ORIGINAL ARTICLE. Abstract INTRODUCTION

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1 International Journal of Rheumatic Diseases 2018 ORIGINAL ARTICLE Clinical and economic implications of upper gastrointestinal adverse events in Asian rheumatological patients on long-term non-steroidal anti-inflammatory drugs Lydia Say Lee POK, 1 Fatiha Hana SHABARUDDIN, 2 Maznah DAHLUI, 3 Sargunan SOCKALINGAM, 1 Mohd Shahrir MOHAMED SAID, 4 Azmillah ROSMAN, 5 Ing Soo LAU, 5 Liza Mohd ISA, 6 Heselynn HUSSEIN, 6 Chin Teck NG 7,8 and Sanjiv MAHADEVA 1 Departments of 1 Medicine, 2 Pharmacy, 3 Social and Preventive Medicine, Faculty of Medicine, University of Malaya, 4 Department of Medicine, Faculty of Medicine, University Kebangsaan Malaysia, Kuala Lumpur, 5 Department of Medicine, Selayang Hospital, Selangor, 6 Department of Medicine, Putrajaya Hospital, Putrajaya, Malaysia, 7 Department of Rheumatology and Immunology, Singapore General Hospital, and 8 l-nus Medical School, Singapore, Singapore Abstract Aim: To determine the incidence and direct costs of NSAID-induced upper GI adverse events in Malaysian rheumatology patients. Methods: A retrospective, multi-centre, cohort study of rheumatology patients on long-term NSAIDs was conducted. Clinical data of patients treated between 2010 and 2013 were collected for a 24-month follow-up period. The costs of managing upper GI adverse events were based on patient level resource use data. Results: Six hundred and thirty-four patients met the inclusion criteria: mean age 53.4 years, 89.9% female, diagnosis of rheumatoid arthritis (RA; 59.3%), osteoarthritis (OA; 10.3%) and both RA and OA (30.3%). Three hundred and seventy-one (58.5%) patients were prescribed non-selective NSAIDs and 263 (41.5%) had cyclooxygenase-2 inhibitors. Eighty-four upper GI adverse events occurred, translating into a risk of 13.2% and an incidence rate of 66.2 per 1000 person-years. GI adverse events comprised: dyspepsia n = 78 (12.3%), peptic ulcer disease (PUD) n = 5 (0.79%) and upper GI bleeding (UGIB) n = 1 (0.16%). The total direct healthcare cost of managing adverse events was Malaysian Ringgit (MR) (US dollars [USD] ) with a mean cost of MR (USD ) per patient, consisting mainly of GI pharmacotherapy (33.8%), oesophagoduodenoscopies (23.1%) and outpatient clinic visits (18.2%). Mean cost per patient by GI events were: dyspepsia, MR (USD ); PUD, MR (USD ); UGIB, MR (USD , n = 1). Conclusion: The economic burden of GI adverse events due to long-term NSAIDs use in Malaysian patients with chronic rheumatic diseases is modest. Key words: economic implication, non-steroidal anti-inflammatory drugs, upper gastrointestinal adverse event. Correspondence: Dr Lydia Say Lee Pok, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia. lydiapok@gmail.com INTRODUCTION Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used medications in the world. More than 30 million people worldwide take NSAIDs daily. 1 The main benefits of NSAIDs are 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd

2 L. S. L. Pok et al. derived from their anti-inflammatory and analgesic effects. Hence, their use in chronic rheumatic disorders such as rheumatoid arthritis (RA) and osteoarthritis (OA) is common. However, NSAIDs have been associated with a well-established spectrum of adverse effects involving the gastrointestinal (GI), cardiovascular, neurological and renal systems. 2 Upper GI adverse effects are the commonest with a reported prevalence of % for dyspepsia, % for peptic ulcer disease (PUD) 6 and % for upper GI bleeding (UGIB). 6,7 Data on NSAID-related upper GI adverse events have been mostly reported in adults from Western countries. There appears to be a paucity of clinical data on GI adverse events among Asian patients on long-term NSAID therapy, despite reports of its frequent use. A previous community-based survey in Malaysia revealed that over-the-counter purchases for NSAIDs for prolonged durations was not uncommon. 8 A previous study reported that prescriptions for NSAIDs per patients were administered annually from a single institution in northern Malaysia, 9 indicating the regular usage of NSAIDs among Asians. The economic burden of diseases, such as the direct and indirect costs to healthcare providers and society, has become an important measure of disease impact. Several studies in Western healthcare systems have reported on the financial impact of GI adverse events due to NSAID use, indicating that it can lead to an increased health-related financial burden However, their data may not be relevant to Asian countries, as the cost of healthcare delivery in Asia is considerably lower compared to more developed nations. 