{"@context":{"@language":"en","Affiliation":"http:\/\/vivoweb.org\/ontology\/core#departmentOrSchool","AggregatedSourceRepository":"http:\/\/www.europeana.eu\/schemas\/edm\/dataProvider","AlternateTitle":"http:\/\/purl.org\/dc\/terms\/alternative","Citation":"https:\/\/open.library.ubc.ca\/terms#identifierCitation","Contributor":"http:\/\/purl.org\/dc\/terms\/contributor","Creator":"http:\/\/purl.org\/dc\/terms\/creator","DateAvailable":"http:\/\/purl.org\/dc\/terms\/issued","DateIssued":"http:\/\/purl.org\/dc\/terms\/issued","Description":"http:\/\/purl.org\/dc\/terms\/description","DigitalResourceOriginalRecord":"http:\/\/www.europeana.eu\/schemas\/edm\/aggregatedCHO","FullText":"http:\/\/www.w3.org\/2009\/08\/skos-reference\/skos.html#note","Genre":"http:\/\/www.europeana.eu\/schemas\/edm\/hasType","IsShownAt":"http:\/\/www.europeana.eu\/schemas\/edm\/isShownAt","Language":"http:\/\/purl.org\/dc\/terms\/language","PeerReviewStatus":"https:\/\/open.library.ubc.ca\/terms#peerReviewStatus","Provider":"http:\/\/www.europeana.eu\/schemas\/edm\/provider","Publisher":"http:\/\/purl.org\/dc\/terms\/publisher","PublisherDOI":"https:\/\/open.library.ubc.ca\/terms#publisherDOI","Rights":"http:\/\/purl.org\/dc\/terms\/rights","RightsURI":"https:\/\/open.library.ubc.ca\/terms#rightsURI","ScholarlyLevel":"https:\/\/open.library.ubc.ca\/terms#scholarLevel","Title":"http:\/\/purl.org\/dc\/terms\/title","Type":"http:\/\/purl.org\/dc\/terms\/type","URI":"https:\/\/open.library.ubc.ca\/terms#identifierURI","SortDate":"http:\/\/purl.org\/dc\/terms\/date"},"Affiliation":[{"@value":"Medicine, Faculty of","@language":"en"},{"@value":"Non UBC","@language":"en"},{"@value":"Medicine, Department of","@language":"en"}],"AggregatedSourceRepository":[{"@value":"DSpace","@language":"en"}],"AlternateTitle":[{"@value":"Hydroxychloroquine and Cardiovascular Events","@language":"en"}],"Citation":[{"@value":"Jorge A, Lu, N, Choi H, Esdaile 1 J, Lacaille D, Avina-Zubieta, JA. Hydroxychloroquine use and cardiovascular events 2 among patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis 3 Care Res (Hoboken). 2021 Dec 23.","@language":"en"}],"Contributor":[{"@value":"Arthritis Research Canada","@language":"en"}],"Creator":[{"@value":"Jorge, April","@language":"en"},{"@value":"Lu, Na","@language":"en"},{"@value":"Choi, Hyon","@language":"en"},{"@value":"Esdaile, John","@language":"en"},{"@value":"Lacaille, Diane","@language":"en"},{"@value":"Avi\u00f1a-Zubieta, J. Antonio","@language":"en"}],"DateAvailable":[{"@value":"2022-12-23T08:00:00Z","@language":"en"}],"DateIssued":[{"@value":"2021-12-23","@language":"en"}],"Description":[{"@value":"Objective: We evaluated the potential temporal association between Hydroxychloroquine (HCQ) use and cardiovascular (CV) events among patients with SLE or RA.\r\nMethods: We conducted a nested case-control study within inception cohorts of SLE and RA patients using administrative health databases including the entire population of British Columbia, Canada. We identified cases with incident CV events, including myocardial infarction (MI), stroke, or venous thromboembolism (VTE). We matched each case with up to three controls on age, sex, and rheumatic disease. HCQ exposure was categorized by the time between the last HCQ prescription date covered and the index date as current use, recent use, remote use, or never used. We used conditional logistic regression to assess the association between HCQ exposure and CV events, using remote use as the reference group.\r\nResults: We identified 10,268 cases and 29,969 controls. Adjusted conditional odd ratios (cORs) (95% CI) for current HCQ use relative to remote use were 0.86 (0.77-0.97) for combined CV events, 0.88 (0.74, 1.05) for MI, 0.87 (0.74, 1.03) for stroke, and 0.74 (0.59, 0.94) for VTE. Recent HCQ users and non-users had similar odds of combined CV events as remote users (cORs 0.93 ([95% CI, 0.77-1.13] and 0.96 [95% CI, 0.88-1.04], respectively).\r\nConclusion: In this nested case-control study of patents with SLE and RA, we found a reduced risk of overall CV events associated with current HCQ use including reductions in VTE and trends towards reductions in MI and stroke. These findings suggest a possible cardiovascular preventative benefit of HCQ use.","@language":"en"}],"DigitalResourceOriginalRecord":[{"@value":"https:\/\/circle.library.ubc.ca\/rest\/handle\/2429\/81622?expand=metadata","@language":"en"}],"FullText":[{"@value":" 1 This is the peer reviewed version of the following article: [Jorge A, Lu, N, Choi H, Esdaile 1 J, Lacaille D, Avina-Zubieta, JA. Hydroxychloroquine use and cardiovascular events 2 among patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis 3 Care Res (Hoboken). 2021 Dec 23. Doi: 10.1002\/acr.24850. Online ahead of print.], which 4 has been published in final form at https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/acr.24850. 5 This article may be used for non-commercial purposes in accordance with Wiley Terms 6 and Conditions for Use of Self-Archived Versions. 7   8  2 Title: Hydroxychloroquine Use and Cardiovascular Events Among Patients with Systemic 1 Lupus Erythematosus and Rheumatoid Arthritis 2 Running Head: Hydroxychloroquine and Cardiovascular Events 3 Authors: April Jorge, MD1; Na Lu, MPH1, 2; Hyon Choi, MD, DrPH1; John M. Esdaile, MD, 4 MPH2,3; Diane Lacaille, MD, MHSc2,3; J. Antonio Avina-Zubieta, MD, PhD2,3 5  6 Affiliations:  7 1Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital 8 2Arthritis Research Canada, Richmond, BC, Canada 9 3Divison of Rheumatology, University of British Columbia, Vancouver, BC, Canada 10  11 Corresponding Author:  12 J. Antonio Avina-Zubieta MD, FRCPC MSc, PhD 13 230-2238 Yukon Street 14 Vancouver, BC V5Y 3P2 15 azubieta@arthritisresearch.ca 16  17 Funding: 18 This work was supported by the Canadian Institutes of Health Research [grant number THC-19 135235]; the National Institute for Arthritis and Musculoskeletal Diseases at the National 20 Institutes of Health [grant number P50-AR-060772]; the Rheumatology Research Foundation 21 Scientist Development Award; and Walter & Marilyn Booth Research Scholarship. 22  23 Financial Disclosure Statement: 24 The authors have not received any financial support from commercial sources for the work 25 reported on in this manuscript. The authors have no other financial conflicts of interest 26 associated with the work reported on in this manuscript.  27  28 Acknowledgements: 29 All inferences, opinions, and conclusions drawn in this publication are those of the authors, and 30 do not reflect the opinions or policies of the Data Steward(s). 31  32 Declaration of Interest: 33 None 34  35 Data Sharing: 36 Data for this study are not publicly available because of a data-use agreement. For requests to 37 access the study, please contact the corresponding author. 38  39  40 Manuscript Word Count: 2,314 41  3 ABSTRACT 1  2 Objective:  We evaluated the potential temporal association between Hydroxychloroquine 3 (HCQ) use and cardiovascular (CV) events among patients with SLE or RA. 4 Methods: We conducted a nested case-control study within inception cohorts of SLE and RA 5 patients using administrative health databases including the entire population of British 6 Columbia, Canada. We identified cases with incident CV events, including myocardial infarction 7 (MI), stroke, or venous thromboembolism (VTE). We matched each case with up to three 8 controls on age, sex, and rheumatic disease. HCQ exposure was categorized by the time between 9 the last HCQ prescription date covered and the index date as current use, recent use, remote use, 10 or never used. We used conditional logistic regression to assess the association between HCQ 11 exposure and CV events, using remote use as the reference group. 12 Results: We identified 10,268 cases and 29,969 controls. Adjusted conditional odd ratios (cORs) 13 (95% CI) for current HCQ use relative to remote use were 0.86 (0.77-0.97) for combined CV 14 events, 0.88 (0.74, 1.05) for MI, 0.87 (0.74, 1.03) for stroke, and 0.74 (0.59, 0.94) for VTE. 15 Recent HCQ users and non-users had similar odds of combined CV events as remote users 16 (cORs 0.93 ([95% CI, 0.77-1.13] and 0.96 [95% CI, 0.88-1.04], respectively).  17 Conclusion: In this nested case-control study of patents with SLE and RA, we found a reduced 18 risk of overall CV events associated with current HCQ use including reductions in VTE and 19 trends towards reductions in MI and stroke. These findings suggest a possible cardiovascular 20 preventative benefit of HCQ use.  21  22   23  4 SIGNIFICANCE and INNOVATIONS 1 \uf0b7 To our knowledge, we provide the first report showing a lower risk of venous 2 thromboembolism associated with current hydroxychloroquine use compared with remote 3 use among patients with rheumatoid arthritis.  