotic / thrombotic cerebrovascular, i.e. stroke (not classified as to type), ischemic stroke, hemorrhagic stroke, congestive heart failure, hypertension(severe) defined as hospital admission with a primary diagnosis of hypertension, renal insufficiency, i.e. renal insufficiency (chronic & acute), dialysis or gastrointestinal, i.e. varix bleeding, esophageal, gastric and duodenal ulcer (with and without complications of bleeding or perforation), intestinal bleeding. ICD codes for the various outcomes are presented in supplementary table series S1.

Analytic approach and statistical analysis The number of observed adverse events of interest, time at risk, and incidence rates including 95% confidence intervals are provided for four groups: etoricoxib, celecoxib, nsNSAID, and unexposed patients. Relative risks are calculated using nsNSAID as referent since it was the most widely used alternative of the three exposures in Sweden. Unadjusted and adjusted outcome rates and relative risks (RR) are provided. Potential confounding factors are age, sex, prior incidence of outcome of interest and compound risk factors, the latter defined as any of the below listed conditions/drugs at study entry for each of the outcomes of interest: For atherosclerotic cardiovascular or cerebrovascular outcomes: any prior atherosclerotic cardiovascular outcomes, atherosclerotic cerebrovascular outcomes, severe hypertension, diabetes mellitus (DM), hyperlipidemia, use of cardiovascular drugs or use of low dose aspirin. Use of anti-coagulants was also added for cerebrovascular outcomes; for severe hypertension outcomes, the compound risk was defined as any prior renal insufficiency, use of corticosteroids or any prior NSAID; for congestive heart failure outcomes:, any prior NSAID usage, severe hypertension, renal insufficiency, cardiac valvular disease, or arrhythmia;. for gastrointestinal outcomes: any prior usage of gastro-protective drugs, prior NSAIDs, aspirin, anti-coagulants or corticosteroids as well as prior alcoholism or liver failure; for renal insufficiency outcomes: any prior anti-diabetic or cardiovascular drug usage as well as prior severe hypertension, alcoholism or liver failure.


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Data are presented for the combined group of AS and other SpA patients. Moreover, various sensitivity analyses were performed for the following groups: prevalent or registry incident cases (with or without diagnosis prior to study start January 1, 2006); AS, SpA patients; adding extra exposure time (+14, +30 and +90 days); excluding naproxen exposure for the atherosclerotic events; and analyzing patients with recent outcomes (within 2 years prior to entry). (See results section and appended tables). The statistical analyses were performed using R version 2.15.2 (19-21). Results A total of 21,872 patients with AS or SpA met the inclusion criteria. During the study period, 764 patients were censored from the study due to death (n=643) and emigration (n=121). Thus, 21,108 patients were available throughout the study period (Figure 1). A total of 7130 patients received their first diagnosis of either AS or SpA during the study period and were labelled as “incident” cases. Baseline medications and comorbidities as presented in Tables 1 reflect a population of established AS/SpA patients. The median age at study inclusion was 46 years (interquartile range 35 to 57 years), 52% were males ranging from 65% in the group of AS patients to 43% in the group of other spondyloarthritis. During the study period, 7.6% of the patients were ever exposed to etoricoxib, 3.9% of patients were exposed to celecoxib, 71.2% were exposed to nsNSAIDs and 19.5% were not exposed to any coxib or nsNSAID. 79.5% of the patients receiving etoricoxib were prescribed DDDs indicating etoricoxib exposure during more than 50% of the time?. The corresponding fraction for celecoxib and nsNSAID were 78.2% and 63.8%, respectively. The cumulative exposure to various NSAID substances are presented in supplemental table S2. Notably, as seen in table 2 the usage of conventional DMARDs and glucocorticoids were higher than the use of biologicals. In addition, women seemed to have greater exposure to nsNSAIDs. Patients receiving celecoxib tended to have higher education levels, had greater exposure to antirheumatics (i.e. DMARDs and biologics), and had slightly higher rates of comorbidities at baseline (either outcome-related or not outcome-related). Only a few patients (n=168) were exposed to all 3 groups of NSAIDs, however quite a accrued exposure to more than one type during follow-up (n=3074). Temporally overlapping exposures constituted < 2% of the total exposure time, and in the case of double exposure, the most recent prescription was counted while the remaining DDDs of the previous prescription were censored (see methods). As can be seen in Table 2, patients unexposed to any NSAIDs during the study period had considerably more comorbidities at baseline and received more medication for outcome related comorbidities. This was also evident when AS and SpA were studied separately. Detailed baseline characteristics for AS and SpA patients can be assessed in supplementary table series S3. Table 2 illustrates the relative risk of clinical outcomes in the combined AS/SpA group for the various exposure groups with adjustment for potential confounding factors. Detailed information about the total number of events, patients and time of exposure for the various outcomes is also presented in Table 2. Absolute rates for any atherosclerotic cardiac event ranged from 8 to 22 events per 1000 patient years at risk in the three exposure groups and the unexposed group. Noteworthy, the relative risk of atherosclerotic cardiac or



cerebrovascular incidents in patients unexposed to NSAID compared to those exposed to nsNSAID was significantly increased in AS/SpA patients (RR 1.5 (95% Confidence Interval (CI) 1.2 to 1.8) and 2.1 (1.6 to 3.1), respectively). However this difference was no longer evident after adjustment for potential confounding factors. Likewise, the relative risk of combined atherosclerotic thrombotic events was significantly increased (RR 1.6 (1.4 to 1.8)) in patients who were unexposed to NSAID compared to those exposed to nsNSAID, a risk that also decreased and became statistically non-significant after adjustment for potential confounding factors. However, non-exposed patients had an increased risk of congestive heart failure of 2.0 (1.3 to 3.2) even after adjustment for confounders. Overall AS/SpA patients who were unexposed to NSAIDs showed a significantly lower RR of gastrointestinal outcomes both unadjusted (RR 0.5 (0.4 to 0.7)) and after adjustment for potential confounders (RR 0.5 (0.3 to 0.7)) compared to those exposed to nsNSAID. The incidence of congestive heart failure was significantly increased in unexposed patients both before and after adjustment for confounders RR 2.0 (1.3 to 3.2). Moreover, renal insufficiency incidents were also increased for unexposed patients; however this difference was not significant after adjustment for confounders. In table 3a and 3b the number of outcome events, crude incidence rates, and adjusted relative risks are presented for AS and other SpA patients separately. For the both AS and SpA the risk for congestive heart failure was raised for unexposed patients. However, only in the subgroup of SpA patients the risk for atherosclerotic cardiac events was increased for the unexposed patients with a RR of 1.7 (1.2 to 2.2). Likewise, in the subgroup of SpA patietns unexposed subjects had a decreased risk for gastrointestinal events of 0.5 (0.3 to 0.9). .

