Hydroxychloroquine Use Is Associated With Decreased Incident Cardiovascular Events in Rheumatoid Arthritis Patients

Tarun S Sharma, Mary Chester M Wasko, Xiaoqin Tang, Deepak Vedamurthy, Xiaowei Yan, Jonida Cote, Androniki Bili, Tarun S Sharma, Mary Chester M Wasko, Xiaoqin Tang, Deepak Vedamurthy, Xiaowei Yan, Jonida Cote, Androniki Bili

Abstract

Background: Cardiovascular disease (CVD) is the leading cause of death in rheumatoid arthritis (RA) patients. This study is the first to report the association of hydroxychloroquine (an antirheumatic medication that has been associated with decreased risk of diabetes, a less atherogenic lipid profile, and antithrombotic properties) with CVD in RA.

Methods and results: A retrospective incident RA cohort from January 1, 2001, to October 31, 2013, excluding patients with CVD prior to RA diagnosis, was constructed. Patients were categorized as hydroxychloroquine users versus nonusers and were allowed to contribute time to either group according to hydroxychloroquine exposure. The primary outcome was adjudicated incident CVD defined as a composite of coronary artery disease, stroke, transient ischemic attack, sudden cardiac death, and peripheral artery disease with arterial revascularization procedure. The secondary outcome was a composite of incident coronary artery disease, stroke, and transient ischemic attack. Cox time-varying regression models were used to estimate the association between hydroxychloroquine exposure and development of CVD, after adjusting for propensity score and relevant confounders, including demographics, CVD-related comorbidities, RA severity, and activity indicators and medications. We included 1266 RA patients, 547 hydroxychloroquine users, and 719 nonusers. During the observation period, 102 CVD events occurred, 3 in hydroxychloroquine users and 99 in nonusers. The fully adjusted Cox model showed a hazard ratio of 0.28 (95% CI 0.12-0.63, P=0.002) for incident CVD and 0.30 (95% CI 0.13-0.68, P=0.004) for incident composite coronary artery disease, stroke, and transient ischemic attack for hydroxychloroquine users versus nonusers, respectively.

Conclusion: In this hypothesis-generating study, hydroxychloroquine use was associated with a 72% decrease in the risk of incident CVD in RA patients. If these preliminary results are confirmed in larger studies, our findings may be used as a rationale for a randomized study of hydroxychloroquine use for primary prevention of CVD in RA or nonrheumatic high-risk patients.

Keywords: cardiovascular diseases; hydroxychloroquine; primary prevention; rheumatoid arthritis.

© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1
Figure 1
Probability of incident CVD according to HCQ use. Kaplan–Meier survival curves: A solid curve represents the HCQ users, and a broken curve represents nonusers. CVD indicates cardiovascular disease; HCQ, hydroxychloroquine; RA, rheumatoid arthritis.