4 \uf0b7 We also found a possible association with current hydroxychloroquine use and lower 5 risks of ischemic stroke and myocardial infarction among patients with systemic lupus 6 erythematosus or rheumatoid arthritis in a general population context.  7 \uf0b7 These findings support possible protective effects of this medication against 8 atherosclerotic and thrombotic events for patients with rheumatoid arthritis and lupus.  9  5 INTRODUCTION: 1 Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are chronic, systemic 2 inflammatory diseases that are both associated with premature cardiovascular (CV) disease.1,2 3 Hydroxychloroquine (HCQ) is near-universally recommended for patients with systemic lupus 4 erythematosus (SLE) and is often used in the treatment of rheumatoid arthritis (RA). Use of 5 HCQ has been associated with reductions in multiple established risk factors for cardiovascular-6 metabolic endpoints. Multiple observational studies have demonstrated a reduction in 7 hyperglycemia and a lower risk of developing diabetes mellitus among patients with SLE and 8 RA who are treated with HCQ.3,4 Its use has also been associated with improved lipid profiles in 9 SLE and RA patients.5,6 Furthermore, HCQ use has been associated with a lower risk of venous 10 thromboembolism among patients with SLE in several small studies.7 However, it is not well 11 established whether HCQ use can prevent other CV events. We aimed to determine the potential 12 temporal association between HCQ use and cardiovascular (CV) events among patients with 13 SLE or RA. 14 PATIENTS and METHODS: 15 Data Source, Study Population, and Study Design  16 We conducted a nested case-control study within a population-based cohort of patients with 17 incident SLE and incident RA. This source population was the entire population of the province 18 of British Columbia, Canada, over 5 million individuals, identified using linked administrative 19 health databases from Population Data BC.8 These databases capture demographics, vital 20 statistics, and healthcare utilization data including all provincially-funded outpatient medical 21 visits and hospitalizations since 1990.9 Medications are captured through the comprehensive 22  6 PharmaNet prescription database, which includes information on the medication, dose dispensed, 1 date dispensed, and quantity and days\u2019 supply dispensed for all outpatient medications since 2 1996.9 These databases have been used previously to conduct population-based cohort studies of 3 patients with SLE, RA, and other inflammatory and rheumatic diseases.10,11  4 Inception cohorts of patients with SLE and RA from Population Data BC have been 5 previously reported.9,10 The SLE cohort includes 6,241 patients at least 18 years of age with SLE 6 diagnosed between 1997-2015. Subjects were classified as having SLE if they met the following 7 criteria: \u22651 International Classification of Diseases, Ninth Revision (ICD-9) or Tenth Revision, 8 Clinical Modification (ICD-10-CM) code for SLE by a rheumatologist or from a hospital 9 encounter (ICD-9 710.0 or ICD-10-CM M32.1, M32.8, and M32.9) or at least two codes for SLE 10 at least two months apart within two years by a non-rheumatologist physician. We excluded 11 individuals with diagnoses of other inflammatory rheumatic diseases (i.e., RA, psoriatic arthritis, 12 and ankylosing spondylitis) occurring in at least two physician visits at least two months apart 13 after the first SLE diagnosis. To ensure incident cases, all individuals were required to have no 14 SLE diagnosis recorded for at least seven years prior to the index date (i.e., from January 1990, 15 the earliest data available). The RA cohort includes 64,012 patients at least 18 years of age with 16 RA diagnosed between 1997-2015. These subjects were classified as having RA if they met the 17 same criteria but with the relevant RA ICD-9 (714.X) or ICD-10-CM codes (M06.X, M05.X). 18  19 Case and Control Ascertainment 20 From this combined incident SLE\/RA cohort, we identified patients with incident CV events 21 (cases) and up to three matched controls selected from risk set samples. In the primary analysis, 22 cases were defined by incident combined CV events, which included myocardial infarction (MI), 23  7 ischemic stroke or transient ischemic attack (TIA), and venous thromboembolism (VTE). Deep 1 vein thrombosis (DVT) and pulmonary embolism (PE) comprised VTE. These events were 2 identified by corresponding ICD-9 and ICD-10 CM codes. Cases and controls were matched by 3 age, sex, and rheumatic disease (i.e., SLE vs RA) on the index dates of the defining CV events 4 for cases, since these variables are considered to be the major confounders for the risk of CV 5 events in this population.  6  We conducted secondary analyses using alternative case definitions of specific CV 7 events. In these alternative case definitions, we defined cases by incident MI, incident 8 stroke\/TIA, and incident VTE, respectively. Cases and controls were matched by the same 9 variables as in the primary analysis.  10  11 Assessment of Exposure 12 The exposure of interest was HCQ use status relative to the index date. Using the PharmaNet 13 database, we determined the dates associated with the end of the medication supply according to 14 the last prescription date covered by the final HCQ dispensation. We categorized HCQ use as 15 current, recent, remote, or never. We classified patients as current HCQ users if they had an 16 active supply of HCQ spanning the index date or if their HCQ supply ended within a 90-day 17 grace prior to the index date to reduce exposure misclassification due to delayed prescription 18 refills and due to the long half-life of the medication. We classified patients as recent users if 19 their HCQ supply ended between 91-365 days prior to the index date, and we classified patients 20 as remote users if their HCQ supply ended more than 365 days prior to the index date. We 21 classified patients as never users if they had no dispensed HCQ prescriptions. 22  8  In a sensitivity analysis, we used alternative definitions of current and recent use, 1 classifying patients as current users if their HCQ supply ended within 30-days prior to the index 2 date or spanned the index date. We classified patients as recent users if their HCQ supply ended 3 between 30-365 days prior to the index date. To assess the potential influence of the duration of 4 HCQ use on the potential association between HCQ use and CV events, we additionally 5 conducted a stratified analysis according to duration of HCQ use of less than one year or at least 6 one year as of the index date. 7  8 Assessment of Covariates 9 Covariates were assessed during the year prior to the index date\/matching and included variables 10 associated with the risk of CV events or associated with illness severity of SLE or RA. These 11 included the Charlson comorbidity index, chronic kidney disease (CKD), prior CV disease, CV 12 medication use (i.e., statins, anti-hypertensives, cardiac glycosides, diuretics, anti-arrhythmics, 13 and nitrates), anticoagulants, glucocorticoid use, immunosuppressive\/disease modifying 14 antirheumatic drug (DMARD) use (i.e., azathioprine, methotrexate, mycophenolate, leflunomide, 15 cyclosporine, and cyclophosphamide), biologic immunosuppressant use (i.e., belimumab, 16 adalimumab, infliximab, golimumab, certolizumab, etanercept, tocilizumab, and abatacept), and 17 healthcare utilization (hospitalizations and outpatient visits). 18  19 Statistical Analysis 20 We generated descriptive statistics for cases and controls. We used conditional logistic 21 regression to calculate the conditional odds ratios (cORs) and 95% confidence intervals (CI) for 22 combined CV events associated with HCQ exposure status (i.e., current use, recent use, remote 23  9 use, or never used), using remote users as the reference group in order to minimize confounding 1 by indication, as in previous studies.11,12 We similarly calculated cORs for specific CV events 2 including MI, stroke\/TIA, and VTE in secondary analyses using the alternate case definitions 3 according to these specific CV events. We additionally calculated cORs for CV events within 4 disease categories of SLE and RA and stratified by duration of HCQ use. Finally, we repeated 5 this analysis using the alternate exposure definitions. Adjusted analyses included the covariates 6 described above. Statistical analyses were performed using SAS (version 9.3, SAS Institute Inc); 7 all p-values were two-sided (\u03b1=0.05).  