Further, a subgroup analysis of the incidence and relative risks of the outcome events were performed for the most common nsNSAID compounds (diclofenac, ketoprofen, naproxen, ibuprofen and indomethacin) and presented in table 4. Expectedly, non-exposed patients had lower risk for gastrointestinal events (RR 0.5 (0.3 to 0.9) compared to diclofenac (referent compound). Moreover, indomethacin displayed a trend towards increased risk for all the various adverse events except for cerebrovascular events, however only a minority of patients were exposed to indomethacin and all the analyses were statistically non-significant. Various further sensitivity analysis studying subgroups of the patients included were performed (see supplemental table S4). These sensitivity analyses revealed generally similar point estimates, and none of the analyses demonstrated any new findings not observed in the main analyses. Finally, excluding naproxen from the outcome analysis regarding atherosclerotic outcome events did not change the risk for patients exposed to nsNSAID compared to patients receiving either etoricoxib or celecoxib. The actual numbers of deaths during the study period are low (n=643), and do not allow for meaningful analysis of relative risks or adjustments. No differences in cause of death or absolute death rates were detected between the different exposure groups. Discussion


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In this nationwide cohort study, no statistically significantly increased risks of cardiovascular, gastrointestinal, and renal events were identified for AS and SpA patients receiving nsNSAID compared to celecoxib and etoricoxib. The study population and the frequency of medication usage are as expected for patients with AS/SpA attending out-patient specialist clinics (22). Notably, the usage of conventional DMARDs and glucocorticoids was rather high. The reasons for this are possibly the frequent peripheral manifestations in this patient group also comprising undifferentiated spondyloarthritis patients. Moreover, conventional DMARDs played a larger role in the historical standard of care in these patients. In addition, whether concomitant DMARD treatment should be used with biologicals is still an open question (23). Patients unexposed to NSAIDs appeared to be a highly selected group of patients with more baseline co-morbidities and higher usage of concomitant medications for other diseases than AS/SpA. Interestingly an elevated unadjusted risk for atherosclerotic events either cardiac or cerebrovascular and congestive heart failure was observed for patients unexposed to NSAIDs. After adjusting for potential confounders the risk for atherosclerotic events only remained significantly increased for cardiac events in the subgroup of SpA patients (table 4b). On the other hand, the risk for congestive heart failure remained significant in unexposed patients after adjustment. Expectedly, unexposed patients showed a decreased risk for gastrointestinal events. When studying various compounds of nsNSAID again the unexposed patients showed decreased risks for gastrointestinal events, but no statistically significant differences were noted between the various compounds. The results present risks for outcome events related to nsNSAID, etoricoxib and celecoxib that are in the range of what would be anticipated in a group of patients with systemic inflammatory disease (2-4) and comparable to the rates in a Swedish middle aged background population, although comparison is hampered by minor differences in event definitions (24). A recent study on AS patients from southern Sweden report higher rates of ischemic heart disease compared to the findings in the current study (25). However, our study enrolled patients on average 6 years younger, included more females, and focussed on outcomes events that lead to hospital care. Taken together, these differences makes our findings consistent with the higher rates reported by Bremander et al (25). The limited power in our study hampers the possibilities to exclude smaller risk differences between the different types of NSAIDs. Furthermore, a high degree of confounding by indication, or, in clinical terms, selection of patients to/away from treatment with different NSAIDs but in accordance with what is known about their side effect profiles, was present. Thus, paradoxically, the group of totally unexposed patients demonstrated higher rates of congestive heart failure and atherosclerotic cardiovascular events during the study period in some analyses. This is in contrast to what has been reported from randomized clinical trials and meta-analyses and is likely due to a conscious clinical choice by the treating physicians (9, 11, 26). Thus, and as expected, controlling for known and measured confounders reduced these increased rates, underscoring the necessity for controlling for confounding when reporting observational data on NSAIDs. Moreover, sensitivity analysis in the current study did not identify reduced cardiovascular risk for naproxen compared to other NSAIDs. These results are in contrast to a recent meta-analysis which demonstrated that high-dose naproxen was associated with less vascular risk than the other NSAIDs. On the other hand, the meta-analysis consistently showed high-dose diclofenac and possibly ibuprofen to have vascular risks similar to the established risks associated with selective coxibs (26). The current study clearly illustrates the challenges of



estimating safety profiles of compounds in clinical practice where responsible physicians adapt to the evidence provided to them. Thus it indeed remains difficult to untangle the true risks of the various NSAIDs in an observational population of AS/SpA patients. Strengths and limitations An evident advantage of the study is the use of nationwide data on all AS and SpA patients diagnosed in inpatient and specialist outpatient care in Sweden, which provides a large sample size while at the same time minimizing the risk for selection bias. Secondly, using routinely prospectively collected data from numerous national registers allows exposure to NSAID treatment, comorbidities and socio-economic factors to be assessed and adjusted for the in the analyses as has previously been done for RA (27). The importance of such adjustments is demonstrated by the sizeable effects of adjustment for confounders in the presented analyses. Nevertheless some limitations should be acknowledged. First, we focused on safety outcomes rather than effectiveness. Our results thus provide no direct risk/benefit assessment from within the same study population. Secondly, there is likely some degree of residual confounding due to inaccurately measured or unmeasured confounders, such as tobacco smoking. Thirdly, some misclassification regarding case definition, exposure time, comorbidities and outcomes of interest could occur. Published data, however, suggest that this is of limited importance, as the misclassification rate based on the case definitions for AS/SpA is less than 10% (22). Moreover, Swedish data support a low degree of misclassification for the outcomes used) in this study such as acute coronary events, where misclassification has been reported to be less than 5% (28, 29). Fourthly, not including patients with AS or SpA only seen in primary care may exclude approximately 15% (22) of cases possibly with milder disease. Finally, the many comparisons being undertaken yields a possibility for mass significance, and thus some of the differences being found could be attributed to matter of coincidence.

