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ARD Online First, published on September 29, 2014 as 10.1136/annrheumdis-2014-205665 Clinical and epidemiological research
EXTENDED REPORT
The risk of deep venous thrombosis and pulmonary embolism in giant cell arteritis: a general population-based study J Antonio Aviña-Zubieta,1,2 Vidula M Bhole,1 Neda Amiri,2 Eric C Sayre,1 Hyon K Choi1,3 Handling editor Tore K Kvien 1
Arthritis Research Centre of Canada, Richmond, British Columbia, Canada 2 Division of Rheumatology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada 3 Department of Rheumatology, Division of Rheumatology, Allergy and Immunology, Harvard Medical School, Boston, USA Correspondence to Dr J Antonio Aviña-Zubieta, Arthritis Research Centre of Canada, University of British Columbia/Division of Rheumatology, 5591 No. 3 Road, Richmond, BC V6X 2C7, Canada;
[email protected] Received 1 April 2014 Revised 22 August 2014 Accepted 13 September 2014
ABSTRACT Importance Patients with giant cell arteritis (GCA) may have an increased risk of pulmonary embolism (PE), similar to other systemic vasculitidies; however, no relevant population data are available to date. Objective To evaluate the future risk and time trends of new venous thromboembolism (VTE) in individuals with incident GCA at the general population level. Design Observational cohort study. Setting General population of British Columbia. Participants 909 patients with incident GCA and 9288 age-matched, sex-matched and entry-timematched control patients without a history of VTE. Main outcome measures We calculated incidence rate ratios (IRR) overall, and stratified by GCA duration. We calculated HR of PE and deep vein thrombosis (DVT), adjusting for potential VTE risk factors. Results Among 909 individuals with GCA (mean age 76 years, 73% women), 18 developed PE and 20 developed DVT. Incidence rates (IR) of VTE, PE and DVT were 13.3, 7.7 and 8.5 per 1000 person-years (PY) in GCA cohort, versus 3.7, 1.9 and 2.2 per 1000 PY in the comparison cohort. The corresponding IRRs (95% CI) for VTE, PE and DVT were 3.58 (2.33 to 5.34), 3.98 (2.22 to 6.81) and 3.82 (2.21 to 6.34) with the highest IRR observed in the first year of GCA diagnosis (7.03, 7.23 and 7.85, respectively). Corresponding fully adjusted HRs (95% CI) were 2.49 (1.45 to 4.30), 2.71 (1.32 to 5.56) and 2.78 (1.39 to 5.54). Conclusions and significance These findings provide general population-based evidence that patients with GCA have an increased risk of VTE, calling for increased vigilance in preventing this serious, but preventable complication, especially within months after GCA diagnosis.
INTRODUCTION
To cite: Aviña-Zubieta JA, Bhole VM, Amiri N, et al. Ann Rheum Dis Published Online First: [ please include Day Month Year] doi:10.1136/annrheumdis2014-205665
Giant cell arteritis (GCA) is a systemic immunemediated disease characterised by granulomatous infiltrates in the walls of medium-sized and large arteries. GCA, the most frequent form of vasculitis in adults,1 is associated with significant morbidity due to vascular problems. For example, studies have found that GCA is associated with arterial complications like blindness,2 aortic aneurysms,3 myocardial infarction4–6 and ischaemic stroke.6–8 These previous studies have focused on arterial events, with the risk of venous thromboembolism (VTE) events in patients with GCA being largely ignored despite an array of plausible mechanisms.9 10
Systemic inflammation associated with GCA may modulate thrombotic responses by upregulating procoagulants, downregulating anticoagulants and suppressing fibrinolysis.10 Furthermore, myointimal thickening, stenosis or occlusion of vessel lumen may contribute to thrombosis.11 Additionally, thrombocytosis with platelet counts of >400 000/mm3 commonly occurs in active GCA and may also play a role.12–15 While a recent Swedish nationwide study of hospitalised patients described a 1.9 times increased risk of pulmonary embolism (PE) in patients with polymyalgia rheumatica (PMR),16 we are not aware of any large-scale or general population data on this outcome among patients with GCA. Since PE represents a common and often fatal vascular event,17 accurate understanding of this risk among this most common vasculitis syndrome is crucial. To address this issue, we evaluated the risk of incident PE and deep vein thrombosis (DVT) among patients with incident GCA compared with controls in an unselected general population context.