8 All procedures were conducted in compliance with British Columbia\u2019s Freedom of 9 Information and Privacy Protection Act. Ethics approval was obtained from the University of 10 British Columbia\u2019s Behavioral Research Ethics Board. 11  12 RESULTS: 13 From the combined RA and SLE inception cohorts (n=70,253), we identified 10,268 cases with 14 CV events and 29,969 matched controls without CV events. This included 532 cases with SLE 15 and 9,736 cases with RA as well as 1,249 and 28,720 controls with SLE and RA, respectively 16 (Table 1). The majority of patients (64%) were female, and the mean age was 74 years at the 17 index date. Cases had a higher mean Charlson comorbidity index score than controls, and a 18 higher proportion of cases used cardiovascular medications. 19  Current HCQ use was associated with an unadjusted cOR of 0.88 (95% CI 0.81-0.97) for 20 combined CV events compared with remote users (Table 2). The fully-adjusted cOR for current 21 HCQ use was 0.86 (0.77-0.97). Recent HCQ use and never use were each associated with similar 22 odds of CV events as remote HCQ use (fully-adjusted cORs 0.93 [95% CI 0.77-1.13] and 0.96 23  10 [95% CI 0.88-1.04], respectively). Current HCQ use was associated with fully-adjusted cORs of 1 0.88 (95% CI 0.74-1.05) for MI, 0.87 (95% CI 0.74-1.03) for stroke\/TIA, and 0.74 (95% CI 2 0.59-0.94) for VTE compared with remote HCQ users (Figure 1, Table 2).  3  In stratified analyses according to rheumatic disease, patients with RA had similar 4 findings as in the overall analysis (Figure 1, Supplemental Table 1). For the smaller subgroup 5 with SLE, these findings did not reach significance.  6  With the alternative exposure definitions requiring current users to have a last 7 prescription date covered within 30 days prior to the index date, overall findings were similar 8 (Supplemental Table 2). When stratified by duration of HCQ use, the results were similar 9 among patients with at least one year of current or prior HCQ use (adjusted cOR 0.83 [95% CI 10 0.73-0.94] among current users compared with remote users) but did not reach significance 11 among patients with less than one year of HCQ use (adjusted cOR for CV events of 0.85 [95% 12 CI 0.70-1.04] (Supplemental Table 3). 13  14 DISCUSSION: 15 In this nested case-control study within a population-based inception cohort of patients with SLE 16 or RA, we found a lower risk of incident CV events associated with current HCQ use compared 17 with remote HCQ use. We observed a lower risk of overall CV events as well as a lower risk of 18 VTE and a trend towards lower risks for MI and ischemic stroke associated with current HCQ 19 use. These associations were also observed in the larger RA subgroup, but we did not observe a 20 significant difference in the odds of CV events according to HCQ use status within the smaller 21 SLE subgroup.  22  11 Multiple prior observational studies have found a lower risk of thrombotic events in HCQ 1 users with SLE than in non-users, including the outcome of VTE with or without stroke.7 Our 2 study adds to this literature by additionally demonstrating lower risks of thrombotic events, 3 including both VTE and ischemic stroke, associated with HCQ use in patients with RA. 4 Although our study did not reach significance in the smaller SLE subgroup, our overall findings 5 are consistent with this prior work. Larger studies would be needed to assess the potential 6 benefits of HCQ use in preventing ischemic stroke and myocardial infarction among patients 7 with SLE.  8 Our findings also suggest that HCQ use may be associated with a lower risk of acute MI. 9 Prior studies have linked HCQ use with improvement in several risk factors for coronary artery 10 disease, including hyperlipidemia5,6 and insulin resistance,3,4 indicating potential mechanisms for 11 prevention of MI. However, it has not been well-established whether HCQ use can prevent actual 12 acute coronary events. A single center study from Israel13 and a population-based study from 13 Taiwan14 each found a protective effect of lower risks of MI in HCQ users than non-users among 14 RA patients. However, a recent study of multiple population-based cohorts did not find a 15 difference in the risk of MI between HCQ users and sulfasalazine users with RA.15 The use of 16 different comparison groups may have contributed to this difference in findings. Our study 17 utilized remote users as the comparison group to minimize confounding by indication, as both 18 the current user and the remote user groups had to have had an indication for HCQ use. In 19 contrast, prior studies that used non-users or sulfasalazine-only users as the reference group may 20 have introduced bias by unmeasured confounders that influence both the use of HCQ and the 21 outcome. Prospective studies are warranted to confirm the possible benefit of HCQ in preventing 22 CAD and MI events in patients with rheumatic disease.  23  12 We additionally observed that patients who had recently discontinued HCQ at least 90 1 days prior to the index date as well as remote HCQ users who discontinued the medication at 2 least one year prior to the index date had similar risks of CV events as patients who had never 3 used HCQ. This may suggest a loss of benefits after HCQ discontinuation which is of relevance 4 to weighing the risks and benefits of continuing long-term use of HCQ in patients with SLE or 5 RA.  6  The main limitations of this study are that of administrative data. The diagnoses of SLE 7 and RA were not clinically confirmed, but they were identified using an administrative algorithm 8 as has been previously reported.9,10 Further, we lack information on disease activity and severity, 9 which may impact the use of HCQ. Although we used a large administrative database with an 10 inception cohort of patients with SLE and RA, the number of cases with SLE was small which 11 limited power for the SLE-only subgroup analysis. A major strength of our study is the use of a 12 comprehensive prescription drug database, which captures all dispensed outpatient medications 13 and the timing of refills. Our ascertainment of HCQ exposure status by actual prescription refills 14 was less susceptible to misclassification of HCQ users than could occur with reliance on 15 prescribing data alone. Furthermore, our population-based data source which includes all patients 16 regardless of age or funding adds to the generalizability of our findings. Additionally, as 17 mentioned, our use of a remote user comparison group was employed to limit potential 18 confounding by indication that can occur when comparing users with non-users and has been 19 employed in other pharmacoepidemiology studies.11,12 However, there may be some variation 20 between current users and remote users. To address this, we adjusted for potential differences in 21 comorbidities, other medications including glucocorticoids and DMARD use, and healthcare 22 utilization between the different HCQ exposure groups. We also conducted a sensitivity analysis 23  13 using a stricter definition of current HCQ users, and the results were unchanged, which 1 contributes to the robustness of our findings. 2  Overall, we found lower risks of CV events associated with current HCQ use in a 3 combined cohort of SLE and RA patients in a general population context. These findings support 4 possible protective effects of this medication for patients with SLE and RA.    5   6  14 REFERENCES: 1 1. Crowson CS, Liao KP, Davis JM, 3rd, Solomon DH, Matteson EL, Knutson KL, et al. 2 Rheumatoid Arthritis and Cardiovascular Disease. Am Heart J. 2013;166:622-8.e1. 3 2. Schoenfeld S, Kasturi S, Costenbader K. The Epidemiology of Atherosclerotic 4 Cardiovascular Disease Among Patients with SLE: A Systematic Review. Semin Arthritis Rheum 5 2013;43:77-95. 6 3. Chen YM, Lin CH, Lan TH, Chen HH, Chang SN, Chen YH, et al. Hydroxychloroquine 7 Reduces Risk of Incident Diabetes Mellitus in Lupus Patients in a Dose-Dependent Manner: A 8 Population-Based Cohort Study. Rheumatology (Oxford). 2015;54:1244-9. 9 4. Solomon DH, Massarotti E, Garg R, Liu J, Canning C, Schneeweiss S. Association 10 Between Disease-Modifying Antirheumatic Drugs and Diabetes Risk in Patients with 11 Rheumatoid Arthritis and Psoriasis. JAMA. 2011;305:2525-31. 12 5. Cairoli E, Rebella M, Danese N, Garra V, Borba EF. Hydroxychloroquine Reduces Low-13 Density Lipoprotein Cholesterol Levels in Systemic Lupus Erythematosus: A Longitudinal 14 Evaluation of the Lipid-Lowering Effect. Lupus. 2012;21:1178-82. 15 6. Rempenault C, Combe B, Barnetche T, Gaujoux-Viala C, Lukas C, Morel J, et al. 16 Metabolic and Cardiovascular Benefits of Hydroxychloroquine in Patients with Rheumatoid 17 Arthritis: A Systematic Review And Meta-Analysis. Ann Rheum Dis. 2018;77:98-103. 