In conclusion, the results of this study suggest that in regular care, the risks for adverse outcome events related to nsNSAID, etoricoxib and celecoxib exposure in AS and SpA patients in Sweden are not statistically different. No significantly increased risks were identified in this population of AS and SpA patients for etoricoxib compared to nsNSAIDs and celecoxib. Unexposed patients had considerably more baseline co-morbidities and a higher relative risk for atherosclerotic events and congestive heart failure suggesting that confounding by indication significantly affects the observed adverse events rates associated with NSAIDs in clinical practice.


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24. Wilhelmsen L, Welin L, Svärdsudd K, Wedel H, Eriksson H, Hansson PO et al. Secular changes in cardiovascular risk factors and attack rate of myocardial infarction among men aged 50 in Gothenburg, Sweden. Accurate prediction using risk models. J Intern Med. 2008 Jun;263(6):636-43

25. Bremander A, Petersson IF, Bergman S, Englund M. Population-based estimates of common comorbidities and cardiovascular disease in ankylosing spondylitis. Arthritis Care Res (Hoboken). 2011 Apr;63(4):550-6

26. Arber N, Baron JA, Bombardier C, Cannon C, Farkouh ME, FitzGerald GA, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013 Aug 31;382(9894):769-79. 27. Neovius M, Simard J, Askling J. Nationwide prevalence of rheumatoid arthritis and penetration of disease-modifying drugs in Sweden. Ann Rheum Dis. 2011 Apr;70(4):624-9 28. The Center for Epidemiology. The Swedish National Board of Health and Welfare. http://www.sos.se/epc 29. Ludvigsson JF, Andersson E, Ekbom A, Feychting M, Kim JL, Reuterwall C et al. External review and validation of the Swedish national inpatient register. BMC Public Health. 2011; 11:450.


Page 17 of 81


Table 1: Patient demographics, medications and comorbidities at baseline (All Patients, N=21,872) N (%) Characteristic Demographics Male Sex Educational level* Low Intermediate High Missing Age 16-19 years 20-29 years 30-39 years 40-49 years 50-59 years 60-69 years 70-79 years >= 80 years Medications Anti-rheumatic treatments overall Corticosteroids DMARDs Biologics Gastroprotective§ NSAID overall Coxib other Etoricoxib Nonselective NSAID Aspirin overall Aspirin used for atherosclerotic prevention Analgesics¤

Etoricoxib Yes (1655) No (20,217)

Celecoxib Yes (858) No (21014)

nsNSAIDs Yes (15580) No (6292)

799 (48.2)

10542 (52.1)

419 (48.8)

10922 (52.0)

8048 (51.6)

3293 (52.3)

298 (18.0) 839 (50.7) 505 (30.5) 13 (0.8)

4179 (20.7) 9716 (48.1) 6193 (30.6) 129 (0.6)

165 (19.2) 395 (46.0) 292 (34.0) 6 (0.7)

4312 (20.5) 10160 (48.4) 6406 (30.5) 136 (0.7)

3037 (19.5) 7575 (48.0) 4873 (31.3) 95 (0.6)

1440 (22.9) 2980 (47.4) 1825 (29.0) 52 (0.8)

18 (1.1) 155 (9.4) 380 (23.0) 432 (26.1) 401 (24.2) 20012.1) 58 (3.6) 11 (0.7)

301 (1.5) 1888 (9.3) 4034 (20.0) 4717 (23.3) 4533 (22.4) 3035 (15.0) 1251 (6.2) 458 (2.3)

6 (0.7) 65 (7.6) 172 (20.1) 227 (26.5) 205 (23.9) 136 (15.9) 37 (4.3) 10 (1.2)

313 (1.5) 1978 (9.4) 4242 (20.2) 4922 (23.4) 4729 (22.5) 3099 (14.8) 1272 (6.1) 459 (2.2)

207 (1.3) 1512 (9.7) 3255 (20.9) 3885 (25.0) 3578 (23.0) 2222 (14.3) 742 (4.7) 179 (1.2)

421(25.4)

5019(24.8)

266(31.0)

5174(24.6)

198(12.0) 275(16.6) 853(5.1) 538(32.9) 1190(71.9) 81(4.9) 346(20.9) 982(59.3) 98(5.9) 87(5.3)

2376(11.8) 3292(16.3) 982(4.9) 4769(23.6) 10962(54.2) 469(2.3) 307(1.5) 10691(52.9) 1704(8.4) 1635(8.1)

115(13.4) 172(20.0) 61(7.1) 315(36.7) 609(71.0) 331(38.6) 29(3.4) 389(45.3) 60(7.0) 56(6.5)

844(51.0)

8301(41.1)

434(50.6)

Non-exposed Yes (4260) No (17612)

2271 (53.2)

9080

(51.5)

999

(23.5) (47.1) 1225 (28.8) 31 (0.6)

3478

2005

8550

112 (1.8) 531 (8.4) 1159 (18.4) 1264 (20.1) 1356 (21.6) 1013 (16.1) 567 (9.0) 290 (4.6)