13 Furthermore, the clinical care and subsequent utilization of healthcare resources may differ between developed and developing nations. 14 Therefore, this study aimed to determine the incidence of NSAID-induced upper GI adverse events in Malaysian rheumatology patients on long-term NSAIDs and calculate the direct costs of these adverse events from the perspective of the healthcare provider. METHODS Study population A retrospective, multi-center cohort study was conducted at four large tertiary care hospitals with rheumatology units in Malaysia. These four institutions are the only public healthcare institutions with rheumatology units within the Klang Valley, an area with the highest population density in Malaysia of almost seven million people. 15 Study protocol Patients diagnosed with RA and/or OA who were on regular rheumatology clinic follow up in 2010 or 2011 in the above-mentioned hospitals were screened via the respective hospitals electronic prescription systems to determine if they were on long-term NSAIDs, defined in this study as having received at least 4 weeks prescription of any type of NSAID. Data from the medical records of these patients were followed up for 24 months by manual review of clinical notes to determine whether they developed upper GI adverse event (s) in the 24 months follow-up period. The following were exclusion criteria for the study: incomplete prescription data, patients who defaulted follow up and GI adverse event within 6 months prior to study recruitment. Data collection Data were collected on demographics, concomitant medications (i.e., prednisone, antiplatelet, anticoagulant), GI prophylactic medications (i.e., proton pump inhibitor [PPI], histamine-2 receptor antagonist) and healthcare utilization for the management of upper GI adverse event(s). Definitions In this study, dyspepsia included patients who presented with upper GI symptoms with no confirmed presence of PUD (i.e., an esophagodeuodenoscopy [OGD] had been performed and did not demonstrate any peptic ulcers or no investigation had been performed). Peptic ulcer disease was defined as the presence of esophageal, gastric or duodenal ulceration at endoscopy, without bleeding. Upper GI bleeding was defined as presence of hematemesis, melena or both. Non-selective NSAIDs were defined as NSAIDs that inhibit both cyclo-oxygenase (COX)-1 and COX-2, such as meloxicam, diclofenac, mefenamic acid and indomethacin, while selective NSAIDs were COX-2-specific inhibitors, such as celecoxib and etoricoxib. Patients who were on a combination of non-selective NSAIDs and COX-2 inhibitors were classified under non-selective NSAIDs in this study. GI medications included PPIs (omeprazole, pantoprazole, esomeprazole, rabeprazole), histamine-2 receptor antagonists (H2RAs; ranitidine, famotidine) and antacids (magnesium triscillicate). 2 International Journal of Rheumatic Diseases 2018

3 Economic implications of GI adverse events Data analysis Data were analyzed using the Statistical Package of Social Sciences (SPSS) version 23 (IBM, Armonk, NY, USA). Descriptive statistics were used for demographic data analysis, frequencies of each type of GI adverse events and for the costing analysis. A P-value of < 0.05 indicated statistical significance for the Chi-square and analysis of variance (ANOVA) tests conducted. Costing methodology Resource use data were collected from the medical records of patients who experienced upper GI adverse events due to NSAIDs during the 24 months follow up. Unit costs were estimated by combining top down (general overheads for hospital services) and bottom up (activity-based costing for clinic visits, hospitalization, procedures and diagnostic investigations) approaches. Cost of managing upper GI adverse events was calculated for each patient who experienced these adverse events based on the patient level healthcare resources utilized from the diagnosis of an adverse event until the resolution of the documented adverse event within the 24 months of available data. To calculate costs relevant to managing a patient with NSAIDs-related adverse event, all healthcare resources related to treatment were documented and costed. For example, cost of treatment of an upper GI bleed was calculated by adding the unit cost of relevant resource use, such as the number of additional clinic visits, A&E (Accident & Emergency) visits, days of hospitalization, OGDs, blood tests, radiological