References

    1. Wolfe F, Mitchell DM, Sibley JT, Fries JF, Bloch DA, Williams CA, Spitz PW, Haga M, Kleinheksel SM, Cathey MA. The mortality of rheumatoid arthritis. Arthritis Rheum. 1994;37:481–494.
    1. Avina‐Zubieta JA, Abrahamowicz M, De Vera MA, Choi HK, Sayre EC, Rahman MM, Sylvestre MP, Wynant W, Esdaile JM, Lacaille D. Immediate and past cumulative effects of oral glucocorticoids on the risk of acute myocardial infarction in rheumatoid arthritis: a population‐based study. Rheumatology (Oxford). 2013;52:68–75.
    1. Solomon DH, Karlson EW, Rimm EB, Cannuscio CC, Mandl LA, Manson JE, Stampfer MJ, Curhan GC. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation. 2003;107:1303–1307.
    1. del Rincon I, Freeman GL, Haas RW, O'Leary DH, Escalante A. Relative contribution of cardiovascular risk factors and rheumatoid arthritis clinical manifestations to atherosclerosis. Arthritis Rheum. 2005;52:3413–3423.
    1. Solomon DH, Kremer J, Curtis JR, Hochberg MC, Reed G, Tsao P, Farkouh ME, Setoguchi S, Greenberg JD. Explaining the cardiovascular risk associated with rheumatoid arthritis: traditional risk factors versus markers of rheumatoid arthritis severity. Ann Rheum Dis. 2010;69:1920–1925.
    1. Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. See comment. Lancet. 2002;359:1173–1177.
    1. Bili A, Tang X, Pranesh S, Bozaite R, Morris SJ, Antohe JL, Kirchner HL, Wasko MC. Tumor necrosis factor alpha inhibitor use and decreased risk for incident coronary events in rheumatoid arthritis. Arthritis Care Res (Hoboken). 2014;66:355–363.
    1. Dixon WG, Watson KD, Lunt M, Hyrich KL; British Society for Rheumatology Biologics Register Control Centre Consortium , Silman AJ, Symmons DP; British Society for Rheumatology Biologics Register . Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti‐tumor necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum. 2007;56:2905–2912.
    1. Davis JM III, Maradit Kremers H, Crowson CS, Nicola PJ, Ballman KV, Therneau TM, Roger VL, Gabriel SE. Glucocorticoids and cardiovascular events in rheumatoid arthritis: a population‐based cohort study. Arthritis Rheum. 2007;56:820–830.
    1. Wasko MC, Hubert HB, Lingala VB, Elliott JR, Luggen ME, Fries JF, Ward MM. Hydroxychloroquine and risk of diabetes in patients with rheumatoid arthritis. JAMA. 2007;298:187–193.
    1. Solomon DH, Massarotti E, Garg R, Liu J, Canning C, Schneeweiss S. Association between disease‐modifying antirheumatic drugs and diabetes risk in patients with rheumatoid arthritis and psoriasis. JAMA. 2011;305:2525–2531.
    1. Bili A, Sartorius JA, Kirchner HL, Morris SJ, Ledwich LJ, Antohe JL, Dancea S, Newman ED, Wasko MC. Hydroxychloroquine use and decreased risk of diabetes in rheumatoid arthritis patients. J Clin Rheumatol. 2011;17:115–120.
    1. Morris SJ, Wasko MC, Antohe JL, Sartorius JA, Kirchner HL, Dancea S, Bili A. Hydroxychloroquine use associated with improvement in lipid profiles in rheumatoid arthritis patients. Arthritis Care Res (Hoboken). 2011;63:530–534.
    1. Achuthan S, Ahluwalia J, Shafiq N, Bhalla A, Pareek A, Chandurkar N, Malhota S. Hydroxychloroquine's efficacy as an antiplatelet agent study in healthy volunteers: a proof of concept study. J Cardiovasc Pharmacol Ther. 2015;20:174–180.
    1. Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97:1837–1847.
    1. van Halm VP, Nurmohamed MT, Twisk JW, Dijkmans BA, Voskuyl AE. Disease‐modifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study. Arthritis Res Ther. 2006;8:R151.
    1. Jung H, Bobba R, Su J, Shariati‐Sarabi Z, Gladman DD, Urowitz M, Lou W, Fortin PR. The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus. Arthritis Rheum. 2010;62:863–868.
    1. Rekedal LR, Massarotti E, Garg RK, Bhatia R, Lu B, Solomon DH. The effect of hydroxychloroquine and methotrexate on glycated hemoglobin. Arthritis Rheum. 2009;60(suppl 10):58.
    1. Mercer E, Rekedal L, Garg R, Lu B, Massarotti EM, Solomon DH. Hydroxychloroquine improves insulin sensitivity in obese non‐diabetic individuals. Arthritis Res Ther. 2012;14:R135.
    1. Kerr G, Aujero M, Richards J, Sayles H, Davis L, Cannon G, Caplan L, Michaud K, Mikuls T. Associations of hydroxychloroquine use with lipid profiles in rheumatoid arthritis: pharmacologic implications. Arthritis Care Res (Hoboken). 2014;66:1619–1626.
    1. Wu TK, Tsapogas MJ, Jordan FR. Prophylaxis of deep venous thrombosis by hydroxychloroquine sulfate and heparin. Surg Gynecol Obstet. 1977;145:714–718.
    1. Carter AE, Eban R. Prevention of postoperative deep venous thrombosis in legs by orally administered hydroxychloroquine sulphate. Br Med J. 1974;3:94–95.
    1. Hansen EH, Jessing P, Lindewald H, Ostergaard P, Olesen T, Malver EI. Hydroxychloroquine sulphate in prevention of deep venous thrombosis following fracture of the hip, pelvis, or thoracolumbar spine. J Bone Joint Surg Am. 1976;58:1089–1093.
    1. Petri M. Use of hydroxychloroquine to prevent thrombosis in systemic lupus erythematosus and in antiphospholipid antibody‐positive patients. Curr Rheumatol Rep. 2011;13:77–80.
    1. Coxib and traditional NSAID Trialists' (CNT) Collaboration , Bhala N, Emberson J, Merhi A, Abramson S, Arber N, Baron JA, Bombardier C, Cannon C, Farkouh ME, FitzGerald GA, Goss P, Halls H, Hawk E, Hawkey C, Hennekens C, Hochberg M, Holland LE, Kearney PM, Laine L, Lanas A, Lance P, Laupacis A, Oates J, Patrono C, Schnitzer TJ, Solomon S, Tugwell P, Wilson K, Wittes J, Baigent C. Vascular and upper gastrointestinal effects of non‐steroidal anti‐inflammatory drugs: meta‐analyses of individual participant data from randomised trials. Lancet. 2013;382:769–779.26.
    1. Antman EM, Bennett JS, Daugherty A, Furberg C, Roberts H, Taubert KA; American Heart Association . Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation. 2007;115:1634–1642.

Source: PubMed

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