(18) (7.8) 715 (16.8) 838 (19.7) 932 (21.9) 715 (16.8) 416 (9.8)

(1.4) (9.7) 3709 (21.0) 4311 (24.5) 4002 (22.7) 2520 (14.3) 893 (5.1)

231(5.5)

238(1.4)

3905(25.1)

1535(24.4)

974 (22.9)

4466 (25.3)

2459(11.7) 3395(16.2) 1006(4.8) 4998(23.8) 11543(54.9) 219(1.0) 624(3.0) 11284(53.7) 1742(8.3) 1666(7.9)

1743(11.1) 2649(17.0) 749(4.8) 3926(25.2) 10327(66.3) 347(2.2) 391(2.5) 10106(64.9) 1124(7.2) 1068(6.9)

831(13.2) 918(14.6) 318(5.1) 1387(22.0) 6292(29.0) 203(3.2) 262(4.2) 1567(24.9) 678(10.8) 654(10.4)

486 (11.4) 586 (13.8) 228 (5.4) 715 (16.8) 0 (0) 0 (0) 0 (0) 0 (0) 476 (11.2) 464 (10.9)

2088 (11.9) 2981 (16.9) 839 (4.8) 4598 (26.1) 12152 (69.0) 550 (3.1) 653 (3.7) 11673 (66.2) 1326 (7.5) 1258 (7.1)

8711(41.5)

6668(42.8)

2477(39.4)

1322 (31.1)

7823 (44.4)


79

334

(19.7) (48.5) 5473 (31.1) 111 (0.7) 240

1709


Cardiovascular Anti-coagulants Anti-diabetics Outcome related comorbidities Atherosclerotic cardiovascular event Atherosclerotic cerebrovascular Severe hypertension Congestive heart failure Gastrointestinal (perforation, ulcer, bleeding or varix bleeding) Renal insufficiency Dialysis

Page 18 of 81

406(24.5) 40(2.4) 52(3.1)

5412(26.8) 649(3.2) 796(3.9)

224(26.1) 21(2.5) 27(3.2)

5594(26.6) 668(3.2) 821(3.9)

3900(25.0) 320(2.1) 513(3.3)

1918(30.5) 369(5.9) 335(5.3)

1340 (31.5) 264 (6.2) 240 (5.7)

4478 (25.4) 425 (2.4) 608 (3.5)

56(3.4)

1217(6.0)

45(5.2)

1228(5.8)

765(4.9)

508(8.1)

389 (9.1)

884 (5.0)

22(1.3)

471(2.3)

10(1.2)

483(2.3)

252(1.6)

241(3.8)

203 (4.8)

290 (1.7)

120(7.3) 17(1.0) 56(3.4)

1837(9.1) 447(2.2) 649(3.2)

60(7.0) 14(1.6) 38(4.4)

1897(9.0) 450(2.1) 667(3.2)

1233(7.9) 197(1.3) 429(2.8)

724(11.5) 267(4.2) 276(4.4)

533 (12.5) 214 (5.1) 192 (4.5)

1424 (8.1) 250 (1.4) 513 (2.9)

4(0.2) 0 (0)

207(1.0) 29(0.1)

4(0.5) 0(0)

207(1.0) 29(0.1)

83(0.5) 7(0.0)

128(2.0) 22(0.4)

110 (2.6) 19 (0.5)

101 (0.6) 10 (0.1)

*Educational level is categorized as a 3-level scale: low - 9 and 12 years of formal school § Including proton pump inhibitors (PPI), histamine 2 receptor blockers (H2-blockers), and misoprostol ¤ Including codeine, morphine / morphine derivatives, tramadol hydrochloride, and prescription acetaminophen. Note use of “over the counter”

analgesics was not captured in the Prescription Drug Register



Page 20 of 81

Table 2: AS/SpA patients. Events, number of patient years at risk, unadjusted and adjusted incidence rates for the outcomes of interest for etoricoxib, nsNSAID, celecoxib and those totally unexposed to any NSAID. Etoricoxib

nsNSAID

Celecoxib

Non-exposed

Unique individuals in exposure group §§

1630

15400

840

4260

Events

8

262

6

317

Person-years (yrs.)

1000

16500

686

14200

Incidence rates per 1000yrs (95% CI)

8.0 (3.3 to 19.3) 15.9 (13.7 to 18.6) 8.8 (3.2 to 24.2)

Relative risks (95% CI)

0.5 (0.2 to1.2) Ref

Atherosclerotic Cardiac Events

Incidence rates per 1000yrs adjusted for potential 1.3 (0.5 to 3.7) 2.2 (1.3 to 3.7) confounding factors* (95% CI) Relative risks adjusted for potential confounding 0.6 (0.2 to 1.7) Ref factors* (95% CI)

0.6 (0.2 to 1.5)

22.3 (19.4 to 25.7) 1.5 (1.2 to 1.8)

1.2 (0.38 to 3.5)

1.9 (1.2 to 3.1)

0.5 (0.2 to 1.6)

0.9 (0.5 to 1.4)

Atherosclerotic Cerebrovascular Events

Etoricoxib

nsNSAID

Celecoxib

Non-exposed


1650

15500

858

4260

Events

5

83

6

155

Person-years (yrs.)

1000

16800

694

14600


5.0 (1.6 to 15.2) 4.9 (3.8 to 6.5)

8.7 (3.1 to 24.0)

10.6 (8.7 to 13.0)


1.0 (0.3 to 3.1) Ref

1.8 (0.6 to 4.9)

2.1 (1.6 to 3.1)

2.4 (0.8 to 7.4)

2.0 (1.2 to 3.4)

1.6 (0.5 to 4.9)

1.3 (0.8 to 2.3)

Incidence rates per 1000yrs adjusted for potential 1.9 (0.6 to 6.4) 1.5 (0.8 to 2.7) confounding factors* (95% CI) Relative risks adjusted for potential confounding 1.3 (0.4 to 4.3) Ref factors* (95% CI) Combined Atherosclerotic Thrombotic (cerebrovascular and cardiac) Unique individuals in exposure group §§

Etoricoxib

nsNSAID

Celecoxib

Non-exposed

1630

15400

840

4260

Events

13

325

11

433

Person-years (yrs.)