imaging, blood transfusion and GI pharmacotherapy. Costs were reported as mean SD (range). All costs were expressed in Malaysian Ringgit (MR: price year 2014) and converted to US dollars. The conversion rate to USD in 2014 was 1 MR to USD. 16 RESULTS The records of 1679 patients attending rheumatology clinics at the four institutions in 2010 or 2011 were screened. Six hundred and thirty-four (37.8%) patients received long-term NSAIDs. Follow-up data were collected from their medical records for 24 months from the date of the NSAID prescription. None of the patients died during this 2-year follow up period. Demographic data Table 1 describes the patients demographics. The mean age was years and most patients (83.0%) were under the age of 65 years. The majority of patients were female (89.9%), reflecting the female predominance of RA, the predominant diagnosis of rheumatic disease in this cohort of patients. Nearly half of the patients (45.1%) were on concomitant prednisone, while aspirin was a concomitant medication in only 8.1% of patients. A small proportion of patients were on other antiplatelet agents (1.7%) and anticoagulants (1.3%). The majority of patients (88.5%) did not have a history of upper GI disease and there were no patients with a history of upper gastrointestinal bleeding. Table 1 Demographic and clinical data Demographic data Number (%) (N = 634) Patients from each centre UMMC 201 (31.7%) HUKM 92 (14.5%) Selayang Hospital 141 (22.2%) Putrajaya Hospital 200 (31.6%) Age Mean SD, years Age group Non-elderly, < 65 years 526 (83.0%) Elderly, 65 years 108 (17.0%) Sex Male 64 (10.1%) Female 570 (89.9%) Rheumatic disease Rheumatoid arthritis (RA) 377 (59.5%) Osteoarthritis (OA) 65 (10.3%) RA and OA 192 (30.3%) Gastrointestinal (GI) history No GI disease 561 (88.5%) Dyspepsia 64 (10.1%) Peptic ulcer disease 9 (1.4%) Concomitant medications Prednisone 286 (45.1%) Aspirin 53 (8.4%) Other antiplatelets (clopidogrel, ticlopidine) 11 (1.7%) Anticoagulant 8 (1.3%) No. of GI risk factors (34.2%) (49.1%) 2 91 (14.4%) 3 14 (2.2%) 4 1 (0.2%) Concomitant GI prophylaxis Yes 234 (36.9%) Established GI risk factors: age 65 years, upper GI history, concomitant medications (prednisone, aspirin, non-aspirin anti-platelet and anticoagulant). UMMC, University of Malaya Medical Centre; HUKM, Hospital Universiti Kebangsaan Malaysia. International Journal of Rheumatic Diseases

4 L. S. L. Pok et al. 400 n = 371 (58.5%) (37.2%) 233 (62.8%) Non-selec ve No GI Prophylaxis NSAID prescription data 96 (36.5%) COX-2 inhibitor GI Prophylaxis n = 263 (41.5%) 167 (63.5%) Figure 1 Number of patients classified into types of non-steroidal anti-inflammatory drugs (NSAIDs) and concurrent gastrointestinal (GI) prophylaxis received. There were 371 (58.5%) patients who were prescribed non-selective NSAIDs (alone or with COX-2 inhibitors) and 263 (41.5%) patients were prescribed COX-2 inhibitors (alone). The proportion of patients on GI prophylaxis in both NSAID groups was similar (37.2% and 36.5% in non-selective and COX-2 inhibitor groups, respectively; Fig. 1). Incidence of upper GI adverse events During the 24 months follow up, a total of 84 upper GI adverse events occurred, which translated into a risk of 13.2% and an incidence rate of 66.2 per 1000 personyears. Of the 84 upper GI adverse events, 78 patients had dyspepsia, five patients had peptic ulcer disease and one patient had upper GI bleeding (Fig. 2). When comparing the two groups of NSAIDs (nonselective vs. COX-2), the rate of adverse events was Laboratory tests 1.5% Radiological investigations 1.7% Blood transfusion 2.2% slightly higher in the COX-2 group (43/263, 16.3%) compared to the non-selective NSAID group (41/371, 11.1%) but this was not statistically significant (Chisquare, P = 0.053). Costing results GI pharmacotherapy 33.8% Accident and Emergency visits 6.2% Inpatient 13.3% OGD 23.1% Outpatient visits 18.2% Figure 3 Cost components of managing non-steroidal antiinflammatory drug (NSAID)-induced upper gastrointestinal (GI) adverse events. Healthcare resources utilized to manage NSAIDinduced upper GI adverse events in the 84 patients were assigned the appropriate unit costs to determine the cost of managing these clinical events. The total cost of managing all upper GI adverse events in 84 patients was MR (USD ). The mean cost per patient to manage NSAID-induced upper GI adverse events was MR (USD ), comprising mainly the costs of GI pharmacotherapy (33.8%), OGD (23.1%) and outpatient clinic visits (18.2%; Fig. 3). Dyspepsia 78 (12.3%) Patients on long-term NSAIDs N = 634 Upper GI adverse event 84 (13.2%) No upper GI adverse event 550 (86.8%) Peptic ulcer disease 5 (0.79%) Upper GI bleeding 1 (0.16%) Figure 2 Upper gastrointestinal (GI) adverse events observed in patients on long-term non-steroidal anti-inflammatory drugs (NSAIDs). 4 International Journal of Rheumatic Diseases 2018