18 7. Wallace DJ, Gudsoorkar VS, Weisman MH, Venuturupalli SR. New Insights into 19 Mechanisms of Therapeutic Effects of Antimalarial Agents in SLE. Nat Rev Rheumatol. 20 2012;8:522-33. 21 8. Population Data BC. (Accessed March 30, 2021 at http:\/\/www.popdata.bc.ca\/data.) 22 9. Avina-Zubieta JA, To F, Vostretsova K, De Vera M, Sayre EC, Esdaile JM. Risk of 23 Myocardial Infarction and Stroke in Newly Diagnosed Systemic Lupus Erythematosus: A 24 General Population-Based Study. Arthritis Care Res (Hoboken). 2017;69:849-56. 25 10. Lacaille D, Avina-Zubieta JA, Sayre EC, Abrahamowicz M. Improvement in 5-Year 26 Mortality in Incident Rheumatoid Arthritis Compared with the General Population-Closing the 27 Mortality Gap. Ann Rheum Dis. 2017;76:1057-63. 28 11. Jorge A, McCormick N, Lu N, Zheng Y, Esdaile J, De Vera M, et al. 29 Hydroxychloroquine and Mortality Among Patients with Systemic Lupus Erythematosus in the 30 General Population. Arthritis Care Res (Hoboken). 2020. 31 12. Dubreuil M, Louie-Gao Q, Peloquin CE, Choi HK, Zhang Y, Neogi T. Risk of 32 Myocardial Infarction with Use of Selected Non-Steroidal Anti-Inflammatory Drugs in Patients 33 with Spondyloarthritis and Osteoarthritis. Ann Rheum Dis. 2018;77:1137-42. 34 13. Shapiro M, Levy Y. The Association between Hydroxychloroquine Treatment and 35 Cardiovascular Morbidity among Rheumatoid Arthritis Patients. Oncotarget. 2018;9:6615-22. 36 14. Hung YM, Wang YH, Lin L, Wang PYP, Chiou JY, Wei JC. Hydroxychloroquine May 37 Be Associated with Reduced Risk of Coronary Artery Diseases in Patients with Rheumatoid 38 Arthritis: A Nationwide Population-Based Cohort Study. Int J Clin Pract. 2018;72:e13095. 39 15. Lane JCE, Weaver J, Kostka K, Duarte-Salles T, Abrahao MTF, Alghoul H, et al. Risk of 40 Hydroxychloroquine Alone and in Combination with Azithromycin in the Treatment of 41 Rheumatoid Arthritis: A Multinational, Retrospective Study. Lancet Rheumatol. 2020;2:e698-42 e711. 43  44   45  15 TABLES and FIGURES: 1  2 Table 1. Characteristics of Systemic Lupus Erythematosus and Rheumatoid Arthritis 3 Cases with Cardiovascular Events and Matched Controls 4 Characteristics* Cases (n=10,268) Controls (n=29,969) SMD Age (mean, SD)    Overall 74 (13) 74 (13) 0.013 Systemic Lupus Erythematosus 59 (14) 57 (13) 0.133 Rheumatoid Arthritis 75 (13) 75 (12) 0.022 Sex (% female)    Overall 63.6 63.7 0.003 Systemic Lupus Erythematosus 91.0 95.4 0.178 Rheumatoid Arthritis 62.1 62.3 0.005 Charlson comorbidity index, mean (SD)    Overall 1.20 (1.21) 1.04 (1.03) 0.147 Systemic Lupus Erythematosus 1.52 (1.36) 1.19 (0.91) 0.285 Rheumatoid Arthritis 1.18 (1.20 1.03 (1.02) 0.138 Cardiovascular Disease (%)    Overall 1.3 0.6 0.077 Systemic Lupus Erythematosus 2.3 0.6 0.136 Rheumatoid Arthritis 1.3 0.6 0.073 Chronic Kidney Disease (%)    Overall 14.3 11.8 0.075 Systemic Lupus Erythematosus 27.3 18.1 0.220 Rheumatoid Arthritis 13.6 11.5 0.063 Medications (%)    Glucocorticoids    Overall 32.0 27.0 0.101 Systemic Lupus Erythematosus 49.4 36.0 0.275 Rheumatoid Arthritis 31.1 27.1 0.089 Cardiovascular medications    Overall 53.6 42.9 0.215 Systemic Lupus Erythematosus 43.4 29.0 0.304 Rheumatoid Arthritis 54.2 43.5 0.214 Anticoagulants (%)    Overall 5.4 3.0 0.120 Systemic Lupus Erythematosus 6.2 1.4 0.250 Rheumatoid Arthritis 5.3 3.1 0.115 Other DMARD use (%)    Overall 15.9 14.6 0.036 Systemic Lupus Erythematosus 19.2 17.1 0.055 Rheumatoid Arthritis 15.8 14.5 0.034 Oral DMARDs (%)    Overall 16.0 17.4 0.038 Systemic Lupus Erythematosus 22.4 20.0 0.060 Rheumatoid Arthritis 15.6 17.3 0.045 Biologic DMARDs (%)    Overall 2.2 1.9 0.024 Systemic Lupus Erythematosus 1.1 1.4 0.028  16 Rheumatoid Arthritis 2.3 1.9 0.027 Healthcare Utilization    Number of hospitalizations, mean (SD)    Overall 0.6 (1.1) 0.4 (0.8) 0.202 Systemic Lupus Erythematosus 1.0 (1.8) 0.5 (0.9) 0.376 Rheumatoid Arthritis 0.6 (1.1) 0.4 (0.8) 0.189 Number of outpatient visits, mean (SD)    Overall 27.2 (19.7) 22.4 (15.5) 0.280 Systemic Lupus Erythematosus 36.2 (26.9) 26.0 (18.9) 0.457 Rheumatoid Arthritis 26.8 (19.1) 22.3 (15.3) 0.266 *Assessed within one year prior to matching\/index date.  1 SMD, standardized mean difference; DMARDs, disease-modifying anti-rheumatic drugs. 2 Includes azathioprine, methotrexate, mycophenolate, leflunomide, cyclosporine, 3 cyclophosphamide, or biologic DMARDs including belimumab, adalimumab, infliximab, 4 golimumab, certolizumab, etanercept, tocilizumab, abatacept, . 5 Cardiovascular medications include anti-hypertensives, cardiac glycosides, diuretics, anti-6 arrhythmics, and nitrates. 7  8  9   10  17 Table 2. Hydroxychloroquine Use and Cardiovascular Events According to 1 Hydroxychloroquine Exposure Status Among Patients with Systemic Lupus 2 Erythematosus and Rheumatoid Arthritis 3  4  Cases,  N Controls,  N Conditional Odds Ratio  (95% CI) Adjusted Conditional Odds Ratio* (95% CI) All Combined CV Events     Remote HCQ Users 1305 3385 1.0 (reference)  1.0 (reference)  Recent HCQ users 244 635 1.00 (0.85, 1.18) 0.93 (0.77, 1.13) Current HCQ users 1182 3449 0.88 (0.81, 0.97) 0.86 (0.77, 0.97) HCQ non-users 7537 22500 0.87 (0.81, 0.93) 0.96 (0.88, 1.04) All Myocardial Infarction         Remote HCQ Users 566 1411 1.0 (reference)  1.0 (reference)  Recent HCQ users 98 242 1.00 (0.78, 1.29) 1.12 (0.82, 1.53) Current HCQ users 517 1495 0.85 (0.74, 0.98) 0.88 (0.74, 1.05) HCQ non-users 3208 9753 0.81 (0.73, 0.91) 0.98 (0.85, 1.12) All Stroke\/TIA         Remote HCQ Users 536 1474 1.0 (reference)  1.0 (reference)  Recent HCQ users 91 249 0.99 (0.76, 1.29) 0.83 (0.61, 1.12) Current HCQ users 435 1401 0.86 (0.74, 0.99) 0.87 (0.74, 1.03) HCQ non-users 3178 9340 0.95 (0.85, 1.05) 1.00 (0.88, 1.13) All Venous Thromboembolism     Remote HCQ Users 321 785 1.0 (reference)  1.0 (reference)  Recent HCQ users 60 155 0.94 (0.68, 1.31) 0.65 (0.44, 0.98) Current HCQ users 266 820 0.78 (0.64, 0.95) 0.74 (0.59, 0.94) HCQ non-users 1475 4475 0.80 (0.69, 0.93) 0.90 (0.75, 1.08) *Additionally adjusted for Charlson comorbidity index, prior CV disease, chronic kidney disease, glucocorticoid 5 use, DMARD use, cardiovascular medication use, anticoagulant use, and healthcare utilization including number of 6 hospitalizations and number of outpatient visits all assessed one year prior to the index date.  7 CV, cardiovascular; HCQ, hydroxychloroquine; TIA, transient ischemic attack 8 Exposure classifications: current use- last prescription date covered <90 days before index date; recent use- last 9 prescription date covered 90-365 days before index date; remote use- >365 days before index date 10  11  12  13  14 15  18 Figure 1. Forest Plots of Adjusted Odds Ratios for Cardiovascular Events Associated with 1 Current Hydroxychloroquine Use Versus Remote Use Among Patients with Systemic 2 Lupus Erythematosus and Rheumatoid Arthritis 3  4 Abbreviations: CV, cardiovascular; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; TIA, transient 5 ischemic attack 6   1 This is the peer reviewed version of the following article: [Jorge A, Lu, N, Choi H, Esdaile 1 J, Lacaille D, Avina-Zubieta, JA. Hydroxychloroquine use and cardiovascular events 2 among patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis 3 Care Res (Hoboken). 2021 Dec 23. Doi: 10.1002\/acr.24850. Online ahead of print.], which 4 has been published in final form at https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/acr.24850. 5 This article may be used for non-commercial purposes in accordance with Wiley Terms 6 and Conditions for Use of Self-Archived Versions. 7   8  2 Title: Hydroxychloroquine Use and Cardiovascular Events Among Patients with Systemic 1 Lupus Erythematosus and Rheumatoid Arthritis 2 Running Head: Hydroxychloroquine and Cardiovascular Events 3 Authors: April Jorge, MD1; Na Lu, MPH1, 2; Hyon Choi, MD, DrPH1; John M. Esdaile, MD, 4 MPH2,3; Diane Lacaille, MD, MHSc2,3; J. Antonio Avina-Zubieta, MD, PhD2,3 5  6 Affiliations:  7 1Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital 8 2Arthritis Research Canada, Richmond, BC, Canada 9 3Divison of Rheumatology, University of British Columbia, Vancouver, BC, Canada 10  11 Corresponding Author:  12 J. Antonio Avina-Zubieta MD, FRCPC MSc, PhD 13 230-2238 Yukon Street 14 Vancouver, BC V5Y 3P2 15 azubieta@arthritisresearch.ca 16  17 Funding: 18 This work was supported by the Canadian Institutes of Health Research [grant number THC-19 135235]; the National Institute for Arthritis and Musculoskeletal Diseases at the National 20 Institutes of Health [grant number P50-AR-060772]; the Rheumatology Research Foundation 21 Scientist Development Award; and Walter & Marilyn Booth Research Scholarship. 22  23 Financial Disclosure Statement: 24 The authors have not received any financial support from commercial sources for the work 25 reported on in this manuscript. The authors have no other financial conflicts of interest 26 associated with the work reported on in this manuscript.  