989

16400

684

13400


13.1 (6.6 to 19.9 (17.3 to 22.8) 16.1 (7.6 to 34.1) 26.2) 0.7 (0.3 to 1.3) Ref 0.8 (0.4 to 1.7)



32.2 (28.6 to 36.3) 1.6 (1.4 to 1.8)

2.8 (1.2 to 6.3)

3.8 (2.6 to 5.4)

0.8 (0.3 to 1.7)

1.0 (0.7 to 1.5)

Hypertension, severe events

Etoricoxib

nsNSAID

Celecoxib

Non-exposed

Unique individuals in exposure group §§ Events Person-years (yrs.)

1580 29

15300 665

827 26

4260 558

959

15800

654

13700


30.2 (19.0 to 42.0 (38.2 to 46.3) 39.8 (24.4 to 64.8) 40.7 (36.6 to 48.0) 45.3) 0.7 (0.5 to 1.2) Ref 0.9 (0.6 to 1.5) 1.0 (0.9 to 1.1)

Relative risks (95 %CI)


Page 21 of 81


Incidence rates (/1000yrs) adjusted for potential confounding factors* (95% CI) Relative risks adjusted for potential confounding factors* (95% CI)

5.9 (3.5 to 10.0) 7.1 (5.3 to 9.6)

6.8 (3.9 to 11.7)

6.9 (5.2 to 9.0)

0.8 (0.5 to 1.4) Ref

0.9 (0.5 to 1.6)

1.0 (0.7 to 1.3)

Congestive Heart Failure Events

Etoricoxib

nsNSAID

Celecoxib

Non-exposed


1650

15500

853

4260

Events

4

83

2

226

Person-years (yrs.)

1010

16800

694

14400


4.0 (1.1 to 13.8) 4.9 (3.8 to 6.5)

2.9 (0.5 to 16.8)


0.8 (0.2 to 2.8) Ref

0.6 (0.1 to 3.4)

15.7 (13.3 to 18.5) 3.3 (2.7 to 3.7)

0.6 (0.1 to 3.6)

2.4 (1.6 to 3.8)

0.5 (0.1 to 3.0)

2.0 (1.3 to 3.2)

Incidence rates per 1000yrs adjusted for potential 1.1 (0.3 to 4.2) 1.2 (0.7 to 2.0) confounding factors* (95% CI) Relative risks adjusted for potential confounding 0.9 (0.3 to 3.5) Ref factors* (95% CI) Gastrointestinal Events

Etoricoxib

nsNSAID

Celecoxib

Non-exposed


1630

15500

845

4260

Events

13

178

6

87

Person-years (yrs.)

985

16700

681

14800


13.2 (6.6 to 10.7 (8.8 to 12.8) 26.3) 1.2 (0.6 to 2.5) Ref

8.8 (3.2 to 24.4)

5.9 (4.5 to 7.7)

0.8 (0.3 to 2.3)

0.5 (0.4 to 0.7)

5.4 (1.8 to 15.8)

3.4 (2.4 to 4.9)

0.8 (0.3 to 2.2)

0.5 (0.3 to 0.7)


Incidence rates per 1000yrs adjusted for potential 9.0 (4.1 to 19.7) 7.1 (4.6 to 10.9) confounding factors* (95% CI) Relative risks adjusted for potential confounding 1.3 (0.6 to 2.7) Ref factors* (95% CI) Renal insufficiency Events

Etoricoxib

nsNSAID

Celecoxib

Non-exposed


1650

15600

854

4260

Events

3

57

0

125

Person-years (yrs.)

1010

16900

695

14700


3.0 (0.7 to 12.5) 3.4 (2.4 to 4.7)

N/A

8.5 (6.8 to 10.7)


0.9 (0.2 to 3.7) Ref

N/A

2.5 (2.0 to 3.2)

N/A

0.6 (0.3 to 1.3)

N/A

1.2 (0.6 to 2.5)




Page 22 of 81

PY (patient years); 95% CI (95% confidence interval); ref (reference group) §§ Patients entering the study experiencing an event other than the one being studied prior to NSAID exposure of interest were censored thus N can vary slightly from outcome to outcome. Patients who were exposed to NSAIDs between July 1, 2005 and January 1, 2006 and then unexposed are not accounted for in these analyses, giving a total N that differs slightly from the demographic baseline tables. * Potential confounding factors are age, sex, prior incidence of outcome of interest and compound risk factors, which are individualized for the outcome of interest as defined here. See text for description of the compound risk factors for each outcome.

Table 3a: AS patients. Events, number of patient years at risk, unadjusted and adjusted incidence rates for the outcomes of interest for etoricoxib, nsNSAID, celecoxib and those totally unexposed to any NSAID. Etoricoxib

nsNSAID

Celecoxib

Non-exposed


808

7750

458

1960

Events and Person-years (yrs)

5 in 579 PY

208 in 9690 PY

3 in 406 PY

179 in 6540 PY


8.6 (2.8 to 26.3) 21.5 (18.1 to 25.5) 7.4 (1.8 to 31.2) 27.4 (22.7 to 33.0)

Relative risks adjusted for potential confounding factors* (95% CI)

0.5 (0.2 to 1.5) Ref

0.3 (0.1 to 1.2) 0.74 (0.6 to 1.0)


813

7810

472

1960


5 in 578 PY

53 in 9690 PY

5 in 411 PY

83 in 6800 PY


8.7 (2.8 to 26.4) 5.3 (3.8 to 7.5)


2.4 (0.8 to 7.9) Ref



12.2 (4.0 to 12.2 (9.3 to 16.0) 37.0) 2.4 (0.8 to 7.7) 1.6 (0.9 to 2.5)