METHODS Data source We used a province-wide database (n=∼4.7 million) from the British Columbia (BC) healthcare system, which is based on universal health coverage. The Population Data (PopData) BC (formerly known as the British Columbia Linked Health Databases, BCLHD) captures population-based administrative data including linkable data files on all provincially funded healthcare professional visits, hospital admissions and discharges, interventions, investigations, demographic data, cancer registry and vital statistics since 1990. Furthermore, PopData BC encompasses the comprehensive prescription drug database, PharmaNet, with data since 1996. Numerous general population-based studies have been successfully conducted based on these databases.18–22
Study design We conducted matched cohort analyses for incident VTE (i.e., PE or DVT) among individuals with incident GCA (GCA cohort) as compared with individuals without GCA (comparison cohort) using data from PopData BC. For the comparison cohorts, we matched up to ten individuals without GCA to each GCA case based on age, sex and calendar year of study entry.
Aviña-Zubieta JA, et al. Ann Rheum 2014;0:1–7. doi:10.1136/annrheumdis-2014-205665 1 Copyright Article author (or their employer) 2014.DisProduced by BMJ Publishing Group Ltd (& EULAR) under licence.
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Clinical and epidemiological research Incident GCA cohort We created an incident GCA cohort with cases diagnosed for the first time between January 1996 and December 2010 with no GCA history or diagnosis recorded over the previous 6 years (i.e., from January 1990). Our study definition of GCA consisted of (1) ≥40 years of age; (2) one International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code for GCA by a rheumatologist (ICD-9-CM 446.5) or from hospital (ICD-9-CM 446.5, ICD-10 M31.5) or two ICD-9-CM codes for GCA at least 2 months and no more than 2 years apart by a nonrheumatologist physician; (3) at least one prescription of oral glucocorticoids between 1 month before and 6 months after the second GCA visit (or first visit if diagnosed in hospital or by a rheumatologist). Similar GCA definitions have been used previously in a general population database and found to have a positive predictive value of 91%.23 24 To further improve specificity, we excluded individuals with at least two visits greater than 2 months apart subsequent to the GCA diagnostic visit with other inflammatory disease diagnoses (e.g., rheumatoid arthritis, psoriatic arthritis, spondyloarthropathies, systemic lupus erythematosus and inflammatory myopathies). Moreover, in a sensitivity analysis, we used a more stringent definition of GCA that required five or more prescriptions of glucocorticoids.
Ascertainment of PE and DVT Incident PE and DVT cases were defined by a corresponding ICD code and prescription of anticoagulant therapy (heparin, warfarin sodium or a similar agent).25 The codes used were as follows: PE (ICD-9-CM: 415.1, 673.2, 639.6; ICD-10-CM: O88.2, I26) and DVT (ICD-9-CM: 453; ICD-10-CM: I82.4, I82.9). Since VTE is a potentially fatal disease, we also included patients with a fatal outcome. As a patient may have died before anticoagulation treatment, patients with a recorded code of DVT or PE were included in the absence of recorded anticoagulant therapy if there was a fatal outcome within 1 month of diagnosis. These definitions have been successfully used in previous studies and found to have a positive predictive value of 94% in a general practice database.25
Assessment of covariates Covariates consisted of potential risk factors for VTE assessed during the year before the index date. These included relevant medical conditions (alcoholism, hypertension, varicose veins, inflammatory bowel disease, fractures and sepsis), trauma, surgery, healthcare use, and use of glucocorticoids, hormone replacement therapy, contraceptives and COX-2 inhibitors. Additionally, a modified Charlson’s comorbidity index for administrative data was calculated in the year before index date.26 27
Cohort follow-up Our study cohorts spanned the period of 1 January 1996 to 31 December 2010. Individuals with GCA entered the case cohort after all inclusion criteria had been met, or after a matched doctor’s visit or hospital admission in the same calendar year for comparison cohort individuals. Participants were followed until they either experienced an outcome, died, dis-enrolled from the health plan (left BC) or the follow-up ended (31 December 2010), whichever occurred first.
Statistical analysis We compared baseline characteristics between the GCA and comparison cohorts. We calculated the incidence rates (IR) per 2
1000 person-years (PY) for respective outcomes for the GCA and comparison cohorts. The associations between GCA and study outcomes are expressed as incidence rate ratios (IRR) with 95% CIs. We calculated and plotted the cumulative IRs of endpoints for individuals with and without GCA accounting for the competing risk of death.28 To evaluate the time-trend of VTE risk according to the time since GCA diagnosis, we estimated IRRs during the first year and during the first 5 years. We also performed subgroup analyses according to age (age