27  28 Acknowledgements: 29 All inferences, opinions, and conclusions drawn in this publication are those of the authors, and 30 do not reflect the opinions or policies of the Data Steward(s). 31  32 Declaration of Interest: 33 None 34  35 Data Sharing: 36 Data for this study are not publicly available because of a data-use agreement. For requests to 37 access the study, please contact the corresponding author. 38  39  40 Manuscript Word Count: 2,314 41  3 ABSTRACT 1  2 Objective:  We evaluated the potential temporal association between Hydroxychloroquine 3 (HCQ) use and cardiovascular (CV) events among patients with SLE or RA. 4 Methods: We conducted a nested case-control study within inception cohorts of SLE and RA 5 patients using administrative health databases including the entire population of British 6 Columbia, Canada. We identified cases with incident CV events, including myocardial infarction 7 (MI), stroke, or venous thromboembolism (VTE). We matched each case with up to three 8 controls on age, sex, and rheumatic disease. HCQ exposure was categorized by the time between 9 the last HCQ prescription date covered and the index date as current use, recent use, remote use, 10 or never used. We used conditional logistic regression to assess the association between HCQ 11 exposure and CV events, using remote use as the reference group. 12 Results: We identified 10,268 cases and 29,969 controls. Adjusted conditional odd ratios (cORs) 13 (95% CI) for current HCQ use relative to remote use were 0.86 (0.77-0.97) for combined CV 14 events, 0.88 (0.74, 1.05) for MI, 0.87 (0.74, 1.03) for stroke, and 0.74 (0.59, 0.94) for VTE. 15 Recent HCQ users and non-users had similar odds of combined CV events as remote users 16 (cORs 0.93 ([95% CI, 0.77-1.13] and 0.96 [95% CI, 0.88-1.04], respectively).  17 Conclusion: In this nested case-control study of patents with SLE and RA, we found a reduced 18 risk of overall CV events associated with current HCQ use including reductions in VTE and 19 trends towards reductions in MI and stroke. These findings suggest a possible cardiovascular 20 preventative benefit of HCQ use.  21  22   23  4 SIGNIFICANCE and INNOVATIONS 1 \uf0b7 To our knowledge, we provide the first report showing a lower risk of venous 2 thromboembolism associated with current hydroxychloroquine use compared with remote 3 use among patients with rheumatoid arthritis.  4 \uf0b7 We also found a possible association with current hydroxychloroquine use and lower 5 risks of ischemic stroke and myocardial infarction among patients with systemic lupus 6 erythematosus or rheumatoid arthritis in a general population context.  7 \uf0b7 These findings support possible protective effects of this medication against 8 atherosclerotic and thrombotic events for patients with rheumatoid arthritis and lupus.  9  5 INTRODUCTION: 1 Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are chronic, systemic 2 inflammatory diseases that are both associated with premature cardiovascular (CV) disease.1,2 3 Hydroxychloroquine (HCQ) is near-universally recommended for patients with systemic lupus 4 erythematosus (SLE) and is often used in the treatment of rheumatoid arthritis (RA). Use of 5 HCQ has been associated with reductions in multiple established risk factors for cardiovascular-6 metabolic endpoints. Multiple observational studies have demonstrated a reduction in 7 hyperglycemia and a lower risk of developing diabetes mellitus among patients with SLE and 8 RA who are treated with HCQ.3,4 Its use has also been associated with improved lipid profiles in 9 SLE and RA patients.5,6 Furthermore, HCQ use has been associated with a lower risk of venous 10 thromboembolism among patients with SLE in several small studies.7 However, it is not well 11 established whether HCQ use can prevent other CV events. We aimed to determine the potential 12 temporal association between HCQ use and cardiovascular (CV) events among patients with 13 SLE or RA. 14 PATIENTS and METHODS: 15 Data Source, Study Population, and Study Design  16 We conducted a nested case-control study within a population-based cohort of patients with 17 incident SLE and incident RA. This source population was the entire population of the province 18 of British Columbia, Canada, over 5 million individuals, identified using linked administrative 19 health databases from Population Data BC.8 These databases capture demographics, vital 20 statistics, and healthcare utilization data including all provincially-funded outpatient medical 21 visits and hospitalizations since 1990.9 Medications are captured through the comprehensive 22  6 PharmaNet prescription database, which includes information on the medication, dose dispensed, 1 date dispensed, and quantity and days\u2019 supply dispensed for all outpatient medications since 2 1996.9 These databases have been used previously to conduct population-based cohort studies of 3 patients with SLE, RA, and other inflammatory and rheumatic diseases.10,11  4 Inception cohorts of patients with SLE and RA from Population Data BC have been 5 previously reported.9,10 The SLE cohort includes 6,241 patients at least 18 years of age with SLE 6 diagnosed between 1997-2015. Subjects were classified as having SLE if they met the following 7 criteria: \u22651 International Classification of Diseases, Ninth Revision (ICD-9) or Tenth Revision, 8 Clinical Modification (ICD-10-CM) code for SLE by a rheumatologist or from a hospital 9 encounter (ICD-9 710.0 or ICD-10-CM M32.1, M32.8, and M32.9) or at least two codes for SLE 10 at least two months apart within two years by a non-rheumatologist physician. We excluded 11 individuals with diagnoses of other inflammatory rheumatic diseases (i.e., RA, psoriatic arthritis, 12 and ankylosing spondylitis) occurring in at least two physician visits at least two months apart 13 after the first SLE diagnosis. To ensure incident cases, all individuals were required to have no 14 SLE diagnosis recorded for at least seven years prior to the index date (i.e., from January 1990, 15 the earliest data available). The RA cohort includes 64,012 patients at least 18 years of age with 16 RA diagnosed between 1997-2015. These subjects were classified as having RA if they met the 17 same criteria but with the relevant RA ICD-9 (714.X) or ICD-10-CM codes (M06.X, M05.X). 18  19 Case and Control Ascertainment 20 From this combined incident SLE\/RA cohort, we identified patients with incident CV events 21 (cases) and up to three matched controls selected from risk set samples. In the primary analysis, 22 cases were defined by incident combined CV events, which included myocardial infarction (MI), 23  7 ischemic stroke or transient ischemic attack (TIA), and venous thromboembolism (VTE). Deep 1 vein thrombosis (DVT) and pulmonary embolism (PE) comprised VTE. These events were 2 identified by corresponding ICD-9 and ICD-10 CM codes. Cases and controls were matched by 3 age, sex, and rheumatic disease (i.e., SLE vs RA) on the index dates of the defining CV events 4 for cases, since these variables are considered to be the major confounders for the risk of CV 5 events in this population.  6  We conducted secondary analyses using alternative case definitions of specific CV 7 events. In these alternative case definitions, we defined cases by incident MI, incident 8 stroke\/TIA, and incident VTE, respectively. Cases and controls were matched by the same 9 variables as in the primary analysis.  10  11 Assessment of Exposure 12 The exposure of interest was HCQ use status relative to the index date. Using the PharmaNet 13 database, we determined the dates associated with the end of the medication supply according to 14 the last prescription date covered by the final HCQ dispensation. We categorized HCQ use as 15 current, recent, remote, or never. We classified patients as current HCQ users if they had an 16 active supply of HCQ spanning the index date or if their HCQ supply ended within a 90-day 17 grace prior to the index date to reduce exposure misclassification due to delayed prescription 18 refills and due to the long half-life of the medication. We classified patients as recent users if 19 their HCQ supply ended between 91-365 days prior to the index date, and we classified patients 20 as remote users if their HCQ supply ended more than 365 days prior to the index date. We 21 classified patients as never users if they had no dispensed HCQ prescriptions. 