Combined Atherosclerotic Thrombotic (cerebrovascular and cardiac) Unique individuals in exposure group §§

Etoricoxib

nsNSAID

Celecoxib

Non-exposed

803

7720

458

1960


10 in 570 PY

248 in 9630 PY

7 in 404 PY

243 in 6100 PY


17.6 (8.0 to 25.7 (22.0 to 30.1) 17.3 (6.8 to 39.8 (33.4 to 46.7) 38.6) 44.4) 0.9 (0.4 to 2.0) Ref 0.6 (0.2 to 1.5) 0.9 (0.7 to 1.1)

Relative risks adjusted for potential confounding factors* (95% CI) Hypertension, severe events

Etoricoxib

nsNSAID

Unique individuals in exposure group §§ Events and Person-years (yrs) Incidence rates per 1000yrs (95% CI)

780 18 in 550 PY 32.7 (18.2 to 58.9) 0.7 (0.4 to 1.4)

7660 452 472 in 9250 PY 18 in 383 PY 51.0 (45.5 to 57.2) 47.0 (26.1 to 84.5) Ref 0.9 (0.5 to 1.6)

1960 317 in 5940 PY 53.3 (46.4 to 61.4)


Celecoxib

Non-exposed

1.0 (0.8 to 1.2)


Etoricoxib

nsNSAID

Celecoxib

Non-exposed


814

7810

470

1960


4 in 585 PY

61 in 9950

2 in 412 PY

142 in 6370 PY


6.8 (2.0 to 23.8) 6.1 (4.5 to 8.4)

4.9 (0.8 to 28.3) 22.3 (18.1 to 27.5)

Relative risks adjusted for potential confounding

1.3 (0.4 to 4.6) Ref

0.5 (0.1 to 3.0)


2.1 (1.3 to 3.3)

Page 23 of 81


factors* (95% CI) Gastrointestinal Events

Etoricoxib

nsNSAID

Celecoxib

Non-exposed


806

7820

464

1960


10 in 568 PY

104 in 9910 PY

4 in 406 PY

50 in 6530 PY


17.6 (8.0 to 10.5 (8.2 to 13.4) 38.7) 1.7 (0.8 to 4.0) Ref


9.9 (2.8 to 34.2) 7.7 (5.4 to 10.9) 0.8 (0.2 to 3.0) 0.6 (0.4 to 1.1)

Renal insufficiency Events

Etoricoxib

nsNSAID

Celecoxib

Non-exposed


817

7830

469

1960


3 in 586 PY

43 in 10001 PY

0 in 412 PY

86 in 6410 PY


5.1 (1.2 to 22.6) 4.3 (2.9 to 6.3)

N/A

13.4 (10.3 to 17.5)


1.7 (0.4 to 7.5) Ref

N/A

1.3 (0.8 to 2.2)

PY (patient years); 95% CI (95% confidence interval); ref (reference group) §§ Patients entering the study experiencing an event other than the one being studied prior to NSAID exposure of interest were censored thus N can vary slightly from outcome to outcome. Patients who were exposed to NSAIDs between July 1, 2005 and January 1, 2006 and then unexposed are not accounted for in these analyses, giving a total N that differs slightly from the demographic baseline tables.

Patients could have both an AS and a SpA diagnosis during the Study Period (n=3142); thus the total number of AS/SpA is not the sum of AS and SpA subgroups. * Potential confounding factors are age, sex, prior incidence of outcome of interest and compound risk factors, which are individualized for the outcome of interest as defined here. See text for description of the compound risk factors for each outcome.

Table 3b: Other SpA patients. Events, number of patient years at risk, unadjusted and adjusted incidence rates for the outcomes of interest for etoricoxib, nsNSAID, celecoxib and those totally unexposed to any NSAID. Etoricoxib

nsNSAID

Celecoxib

Non-exposed


1100


3 in 602 PY

10009

536

2710

99 in 9640 PY

4 in 422 PY

158 in 8720 PY


5.0 (1.2 to 21.0) 10.3 (8.0 to 13.2)

9.5 (2.7to 33.0)

0.5 (0.2 to 1.8) Ref

1.1 (0.3 to 3.9)

18.1 (14.9 to 22.1) 1.7 (1.2 to 2.2)




Etoricoxib

nsNSAID

Celecoxib

Non-exposed


1100

10100

542

2710


2 in 603 PY

46 in 9770 PY

4 in 425

85 in 8860 PY

Person-years (yrs.) Incidence rates per 1000yrs (95% CI)

3.3 (0.6 to 19.3) 4.7 (3.3 to 6.8)

9.4 (2.7 to 32.7)

9.6 (7.3 to 12.6)


1.3 (0.4 to 4.3) Ref

1.7 (0.5 to 6.2)

1.4 (0.8 to 2.3)



Page 24 of 81

Combined Atherosclerotic Thrombotic (cerebrovascular and cardiac) Unique individuals in exposure group §§

Etoricoxib

nsNSAID

Celecoxib

Non-exposed

1090

9990

536

2710


5 in 598 PY

133 in 9610 PY

8 in 421 PY

222 in 8610 PY


8.4 (2.7 to 25.5) 13.8 (11.2 to 17.2) 19.0 (7.9 to 45.8)


0.7 (0.2 to 2.2) Ref

1.5 (0.6 to 3.7)

25.8 (21.8 to 30.5) 1.2 (0.9 to 1.6)

Hypertension, severe events

Etoricoxib

nsNSAID

Celecoxib

Non-exposed

Unique individuals in exposure group §§ Events and Person-years (yrs) Incidence rates per 1000yrs (95% CI)

1060

9940

525

2710

16 in 577 PY

321 in 9310 PY

17 in 401 PY

291 in 8400 PY


27.7 (14.9 to 34.5 (30.0 to 39.6) 42.4 (23.2 to 77.6) 34.7 (30.0 to 51.7) 40.1) 0.9 (0.5 to 1.7) Ref 1.3 (0.7 to 2.4) 1.0 (0.8 to 1.3)