5 Economic implications of GI adverse events Table 2 Healthcare utilization and mean cost of managing nonsteroidal anti-inflammatory drug-induced upper gastrointestinal adverse events Cost component Dyspepsia (n = 78) Peptic ulcer disease (PUD) (n = 5) Upper gastrointestinal bleeding (UGIB) (n = 1) All patients with adverse events (n = 84) Outpatient clinic visits additional visit patient in MR Accident and Emergency (A&E) visits A&E presentations Inpatient admission admission per patient hospitalisation days per admission Esophagoduodenoscopy (OGD) OGDs per patient Lab tests Radiological investigations (23.42) (44.55) (44.55) (25.04) (8.57) (44.55) (8.49) (14.19) (41.49) (207.44) (18.11) (26.12) (77.43) (64.52) (31.49) 4.24 (1.30) (9.86) (17.40) 6.54 (2.00) 8.27 (2.53) (2.53) International Journal of Rheumatic Diseases

6 L. S. L. Pok et al. Table 2 (continued) All patients with adverse events (n = 84) Upper gastrointestinal bleeding (UGIB) (n = 1) Cost component Dyspepsia (n = 78) Peptic ulcer disease (PUD) (n = 5) Blood transfusion blood transfusions 3.60 (1.10) (17.12) (85.60) (3.06) patient in MR (45.81) (55.95) (25.68) (46.18) Gastrointestinal pharmacotherapy patient in MR Total cost in MR ( ) ( ) (489.74) ( ) (489.74) patient in ( ) ( ) ( ) MR SD MR, Malaysian Ringgit; USD, US dollars. Costs were also analyzed based on the clinical characteristics of the upper GI adverse events, to describe the mean cost to the healthcare system of managing different adverse events. Table 2 details the mean costs and the associated resource use for each cost category. Mean cost to clinically manage one patient who developed dyspepsia was MR , range (USD , range ), which comprised of an average of 0.53 additional outpatient clinic visits, 0.19 A&E presentations, 0.44 OGDs, and MR (USD 45.81) additional pharmacotherapy per patient with dyspepsia. The mean cost of managing a patient with PUD was MR , range (USD , range ) per patient and that of UGIB was MR (USD , n = 1) per patient. The mean costs of managing each type of adverse event were significantly different (independent betweengroups ANOVA test P=0.024). DISCUSSION Risk of upper GI adverse events This retrospective cohort study has identified a 13.2% risk of NSAID-induced upper GI adverse events in Asian patients with chronic rheumatic disorders. Our findings are comparable to a previous large, prospective study of 1921 patients with RA from ARAMIS (Arthritis, Rheumatism and Aging Medical Information System) centers in the United States and Canada, which reported a risk of 15%. 4 However, the rates of dyspepsia (12.3%), PUD (0.79%) and UGIB (0.16%) were considerably lower than previous published reports. 3 7 A possible explanation is that some studies used only non-selective NSAIDs 3,4,6 in contrast to the use of both non-selective and COX-2 inhibitors in this study. Second, patients in our cohort were treated in tertiary care centers by rheumatology specialists who were likely to be aware of NSAIDinduced upper GI effects and had been prudent in prescribing long-term NSAIDs. Additionally, some prospective studies, where all patients were asked about upper GI symptoms at follow up 4,5 and questionnaire-based studies 3 would have captured more self-reported symptoms. While the retrospective design of the study and data collection based on medical records may have missed such detailed clinical data, the 24 months follow up was also intended to capture any occurrence of more severe GI adverse events (PUD and UGIB) treated in other hospitals, which is usually reported by the patients when they present during follow up. This study found there was no statistically significant difference between the incidence of upper GI adverse 6 International Journal of Rheumatic Diseases 2018