22  8  In a sensitivity analysis, we used alternative definitions of current and recent use, 1 classifying patients as current users if their HCQ supply ended within 30-days prior to the index 2 date or spanned the index date. We classified patients as recent users if their HCQ supply ended 3 between 30-365 days prior to the index date. To assess the potential influence of the duration of 4 HCQ use on the potential association between HCQ use and CV events, we additionally 5 conducted a stratified analysis according to duration of HCQ use of less than one year or at least 6 one year as of the index date. 7  8 Assessment of Covariates 9 Covariates were assessed during the year prior to the index date\/matching and included variables 10 associated with the risk of CV events or associated with illness severity of SLE or RA. These 11 included the Charlson comorbidity index, chronic kidney disease (CKD), prior CV disease, CV 12 medication use (i.e., statins, anti-hypertensives, cardiac glycosides, diuretics, anti-arrhythmics, 13 and nitrates), anticoagulants, glucocorticoid use, immunosuppressive\/disease modifying 14 antirheumatic drug (DMARD) use (i.e., azathioprine, methotrexate, mycophenolate, leflunomide, 15 cyclosporine, and cyclophosphamide), biologic immunosuppressant use (i.e., belimumab, 16 adalimumab, infliximab, golimumab, certolizumab, etanercept, tocilizumab, and abatacept), and 17 healthcare utilization (hospitalizations and outpatient visits). 18  19 Statistical Analysis 20 We generated descriptive statistics for cases and controls. We used conditional logistic 21 regression to calculate the conditional odds ratios (cORs) and 95% confidence intervals (CI) for 22 combined CV events associated with HCQ exposure status (i.e., current use, recent use, remote 23  9 use, or never used), using remote users as the reference group in order to minimize confounding 1 by indication, as in previous studies.11,12 We similarly calculated cORs for specific CV events 2 including MI, stroke\/TIA, and VTE in secondary analyses using the alternate case definitions 3 according to these specific CV events. We additionally calculated cORs for CV events within 4 disease categories of SLE and RA and stratified by duration of HCQ use. Finally, we repeated 5 this analysis using the alternate exposure definitions. Adjusted analyses included the covariates 6 described above. Statistical analyses were performed using SAS (version 9.3, SAS Institute Inc); 7 all p-values were two-sided (\u03b1=0.05).  8 All procedures were conducted in compliance with British Columbia\u2019s Freedom of 9 Information and Privacy Protection Act. Ethics approval was obtained from the University of 10 British Columbia\u2019s Behavioral Research Ethics Board. 11  12 RESULTS: 13 From the combined RA and SLE inception cohorts (n=70,253), we identified 10,268 cases with 14 CV events and 29,969 matched controls without CV events. This included 532 cases with SLE 15 and 9,736 cases with RA as well as 1,249 and 28,720 controls with SLE and RA, respectively 16 (Table 1). The majority of patients (64%) were female, and the mean age was 74 years at the 17 index date. Cases had a higher mean Charlson comorbidity index score than controls, and a 18 higher proportion of cases used cardiovascular medications. 19  Current HCQ use was associated with an unadjusted cOR of 0.88 (95% CI 0.81-0.97) for 20 combined CV events compared with remote users (Table 2). The fully-adjusted cOR for current 21 HCQ use was 0.86 (0.77-0.97). Recent HCQ use and never use were each associated with similar 22 odds of CV events as remote HCQ use (fully-adjusted cORs 0.93 [95% CI 0.77-1.13] and 0.96 23  10 [95% CI 0.88-1.04], respectively). Current HCQ use was associated with fully-adjusted cORs of 1 0.88 (95% CI 0.74-1.05) for MI, 0.87 (95% CI 0.74-1.03) for stroke\/TIA, and 0.74 (95% CI 2 0.59-0.94) for VTE compared with remote HCQ users (Figure 1, Table 2).  3  In stratified analyses according to rheumatic disease, patients with RA had similar 4 findings as in the overall analysis (Figure 1, Supplemental Table 1). For the smaller subgroup 5 with SLE, these findings did not reach significance.  6  With the alternative exposure definitions requiring current users to have a last 7 prescription date covered within 30 days prior to the index date, overall findings were similar 8 (Supplemental Table 2). When stratified by duration of HCQ use, the results were similar 9 among patients with at least one year of current or prior HCQ use (adjusted cOR 0.83 [95% CI 10 0.73-0.94] among current users compared with remote users) but did not reach significance 11 among patients with less than one year of HCQ use (adjusted cOR for CV events of 0.85 [95% 12 CI 0.70-1.04] (Supplemental Table 3). 13  14 DISCUSSION: 15 In this nested case-control study within a population-based inception cohort of patients with SLE 16 or RA, we found a lower risk of incident CV events associated with current HCQ use compared 17 with remote HCQ use. We observed a lower risk of overall CV events as well as a lower risk of 18 VTE and a trend towards lower risks for MI and ischemic stroke associated with current HCQ 19 use. These associations were also observed in the larger RA subgroup, but we did not observe a 20 significant difference in the odds of CV events according to HCQ use status within the smaller 21 SLE subgroup.  22  11 Multiple prior observational studies have found a lower risk of thrombotic events in HCQ 1 users with SLE than in non-users, including the outcome of VTE with or without stroke.7 Our 2 study adds to this literature by additionally demonstrating lower risks of thrombotic events, 3 including both VTE and ischemic stroke, associated with HCQ use in patients with RA. 4 Although our study did not reach significance in the smaller SLE subgroup, our overall findings 5 are consistent with this prior work. Larger studies would be needed to assess the potential 6 benefits of HCQ use in preventing ischemic stroke and myocardial infarction among patients 7 with SLE.  8 Our findings also suggest that HCQ use may be associated with a lower risk of acute MI. 9 Prior studies have linked HCQ use with improvement in several risk factors for coronary artery 10 disease, including hyperlipidemia5,6 and insulin resistance,3,4 indicating potential mechanisms for 11 prevention of MI. However, it has not been well-established whether HCQ use can prevent actual 12 acute coronary events. A single center study from Israel13 and a population-based study from 13 Taiwan14 each found a protective effect of lower risks of MI in HCQ users than non-users among 14 RA patients. However, a recent study of multiple population-based cohorts did not find a 15 difference in the risk of MI between HCQ users and sulfasalazine users with RA.15 The use of 16 different comparison groups may have contributed to this difference in findings. Our study 17 utilized remote users as the comparison group to minimize confounding by indication, as both 18 the current user and the remote user groups had to have had an indication for HCQ use. In 19 contrast, prior studies that used non-users or sulfasalazine-only users as the reference group may 20 have introduced bias by unmeasured confounders that influence both the use of HCQ and the 21 outcome. Prospective studies are warranted to confirm the possible benefit of HCQ in preventing 22 CAD and MI events in patients with rheumatic disease.  23  12 We additionally observed that patients who had recently discontinued HCQ at least 90 1 days prior to the index date as well as remote HCQ users who discontinued the medication at 2 least one year prior to the index date had similar risks of CV events as patients who had never 3 used HCQ. This may suggest a loss of benefits after HCQ discontinuation which is of relevance 4 to weighing the risks and benefits of continuing long-term use of HCQ in patients with SLE or 5 RA.  6  The main limitations of this study are that of administrative data. The diagnoses of SLE 7 and RA were not clinically confirmed, but they were identified using an administrative algorithm 8 as has been previously reported.9,10 Further, we lack information on disease activity and severity, 9 which may impact the use of HCQ. Although we used a large administrative database with an 10 inception cohort of patients with SLE and RA, the number of cases with SLE was small which 11 limited power for the SLE-only subgroup analysis. A major strength of our study is the use of a 12 comprehensive prescription drug database, which captures all dispensed outpatient medications 13 and the timing of refills. Our ascertainment of HCQ exposure status by actual prescription refills 14 was less susceptible to misclassification of HCQ users than could occur with reliance on 15 prescribing data alone. Furthermore, our population-based data source which includes all patients 16 regardless of age or funding adds to the generalizability of our findings. Additionally, as 17 mentioned, our use of a remote user comparison group was employed to limit potential 18 confounding by indication that can occur when comparing users with non-users and has been 19 employed in other pharmacoepidemiology studies.11,12 However, there may be some variation 20 between current users and remote users. To address this, we adjusted for potential differences in 21 comorbidities, other medications including glucocorticoids and DMARD use, and healthcare 22 utilization between the different HCQ exposure groups. We also conducted a sensitivity analysis 23  13 using a stricter definition of current HCQ users, and the results were unchanged, which 1 contributes to the robustness of our findings. 