Etoricoxib

nsNSAID

Celecoxib

Non-exposed


1110

10100

539

2710


0 in 605 PY

32 in 9770

1 in 425 PY

103 in 8840 PY


N/A

3.3 (2.1 to 5.1)

2.4 (0.2 to 28.4)

11.7 (9.1 to 14.9)


N/A

Ref

0.7 (0.1 to 8.5)

2.8 (1.5 to 5.1)

Gastrointestinal Events

Etoricoxib

nsNSAID

Celecoxib

Non-exposed


1090

10100

533

2710


10 in 590 PY

102 in 9700 PY

4 in 412 PY

48 in 8920 PY


17.0 (7.7 to 10.5 (8.2 to 13.5) 37.3) 1.6 (0.7 to 3.7) Ref

9.7 (2.8 to 33.7)

5.4 (3.8 to 7.7)

0.9 (0.2 to 3.1)

0.5 (0.3 to 0.9)

Relative risks adjusted for potential confounding factors* (95% CI) Renal insufficiency Events

Etoricoxib

nsNSAID

Celecoxib

Non-exposed


1110

10100

541

2710


0 in 606 PY

24 in 9790 PY

0 in 426 PY

52 in 8910 PY


N/A

2.5 (1.5 to 4.1)

N/A

5.8 (4.1 to 8.2)


N/A

Ref

N/A

1.2 (0.7 to 2.4)

Person-years (yrs.)

PY (patient years); 95% CI (95% confidence interval); ref (reference group) §§ Patients entering the study experiencing an event other than the one being studied prior to NSAID exposure of interest were censored thus N can vary slightly from outcome to outcome. Patients who were exposed to NSAIDs between July 1, 2005 and January 1, 2006 and then unexposed are not accounted for in these analyses, giving a total N that differs slightly from the demographic baseline tables. Patients could have both an AS and a SpA diagnosis during the Study Period (n=3142); thus the total number of AS/SpA is not the sum of AS and SpA subgroups. * Potential confounding factors are age, sex, prior incidence of outcome of interest and compound risk factors, which are individualized for the outcome of interest as defined here. See text for description of the compound risk factors for each outcome.


Page 25 of 81


Table 4: AS/SpA patients. Events, number of patient years at risk, unadjusted incidence rates, and adjusted relative risks for the outcomes of interest for the subgroups of most used nsNSAID (diclofenac, ketoprofen, naproxen, ibuprofen and indomethacin) and patients not exposed to any NSAID. Diclofenac (n=7390) §§

Ibuprofen (n=3200)

Indomethacin (n=907)

Ketoprofen (n=5010)

Naproxen (n= 3250)

63 in 3190 PY

28 in 1920 PY

29 in 823 PY

66 in 6030 PY

46 in 2640 PY

Nonexposed (n=4260) 317 in 14200 PY

19.7 (13.9 to 28.0)

14.6 (8.7 to 24.7)

35.2 (21.1 to 58.9)

11.0 (7.8 to 15.4)

17.4 (11.6 to 26.2)

22.3 (19.4 to 25.7)

Ref

0.87 (0.5 to 1.6)

1.6 (0.9 to 2.9)

0.7 (0.4 to 1.1)

0.83 (0.5 to 1.4)

0.8 (0.5 to 1.2)

Diclofenac (n=7490) §§

Ibuprofen (n=3240)


Ketoprofen (n=5040)

Naproxen (n= 3300)

Atherosclerotic Cerebrovascular Events (n/PY)

24 in 3260 PY

9 in 1940 PY

6 in 860 PY

22 in 6120 PY

13 in 2710 PY

Nonexposed (n=4260) 155 in 14600PY

Incidence rate per 1000PY (95% CI) Relative risks adjusted for potential confounding factors*(95% CI)

7.4 (4.2 to 12.9)

4.6 (8.9 to 11.7)

7.0 (2.3 to 21.6)

3.6 (2.0 to 6.5)

4.8 (2.2 to 7.3)

10.6 (8.7 to 13.0)

ref

0.8 (0.3 to 2.8)

0.7 (0.2 to 2.5)

0.7 (0.3 to 1.5)

0.7 (0.3 to 1.7)

1.15 (0.62 to 2.13)


Ibuprofen (n=3190)


Ketoprofen (n=5010)

Naproxen (n= 3240)

Combined Atherosclerotic Thrombotic (cerebrovascular and cardiac) (n/PY)

81 in 3170 PY

36 in 1910 PY

32 in 813 PY

81 in 6010 PY

59 in 2620 PY



25.6 (18.8 to 34.7)

18.9 (11.9 to 30.0)

39.3 (24.1 to 64.1)

13.5 (9.9 to 18.3)

22.5 (15.7 to 32.2)

32.2 (28.6 to 36.3)

Ref

0.9 (0.5 to 1.5)

1.3 (0.7 to 2.3)

0.7 (0.4 to 1.1)

0.9 (0.6 to 1.4)

0.9 (0.6 to 1.2)


Ibuprofen (n=3130)


Ketoprofen (n=4950)

Naproxen (n= 3210)

Nonexposed (n=4260)

Atherosclerotic cardiac events (n/PY) Incidence rate per 1000PY (95% CI) Relative risks adjusted for potential confounding factors*(95% CI)



Page 26 of 81

Severe hypertension (n/PY)

157 in 3070 PY

71 in 1830 PY

63 in 783 PY

170 in 5850 PY

106 in 2530 PY

558 in 13700 PY


51.1 (41.0 to 63.8)

38.8 (28.0 to 53.9)

80.5 (56.8 to 114.0)

29.0 (23.5 to 35.6)

42.0 (32.1 to 54.9)

40.7 (36.6 to 45.3)

ref

0.8 (0.6 to 1.2)

1.2 (0.8 to 1.8)

0.8 (0.6 to 1.1)

0.8 (0.6 to 1.1)