7 Economic implications of GI adverse events Table 3 Estimated cost savings achieved due to low incidence rate observed in study population GI adverse event Incidence rate (%) in this study Mean cost of managing each adverse event in this study Incidence rate (%) reported in other studies Estimated costs of managing each adverse event based on incidence from other studies Potential cost savings due to low incidence of adverse events Dyspepsia , PUD UGIB , Total GI, gastrointestinal; USD, US dollars; PUD, peptic ulcer disease; UGIB, upper gastrointestinal bleeding. events in the COX-2 group (16.3%) and non-selective NSAIDs group (11.1%). There could be several reasons for this observation. First, patients who were prescribed COX-2 inhibitors may have been identified to be at a higher risk of developing an upper GI event (and therefore were preferentially prescribed a COX-2 inhibitor or gastro-protective medication with NSAID), possibly confounding the results in this study. Second, the retrospective design of this study, which relied on prescriptions for data on NSAID consumption, was not able to capture over-the-counter usage of NSAIDs, which may have diluted our categories of non-selective NSAID and COX-2 inhibitors. Several other studies such as CLASS, 5 TARGET 17 and SUCCCESS-I 18 reported that COX-2 inhibitors produced significantly fewer GI adverse events compared to non-selective NSAIDs but these studies were all prospective, double-blinded, randomised controlled trials where patients were routinely asked about GI adverse events at each follow-up visit. Direct cost of upper GI adverse events This study has provided an estimate of direct healthcare costs of managing NSAIDs-related upper GI adverse events among rheumatological patients in Malaysia, which is an example of a middle income country in the South East Asian region. This estimate is based on the healthcare provider perspective and did not incorporate direct non-medical costs (such as out-of-pocket expenses and transportation costs) and indirect costs (such as productivity losses). This study identified that the largest component of direct costs in the management of upper GI adverse events was from prescription of GI medications (33.8%), followed by OGDs (23.1%), outpatient clinic costs (18.2%) and hospitalization (13.3%). This is consistent with other studies, 10,19 which have explored the economic impact of GI adverse events in NSAID users. One study conducted in the USA when NSAIDs were first introduced found that the management of NSAIDs-related GI adverse events (which occurred in 25% of 527 rheumatology patients 10 comprised mainly the cost of GI pharmacotherapy [42%], followed by hospitalization costs [38%] and outpatient clinic visits [20%]). Another US study based on healthcare claims similarly reported that GI medication followed by hospitalization were the two main drivers of costs relating to NSAIDs-related GI adverse events therapy. 17 Comparing the cost of various GI adverse events to published literature The incidence of NSAIDs adverse events in this study was lower than that found in previous studies. We postulate that this lower rate of GI adverse events may have translated to a potential direct healthcare cost saving for Asian rheumatological patients on long-term NSAIDs. Based on published rates of the various upper GI adverse events, we extrapolated our costing data and calculated an estimated potential cost saving of MR (USD ) in our population compared to the costs of managing a higher incidence of adverse events (Table 3). The potential cost savings estimated for Asian patients on long-term NSAIDs is also in line with a previous report by Mahadeva et al. 14 which indicated that the economic impact of functional dyspepsia was less in Asia compared to the West, largely due to differences in direct healthcare costs and socio-economic factors. Limitations and strengths We have already alluded to some of the limitations of the retrospective design of this study. Additionally, some of the costs of managing these adverse events may not be captured if the adverse event occurred near the end of the 24 months follow-up period or if the management of the adverse event continued beyond the follow-up period due to the study duration. The study sample consisted of a low proportion of older (aged < 65 years) patients, in contrast to previous publications. This is largely due to the distribution of International Journal of Rheumatic Diseases