2  Overall, we found lower risks of CV events associated with current HCQ use in a 3 combined cohort of SLE and RA patients in a general population context. These findings support 4 possible protective effects of this medication for patients with SLE and RA.    5   6  14 REFERENCES: 1 1. Crowson CS, Liao KP, Davis JM, 3rd, Solomon DH, Matteson EL, Knutson KL, et al. 2 Rheumatoid Arthritis and Cardiovascular Disease. Am Heart J. 2013;166:622-8.e1. 3 2. Schoenfeld S, Kasturi S, Costenbader K. The Epidemiology of Atherosclerotic 4 Cardiovascular Disease Among Patients with SLE: A Systematic Review. Semin Arthritis Rheum 5 2013;43:77-95. 6 3. Chen YM, Lin CH, Lan TH, Chen HH, Chang SN, Chen YH, et al. Hydroxychloroquine 7 Reduces Risk of Incident Diabetes Mellitus in Lupus Patients in a Dose-Dependent Manner: A 8 Population-Based Cohort Study. Rheumatology (Oxford). 2015;54:1244-9. 9 4. Solomon DH, Massarotti E, Garg R, Liu J, Canning C, Schneeweiss S. Association 10 Between Disease-Modifying Antirheumatic Drugs and Diabetes Risk in Patients with 11 Rheumatoid Arthritis and Psoriasis. JAMA. 2011;305:2525-31. 12 5. Cairoli E, Rebella M, Danese N, Garra V, Borba EF. Hydroxychloroquine Reduces Low-13 Density Lipoprotein Cholesterol Levels in Systemic Lupus Erythematosus: A Longitudinal 14 Evaluation of the Lipid-Lowering Effect. Lupus. 2012;21:1178-82. 15 6. Rempenault C, Combe B, Barnetche T, Gaujoux-Viala C, Lukas C, Morel J, et al. 16 Metabolic and Cardiovascular Benefits of Hydroxychloroquine in Patients with Rheumatoid 17 Arthritis: A Systematic Review And Meta-Analysis. Ann Rheum Dis. 2018;77:98-103. 18 7. Wallace DJ, Gudsoorkar VS, Weisman MH, Venuturupalli SR. New Insights into 19 Mechanisms of Therapeutic Effects of Antimalarial Agents in SLE. Nat Rev Rheumatol. 20 2012;8:522-33. 21 8. Population Data BC. (Accessed March 30, 2021 at http:\/\/www.popdata.bc.ca\/data.) 22 9. Avina-Zubieta JA, To F, Vostretsova K, De Vera M, Sayre EC, Esdaile JM. Risk of 23 Myocardial Infarction and Stroke in Newly Diagnosed Systemic Lupus Erythematosus: A 24 General Population-Based Study. Arthritis Care Res (Hoboken). 2017;69:849-56. 25 10. Lacaille D, Avina-Zubieta JA, Sayre EC, Abrahamowicz M. Improvement in 5-Year 26 Mortality in Incident Rheumatoid Arthritis Compared with the General Population-Closing the 27 Mortality Gap. Ann Rheum Dis. 2017;76:1057-63. 28 11. Jorge A, McCormick N, Lu N, Zheng Y, Esdaile J, De Vera M, et al. 29 Hydroxychloroquine and Mortality Among Patients with Systemic Lupus Erythematosus in the 30 General Population. Arthritis Care Res (Hoboken). 2020. 31 12. Dubreuil M, Louie-Gao Q, Peloquin CE, Choi HK, Zhang Y, Neogi T. Risk of 32 Myocardial Infarction with Use of Selected Non-Steroidal Anti-Inflammatory Drugs in Patients 33 with Spondyloarthritis and Osteoarthritis. Ann Rheum Dis. 2018;77:1137-42. 34 13. Shapiro M, Levy Y. The Association between Hydroxychloroquine Treatment and 35 Cardiovascular Morbidity among Rheumatoid Arthritis Patients. Oncotarget. 2018;9:6615-22. 36 14. Hung YM, Wang YH, Lin L, Wang PYP, Chiou JY, Wei JC. Hydroxychloroquine May 37 Be Associated with Reduced Risk of Coronary Artery Diseases in Patients with Rheumatoid 38 Arthritis: A Nationwide Population-Based Cohort Study. Int J Clin Pract. 2018;72:e13095. 39 15. Lane JCE, Weaver J, Kostka K, Duarte-Salles T, Abrahao MTF, Alghoul H, et al. Risk of 40 Hydroxychloroquine Alone and in Combination with Azithromycin in the Treatment of 41 Rheumatoid Arthritis: A Multinational, Retrospective Study. Lancet Rheumatol. 2020;2:e698-42 e711. 43  44   45  15 TABLES and FIGURES: 1  2 Table 1. Characteristics of Systemic Lupus Erythematosus and Rheumatoid Arthritis 3 Cases with Cardiovascular Events and Matched Controls 4 Characteristics* Cases (n=10,268) Controls (n=29,969) SMD Age (mean, SD)    Overall 74 (13) 74 (13) 0.013 Systemic Lupus Erythematosus 59 (14) 57 (13) 0.133 Rheumatoid Arthritis 75 (13) 75 (12) 0.022 Sex (% female)    Overall 63.6 63.7 0.003 Systemic Lupus Erythematosus 91.0 95.4 0.178 Rheumatoid Arthritis 62.1 62.3 0.005 Charlson comorbidity index, mean (SD)    Overall 1.20 (1.21) 1.04 (1.03) 0.147 Systemic Lupus Erythematosus 1.52 (1.36) 1.19 (0.91) 0.285 Rheumatoid Arthritis 1.18 (1.20 1.03 (1.02) 0.138 Cardiovascular Disease (%)    Overall 1.3 0.6 0.077 Systemic Lupus Erythematosus 2.3 0.6 0.136 Rheumatoid Arthritis 1.3 0.6 0.073 Chronic Kidney Disease (%)    Overall 14.3 11.8 0.075 Systemic Lupus Erythematosus 27.3 18.1 0.220 Rheumatoid Arthritis 13.6 11.5 0.063 Medications (%)    Glucocorticoids    Overall 32.0 27.0 0.101 Systemic Lupus Erythematosus 49.4 36.0 0.275 Rheumatoid Arthritis 31.1 27.1 0.089 Cardiovascular medications    Overall 53.6 42.9 0.215 Systemic Lupus Erythematosus 43.4 29.0 0.304 Rheumatoid Arthritis 54.2 43.5 0.214 Anticoagulants (%)    Overall 5.4 3.0 0.120 Systemic Lupus Erythematosus 6.2 1.4 0.250 Rheumatoid Arthritis 5.3 3.1 0.115 Other DMARD use (%)    Overall 15.9 14.6 0.036 Systemic Lupus Erythematosus 19.2 17.1 0.055 Rheumatoid Arthritis 15.8 14.5 0.034 Oral DMARDs (%)    Overall 16.0 17.4 0.038 Systemic Lupus Erythematosus 22.4 20.0 0.060 Rheumatoid Arthritis 15.6 17.3 0.045 Biologic DMARDs (%)    Overall 2.2 1.9 0.024 Systemic Lupus Erythematosus 1.1 1.4 0.028  16 Rheumatoid Arthritis 2.3 1.9 0.027 Healthcare Utilization    Number of hospitalizations, mean (SD)    Overall 0.6 (1.1) 0.4 (0.8) 0.202 Systemic Lupus Erythematosus 1.0 (1.8) 0.5 (0.9) 0.376 Rheumatoid Arthritis 0.6 (1.1) 0.4 (0.8) 0.189 Number of outpatient visits, mean (SD)    Overall 27.2 (19.7) 22.4 (15.5) 0.280 Systemic Lupus Erythematosus 36.2 (26.9) 26.0 (18.9) 0.457 Rheumatoid Arthritis 26.8 (19.1) 22.3 (15.3) 0.266 *Assessed within one year prior to matching\/index date.  1 SMD, standardized mean difference; DMARDs, disease-modifying anti-rheumatic drugs. 2 Includes azathioprine, methotrexate, mycophenolate, leflunomide, cyclosporine, 3 cyclophosphamide, or biologic DMARDs including belimumab, adalimumab, infliximab, 4 golimumab, certolizumab, etanercept, tocilizumab, abatacept, . 5 Cardiovascular medications include anti-hypertensives, cardiac glycosides, diuretics, anti-6 arrhythmics, and nitrates. 7  8  9   10  17 Table 2. Hydroxychloroquine Use and Cardiovascular Events According to 1 Hydroxychloroquine Exposure Status Among Patients with Systemic Lupus 2 Erythematosus and Rheumatoid Arthritis 3  4  Cases,  N Controls,  N Conditional Odds Ratio  (95% CI) Adjusted Conditional Odds Ratio* (95% CI) All Combined CV Events     Remote HCQ Users 1305 3385 1.0 (reference)  1.0 (reference)  Recent HCQ users 244 635 1.00 (0.85, 1.18) 0.93 (0.77, 1.13) Current HCQ users 1182 3449 0.88 (0.81, 0.97) 0.86 (0.77, 0.97) HCQ non-users 7537 22500 0.87 (0.81, 0.93) 0.96 (0.88, 1.04) All Myocardial Infarction         Remote HCQ Users 566 1411 1.0 (reference)  1.0 (reference)  Recent HCQ users 98 242 1.00 (0.78, 1.29) 1.12 (0.82, 1.53) Current HCQ users 517 1495 0.85 (0.74, 0.98) 0.88 (0.74, 1.05) HCQ non-users 3208 9753 0.81 (0.73, 0.91) 0.98 (0.85, 1.12) All Stroke\/TIA         Remote HCQ Users 536 1474 1.0 (reference)  1.0 (reference)  Recent HCQ users 91 249 0.99 (0.76, 1.29) 0.83 (0.61, 1.12) Current HCQ users 435 1401 0.86 (0.74, 0.99) 0.87 (0.74, 1.03) HCQ non-users 3178 9340 0.95 (0.85, 1.05) 1.00 (0.88, 1.13) All Venous Thromboembolism     Remote HCQ Users 321 785 1.0 (reference)  1.0 (reference)  Recent HCQ users 60 155 0.94 (0.68, 1.31) 0.65 (0.44, 0.98) Current HCQ users 266 820 0.78 (0.64, 0.95) 0.74 (0.59, 0.94) HCQ non-users 1475 4475 0.80 (0.69, 0.93) 0.90 (0.75, 1.08) *Additionally adjusted for Charlson comorbidity index, prior CV disease, chronic kidney disease, glucocorticoid 5 use, DMARD use, cardiovascular medication use, anticoagulant use, and healthcare utilization including number of 6 hospitalizations and number of outpatient visits all assessed one year prior to the index date.  7 CV, cardiovascular; HCQ, hydroxychloroquine; TIA, transient ischemic attack 8 Exposure