0.9 (0.7 to 1.2)


Ibuprofen (n=3250)


Ketoprofen (n=5040)

Naproxen (n= 3300)

Congestive Heart Failure (n/PY)

22 in 3270 PY

9 in 1940 PY

9 in 860 PY

23 in 6120 PY

14 in 2700 PY



6.7 (3.7 to 12.1)

4.6 (1.8 to 11.6)

10.5 (4.2 to 26.3)

3.8 (2.1 to 6.7)

5.2 (2.5 to 10.8)

15.7 (13.3 to 18.5)

ref

0.8 (0.3 to 2.4)

1.3 (0.4 to 3.8)

0.8 (0.4 to 1.8)

0.9 (0.3 to 2.2)

1.8 (0.9 to 3.4)


Ibuprofen (n=3240)


Ketoprofen (n=5030)

Naproxen (n= 3290)

Gastrointestinal Events (n/PY)

39 in 3260 PY

12 in 1940 PY

14 in 856 PY

65 in 6060 PY

27 in 2700 PY



12.0 (7.7 to 18.6)

6.2 (2.8 to 13.8)

16.4 (7.8 to 34.3)

10.7 (7.6 to 15.1)

10.0 (5.9 to 17.0)

5.9 (4.5 to 7.7)

ref

0.6 (0.2 to 1.4)

1.2 (0.5 to 2.8)

1.1 (0.6 to 1.8)

0.9 (0.4 to 1.7)

0.5 (0.3 to 0.9)


Ibuprofen (n=3250)


Ketoprofen (n=5040)

Naproxen (n= 3310)

Renal insufficiency (n/PY)

15 in 3280 PY

6 in 1950 PY

7 in 867 PY

11 in 6130 PY

12 in 2170 PY


Incidence rate per 1000PY (95% CI) Relative risks adjusted for potential confounding factors*(95%

4.6 (2.2 to 9.3)

3.1 (1.0 to 9.5)

8.1 (2.8 to 23.0)

1.8 (0.8 to 4.1)

4.4 (2.0 to 9.8)

8.5 (6.8 to 10.7)

ref

0.7 (0.2 to 2.6)

1.8 (0.5 to 6.2)

0.6 (0.2 to 1.6)

1.2 (0.4 to 3.3)

1.1 (0.5 to 2.4)


Page 27 of 81


CI) PY (patient years); 95% CI (95% confidence interval); ref (reference group) §§ Patients entering the study experiencing an event other than the one being studied prior to NSAID exposure of interest were censored thus N can vary slightly from outcome to outcome. Patients who were exposed to NSAIDs between July 1, 2005 and January 1, 2006 and then unexposed are not accounted for in these analyses, giving a total N that differs slightly from the demographic baseline tables. * Potential confounding factors are age, sex, prior incidence of outcome of interest and compound risk factors, which are individualized for the outcome of interest as defined here. See text for description of the compound risk factors for each outcome.



Figure 1 illustrates the flow of selection and censoring of AS/SpA patients prior to and during the study period (01 Jan 2006 thru 31 Dec 2009)

22,919 patients with AS/SpA initially retrieved (from 1987 thru 2009)

634 patients excluded due to age

Validity of ankylosing spondylitis and undifferentiated spondyloarthritis diagnoses in the Swedish National Patient Register.

Safety of celecoxib and nonselective nonsteroidal anti-inflammatory drugs in juvenile idiopathic arthritis: results of the Phase 4 registry.

Non-steroidal anti-inflammatory drugs (NSAIDs) for axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis).

Progression of Nonradiographic Axial Spondyloarthritis to Ankylosing Spondylitis: A Population-Based Cohort Study.

Nonsteroidal antiinflammatory drugs--differences and similarities.

Preventing upper gastrointestinal bleeding in patients receiving nonsteroidal antiinflammatory drugs.

Collagenous colitis in setting of nonsteroidal antiinflammatory drugs and antibiotics.

Progression rate of ankylosing spondylitis in patients with undifferentiated spondyloarthritis: A systematic review and meta-analysis.

Gastrointestinal damage associated with nonsteroidal antiinflammatory drugs.

Amelioration of small bowel injury by switching from nonselective nonsteroidal anti-inflammatory drugs to celecoxib in rheumatoid arthritis patients: a pilot study.

Informed consent and the prescription of nonsteroidal antiinflammatory drugs.

The Nonradiographic Axial Spondyloarthritis, the Radiographic Axial Spondyloarthritis, and Ankylosing Spondylitis: The Tangled Skein of Rheumatology.

Back pain and health status in patients with clinically diagnosed ankylosing spondylitis, psoriatic arthritis and other spondyloarthritis: a cross-sectional population-based study.

Efficacy and safety of celecoxib in chinese patients with ankylosing spondylitis: a 6-week randomized, double-blinded study with 6-week open-label extension treatment.

Effects of hypotensive anesthesia, nonsteroidal antiinflammatory drugs, and polymethylmethacrylate on bleeding in total hip arthroplasty patients.

Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs.

Immortal time bias in drug safety cohort studies: spontaneous abortion following nonsteroidal antiinflammatory drug exposure.

Ankylosing spondylitis and other inflammatory spondyloarthritis increase the risk of developing type 2 diabetes in an Asian population.

The risk for depression in patients with ankylosing spondylitis: a population-based cohort study.

Is nephrolithiasis an unrecognized extra-articular manifestation in ankylosing spondylitis? A prospective population-based Swedish national cohort study with matched general population comparator subjects.

Effects of prescription nonsteroidal antiinflammatory drugs on symptoms and disease progression among patients with knee osteoarthritis.

Discriminating Value of Calprotectin in Disease Activity and Progression of Nonradiographic Axial Spondyloarthritis and Ankylosing Spondylitis.

Efficacy and safety of adalimumab in ankylosing spondylitis.

Increased risk of cancer for patients with ankylosing spondylitis: a nationwide population-based retrospective cohort study.