8 L. S. L. Pok et al. rheumatological diseases in this cohort of subjects almost 70% had RA and approximately 20% had OA. Nevertheless, this data is fairly robust for several reasons. First, the GI events were observed in a uniform group of patients (i.e., mainly with rheumatological disorders), and there are unlikely to be other confounders for GI complications in these patients apart from their concomitant treatment for rheumatological diseases. Second, the study subjects were representative of most Malaysian patients with rheumatological diseases, as the public healthcare system in Malaysia manages the majority of adults with complex, chronic diseases. There was also comprehensive data on all medication prescriptions as this was available electronically in all four centers and was therefore not subjected to any recall bias. We conclude that the risk of upper GI adverse events in Malaysian rheumatological patients on longterm NSAIDs was low at 13.2%. The economic impact of these adverse events was modest, largely due to the higher incidence and management of dyspepsia rather than more complicated and severe GI adverse events. We postulate that the management of such patients at rheumatology centers may have potential cost savings in an Asian setting. CONCLUSION Long-term NSAIDs use in Malaysian patients with chronic rheumatic diseases resulted in a modest economic burden for the management of adverse events, which was mostly due to dyspepsia. ACKNOWLEDGEMENTS This study received an Investigator Initiated Research Grant from Pfizer Pharmaceuticals, no. WI We gratefully acknowledge assistance from Ms Teng Jie Ying for her contribution in collecting data at the University of Malaya Medical Centre (UMMC). REFERENCES 1 Singh G (2000) Gastrointestinal complications of prescription and over-the-counter nonsteroidal anti-inflammatory drugs: a view from the ARAMIS database. Arthritis, Rheumatism, and Aging Medical Information System. Am J Ther 7 (2), Schneider V, Levesque LE, Zhang B, Hutchinson T, Brophy JM (2006) Association of selective and conventional nonsteroidal antiinflammatory drugs with acute renal failure: a population-based, nested case-control analysis. Am J Epidemiol 164 (9), Larkai EN, Smith JL, Lidsky MD, Sessoms SL, Graham DY (1989) Dyspepsia in NSAID users: the size of the problem. J Clin Gastroenterol 11 (2), Singh G, Ramey DR, Morfeld D, Shi H, Hatoum HT, Fries JF (1996) Gastrointestinal tract complications of nonsteroidal anti-inflammatory drug treatment in rheumatoid arthritis. A prospective observational cohort study. Arch Intern Med 156 (14), Silverstein FE, Faich G, Goldstein JL et al. (2000) Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib long-term arthritis safety study. JAMA 284 (10), Rostom A, Muir K, Dube C et al. (2007) Gastrointestinal safety of cyclooxygenase-2 inhibitors: a Cochrane Collaboration systematic review. Clin Gastroenterol Hepatol 5 (7), , 28 e1 5; quiz Chan FK, Lanas A, Scheiman J, Berger MF, Nguyen H, Goldstein JL (2010) Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial. Lancet 376 (9736), Chua SS, Paraidathathu T (2005) Utilisation of non-steroidal anti-inflammatory drugs (NSAIDs) through community pharmacies in Malaysia. Asia Pac J Public Health 17 (2), Dhabali AA, Awang R, Hamdan Z, Zyoud SH (2012) Associations between prescribing nonsteroidal anti-inflammatory drugs and the potential prescription-related problems in a primary care setting. Int J Clin Pharmacol Ther 50 (12), Bloom BS (1988) Direct medical costs of disease and gastrointestinal side effects during treatment for arthritis. Am J Med 84 (2A), Rahme E, Joseph L, Kong SX, Watson DJ, LeLorier J (2001) Cost of prescribed NSAID-related gastrointestinal adverse events in elderly patients. Br J Clin Pharmacol 52 (2), Sturkenboom MC, Romano F, Simon G et al. (2002) The iatrogenic costs of NSAID therapy: a population study. Arthritis Rheum 47 (2), Baldwin S, Ruse W (2014) Healthcare systems around the world. Glob Health 4 (1), ISSN X. [Cited 24 Dec 2017.] Available from URL: dex.php/gh/article/view/20 14 Mahadeva S, Goh KL (2013) Letter: East-West differences in the economic impact of functional dyspepsia. Aliment Pharmacol Ther 38 (6), Department of Statistics, Malaysia. [Cited 22 July 2016.] Available from URL: 16 Koch M, Dezi A, Ferrario F, Capurso I (1996) Prevention of nonsteroidal anti-inflammatory drug-induced gastrointestinal mucosal injury. A meta-analysis of randomized controlled clinical trials. Arch Intern Med 156 (20), Schnitzer TJ, Burmester GR, Mysler E et al. (2004) Comparison of lumiracoxib with naproxen and ibuprofen in 8 International Journal of Rheumatic Diseases 2018

9 Economic implications of GI adverse events the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 364 (9435), Singh G, Fort JG, Goldstein JL et al. (2006) Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I Study. Am J Med 119 (3), Smalley WE, Griffin MR, Fought RL, Ray WA (1996) Excess costs from gastrointestinal disease associated with nonsteroidal anti-inflammatory drugs. J Gen Intern Med 11 (8), International Journal of Rheumatic Diseases