classifications: current use- last prescription date covered <90 days before index date; recent use- last 9 prescription date covered 90-365 days before index date; remote use- >365 days before index date 10  11  12  13  14 15  18 Figure 1. Forest Plots of Adjusted Odds Ratios for Cardiovascular Events Associated with 1 Current Hydroxychloroquine Use Versus Remote Use Among Patients with Systemic 2 Lupus Erythematosus and Rheumatoid Arthritis 3  4 Abbreviations: CV, cardiovascular; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; TIA, transient 5 ischemic attack 6  Supplementary Material: Hydroxychloroquine Use and Cardiovascular Events Among Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis Running Head: Hydroxychloroquine and Cardiovascular Events Authors: April Jorge, MD1; Leo Lu, MPH1, 2; Hyon Choi, MD, DrPH1; John M. Esdaile, MD, MPH2,3; Diane Lacaille, MD, MHSc2,3; J. Antonio Avina-Zubieta, MD, PhD2,3 Affiliations:  1Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital 2Arthritis Research Canada, Richmond, BC, Canada 3Divison of Rheumatology, University of British Columbia, Vancouver, BC, Canada  Corresponding Author:  J. Antonio Avina-Zubieta MD, FRCPC MSc, PhD 230-2238 Yukon Street Vancouver, BC V5Y 3P2 azubieta@arthritisresearch.ca                           Supplemental Table 1. Hydroxychloroquine Use and Cardiovascular Events According to Hydroxychloroquine Exposure Status and Rheumatic Disease   Cases, N Controls, N Conditional Odds Ratio (95% CI) Conditional Adjusted* Odds Ratio (95% CI) SLE Combined CV Events      Remote HCQ Users 110 232 1.0 (reference) 1.0 (reference) Recent HCQ users 32 69 1.05 (0.65-1.72) 1.11 (0.62-2.00) Current HCQ users 171 386 0.95 (0.71-1.28) 0.90 (0.62-1.29) HCQ non-users 219 562 0.78 (0.58-1.04) 0.78 (0.55-1.11) RA Combined CV Events     Remote HCQ Users 1195 3153 1.0 (reference) 1.0 (reference) Recent HCQ users 212 566 0.99 (0.84-1.18) 0.90 (0.73-1.11) Current HCQ users 1011 3063 0.87 (0.79-0.96) 0.86 (0.76-0.96) HCQ non-users 7318 21938 0.87 (0.81-0.94) 0.96 (0.88-1.05) SLE Myocardial Infarction     Remote HCQ Users 36 79 1.0 (reference) 1.0 (reference) Recent HCQ users 11 22 1.25 (0.53-2.94) 1.40 (0.45-4.42) Current HCQ users 60 140 0.91 (0.55-1.51) 1.01 (0.52-1.96) HCQ non-users 91 210 0.86 (0.53-2.37) 1.11 (0.59-2.10) RA Myocardial Infarction     Remote HCQ Users 530 1332 1.0 (reference) 1.0 (reference) Recent HCQ users 87 220 0.98 (0.75-1.28) 1.11 (0.80-1.54) Current HCQ users 457 1355 0.84 (0.73-0.98) 0.87 (0.73-1.05) HCQ non-users 3117 9543 0.81 (0.73-1.17) 0.97 (0.85-1.12) SLE Stroke\/TIA     Remote HCQ Users 47 105 1.0 (reference) 1.0 (reference) Recent HCQ users 16 35 1.05 (0.53-2.07) 1.01 (0.45-2.28) Current HCQ users 69 153 1.11 (0.71-1.74) 0.95 (0.55-1.62) HCQ non-users 80 216 0.83 (0.53-1.29) 0.61 (0.36-1.04) RA Stroke\/TIA     Remote HCQ Users 489 1369 1.0 (reference) 1.0 (reference) Recent HCQ users 75 214 0.98 (0.74-1.30) 0.80 (0.58-1.10) Current HCQ users 399 1248 0.82 (0.70-0.96) 0.84 (0.71-1.00) HCQ non-users 3098 9124 0.95 (0.85-1.06) 1.01 (0.89-1.15) SLE Venous Thromboembolism     Remote HCQ Users 43 94 1.0 (reference) 1.0 (reference) Recent HCQ users 14 29 1.15 (0.54-2.47) 0.84 (0.30-2.34) Current HCQ users 55 159 0.75 (0.45-1.24) 0.67 (0.34-1.28) HCQ non-users 80 204 0.83 (0.52-1.32) 0.89 (0.48-1.64) RA Venous Thromboembolism     Remote HCQ Users 278 691 1.0 (reference) 1.0 (reference) Recent HCQ users 46 126 0.90 (0.62-1.30) 0.63 (0.41-0.99) Current HCQ users 211 661 0.79 (0.64-0.97) 0.76 (0.59-0.98) HCQ non-users 1395 4271 0.80 (0.68-0.93) 0.91 (0.75-1.10) *Additionally adjusted for Charlson comorbidity index, prior CV disease, chronic kidney disease, glucocorticoid use, DMARD use, cardiovascular medication use, anticoagulant use, and healthcare utilization including number of hospitalizations and number of outpatient visits all assessed one year prior to the index date.  Exposure classifications: current use- last prescription date covered <90 days before index date; recent use- last prescription date covered 90-365 days before index date; remote use- >365 days before index date   Supplemental Table 2. Hydroxychloroquine Use and Cardiovascular Events According to Hydroxychloroquine Exposure Status Among Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis, Alternate Exposure Classification   Cases, N Controls, N Conditional Odds Ratio  (95% CI) Conditional Adjusted* Odds Ratio (95% CI) All Combined CV Events     Remote HCQ Users 1305 3385 1.0 (reference) 1.0 (reference) Recent HCQ users 359 857 1.09 (0.95-1.25) 0.99 (0.84-1.18) Current HCQ users 1067 3327 0.85 (0.78-0.94) 0.85 (0.76-0.95) HCQ non-users 7537 22500 0.87 (0.81-0.93) 0.96 (0.84-1.18) All Myocardial Infarction     Remote HCQ Users 480 1384 1.0 (reference) 1.0 (reference) Recent HCQ users 135 353 0.94 (0.75-1.18) 1.03 (0.79-1.36) Current HCQ users 566 1411 0.85 (0.74-0.98) 0.88 (0.74-1.06) HCQ non-users 3208 9753 0.81 (0.73-0.91) 0.98 (0.85-1.12) All Stroke\/TIA     Remote HCQ Users 536 1474 1.0 (reference) 1.0 (reference) Recent HCQ users 121 333 0.99 (0.79-1.25) 0.82 (0.63-1.07) Current HCQ users 405 1317 0.85 (0.73-0.99) 0.89 (0.75-1.05) HCQ non-users 3178 9340 0.95 (0.85-1.05) 1.00 (0.88-1.13) All Venous Thromboembolism     Remote HCQ Users 321 785 1.0 (reference) 1.0 (reference) Recent HCQ users 86 202 1.03 (0.77-1.37) 0.75 (0.52-1.06) Current HCQ users 240 773 0.75 (0.61-0.91) 0.73 (0.57-0.92) HCQ non-users 1475 4475 0.80 (0.77-1.37) 0.90 (0.75-1.08) *Additionally adjusted for Charlson comorbidity index, prior CV disease, chronic kidney disease, glucocorticoid use, DMARD use, cardiovascular medication use, anticoagulant use, and healthcare utilization including number of hospitalizations and number of outpatient visits all assessed one year prior to the index date.  CV, cardiovascular; HCQ, hydroxychloroquine; TIA, transient ischemic attack Exposure classifications: current use- last prescription date covered <30 days before index date; recent use- last prescription date covered 30-365 days before index date; remote use- >365 days before index date    Supplemental Table 3. Hydroxychloroquine Use and Cardiovascular Events According to Hydroxychloroquine Exposure Status Among Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis: Stratified Analysis by Duration of Hydroxychloroquine Use  All Combined CV Events Cases,  N Controls, N Conditional Odds Ratio (95% CI) Conditional Adjusted* Odds Ratio (95% CI) Duration of HCQ Use <1 Year     Remote HCQ Users 733 1816 1.0 (reference)  1.0 (reference)  Recent HCQ users 90 226 0.96 (0.73, 1.26) 0.94 (0.71, 1.24) Current HCQ users 213 569 0.91 (0.75, 1.10) 0.85 (0.70, 1.04) HCQ non-users 7537 22500 0.83 (0.75, 0.91) 0.92 (0.84, 1.02) Duration of HCQ Use  \u2265 1 Year     Remote HCQ Users 150 572 1.0 (reference)  1.0 (reference)  Recent HCQ users 154 409 1.04 (0.84, 1.29) 1.00 (0.80, 1.25) Current HCQ users 969 2880 0.92 (0.81, 1.04) 0.83 (0.73, 0.94) HCQ non-users 7537 22500 0.91 (0.82, 1.01) 1.01 (0.91, 1.12) *Additionally adjusted for Charlson comorbidity index, prior CV disease, chronic kidney disease, glucocorticoid use, DMARD use, cardiovascular medication use, anticoagulant use, and healthcare utilization including number of hospitalizations and number of outpatient visits all assessed one year prior to the index date.  CV, cardiovascular; HCQ, hydroxychloroquine; TIA, transient ischemic attack Exposure classifications: current use- last prescription date covered <90 days before index date; recent use- last prescription date covered 90-365 days before index date; remote use- >365 days before index date   ","@language":"en"}],"Genre":[{"@value":"Article","@language":"en"},{"@value":"Postprint","@language":"en"}],"IsShownAt":[{"@value":"10.14288\/1.0413682","@language":"en"}],"Language":[{"@value":"eng","@language":"en"}],"PeerReviewStatus":[{"@value":"Reviewed","@language":"en"}],"Provider":[{"@value":"Vancouver : University of British Columbia Library","@language":"en"}],"Publisher":[{"@value":"Wiley","@language":"en"}],"PublisherDOI":[{"@value":"10.1002\/acr.24850","@language":"en"}],"Rights":[{"@value":"Attribution-NonCommercial-NoDerivatives 4.0 International","@language":"*"}],"RightsURI":[{"@value":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/","@language":"*"}],"ScholarlyLevel":[{"@value":"Faculty","@language":"en"},{"@value":"Researcher","@language":"en"}],"Title":[{"@value":"Hydroxychloroquine Use and Cardiovascular Events Among Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis","@language":"en"}],"Type":[{"@value":"Text","@language":"en"}],"URI":[{"@value":"http:\/\/hdl.handle.net\/2429\/81622","@language":"en"}],"SortDate":[{"@value":"2021-12-23 AD","@language":"en"}],"@id":"doi:10.14288\/1.0413682"}