CLINICAL RESEARCH STUDY
Risk of Venous Thromboembolism in Patients with Rheumatoid Arthritis: Initiating Disease-Modifying Antirheumatic Drugs Seoyoung C. Kim, MD, MSCE, ScD,a,b,c Daniel H. Solomon, MD, MPH,a,b Jun Liu, MD, MPH,a Jessica M. Franklin, PhD,a Robert J. Glynn, ScD, PhD,a Sebastian Schneeweiss, MD, ScDa,c a Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Boston, Mass; bDivision of Rheumatology, Allergy and Immunology, Brigham and Women’s Hospital, Boston, Mass; cDepartment of Epidemiology, Harvard School of Public Health, Boston, Mass.
ABSTRACT OBJECTIVES: Recent research suggests that rheumatoid arthritis increases the risk of venous thromboembolism. This study compared the risk of venous thromboembolism in patients with newly diagnosed rheumatoid arthritis initiating a biologic disease-modifying antirheumatic drug (DMARD) with those initiating methotrexate or a nonbiologic DMARD. METHODS: We conducted a population-based cohort study using US insurance claims data (2001-2012). Three mutually exclusive, hierarchical DMARD groups were used: (1) a biologic DMARD with and without nonbiologic DMARDs; (2) methotrexate without a biologic DMARD; or (3) nonbiologic DMARDs without a biologic DMARD or methotrexate. We calculated the incidence rates of venous thromboembolism. Cox proportional hazard models stratified by propensity score (PS) deciles after asymmetric PS trimming were used for 3 pairwise comparisons, controlling for potential confounders at baseline. RESULTS: We identified 29,481 patients with rheumatoid arthritis with 39,647 treatment episodes. From the pairwise comparison after asymmetric PS trimming, the incidence rate of hospitalization for venous thromboembolism per 1000 person-years was 5.5 in biologic DMARD initiators versus 4.4 in nonbiologic DMARD initiators and 4.8 in biologic DMARD initiators versus 3.5 in methotrexate initiators. The PS decile-stratified hazard ratio of venous thromboembolism associated with biologic DMARDs was 1.83 (95% confidence interval [CI], 0.91-3.66) versus nonbiologic DMARDs and 1.39 (95% CI, 0.73-2.63) versus methotrexate. The hazard ratio of venous thromboembolism in biologic DMARD initiators was the highest in the first 180 days versus nonbiologic DMARD initiators (2.48; 95% CI, 1.14-5.39) or methotrexate initiators (1.80; 95% CI, 0.90-3.62). CONCLUSIONS: The absolute risk for venous thromboembolism was low in patients with newly diagnosed rheumatoid arthritis. Initiation of a biologic DMARD seems to be associated with an increased short-term risk of hospitalization for venous thromboembolism compared with initiation of a nonbiologic DMARD or methotrexate. Ó 2015 Elsevier Inc. All rights reserved. The American Journal of Medicine (2015) 128, 539.e7-539.e17 KEYWORDS: Disease-modifying antirheumatic drugs; Rheumatoid arthritis; Venous thromboembolism
Several studies recently showed that patients with rheumatoid arthritis have a 1.5 to 6 times increased risk of venous Funding: See last page of article. Conflict of Interest: See last page of article. Authorship: See last page of article. Requests for reprints should be addressed to Seoyoung C. Kim, MD, ScD, MSCE, 1620 Tremont St, Suite 3030, Boston MA 02120. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2014.11.025
thromboembolism, including pulmonary embolism and deep vein thrombosis.1-5 It is thought that active systemic inflammation may lead to the development of venous thromboembolism because inflammatory cytokines such as interleukin-6, interleukin-8, and tumor necrosis factor (TNF)-a activate coagulation pathways and thus alter thrombotic tendency.6,7 To date, limited evidence is available on whether treatment of rheumatoid arthritis with any
539.e8
The American Journal of Medicine, Vol 128, No 5, May 2015
disease-modifying antirheumatic drugs (DMARDs) or a rheumatoid arthritis diagnosis and to be free of any DMARD specific type of DMARD, such as biologic DMARDs dispensing any time before their first rheumatoid arthritis including TNF-a inhibitors, increases or decreases the risk diagnosis. Patients were also required to have less than of venous thromboembolism. Although several studies 365 days between the first rheumatoid arthritis diagnosis and report cases of venous thromboembolism or peripheral the first DMARD dispensing. Subjects with malignancies, thrombosis after treatment with TNF-a inhibitors for rheuprior venous thromboembolism, or dispensing for an matoid arthritis or other inflamanticoagulant any time before their matory diseases,8-12 a few small index date were excluded CLINICAL SIGNIFICANCE studies found that TNF-a (Supplementary Table 1, blockade with infliximab in paavailable online). Initiation of a biologic diseasetients with rheumatoid arthritis modifying antirheumatic drug (DMARD) decreases inflammatory and coagseems to be associated with an increased Disease-Modifying ulation markers and reduces the short-term risk of hospitalization for 13,14 Antirheumatic Drug inhibition of fibrinolysis. venous thromboembolism compared Furthermore, a cohort study Exposures with initiation of a nonbiologic DMARD based on the British Society for We defined 3 mutually exclusive, or methotrexate. Rheumatology Biologics Register hierarchical groups of DMARDs: (BSRBR) showed no significant (1) a biologic DMARD with and The absolute risk of hospitalization for association between TNF-a inwithout methotrexate or other venous thromboembolism was low in hibitors and venous thromboemnonbiologic DMARDs; (2) methpatients with rheumatoid arthritis initibolism in patients with rheumatoid otrexate with and without other ating biologic DMARDs or nonbiologic arthritis.15 nonbiologic DMARDs; or (3) 1 or DMARDs. On the basis of the potential more nonbiologic DMARDs other link between DMARD treatment than methotrexate (Supplementary and thrombosis, we examined the Table 2, available online). risk of incident venous thromboembolism in patients with Subjects in the methotrexate group could not simultaneously newly diagnosed rheumatoid arthritis initiating a biologic use a biologic DMARD; however, they could use other DMARD, methotrexate, or other nonbiologic DMARDs. In nonbiologic DMARDs (eg, triple therapy). The nonbiologic addition, we investigated both short- and long-term risks of DMARD group could not simultaneously use a biologic venous thromboembolism associated with the use of specific DMARD or methotrexate, but they could start more than 1 DMARD treatment. other nonbiologic DMARD at the index date (eg, concurrent use of hydroxychloroquine and leflunomide). The date of initiating a DMARD in 1 of these 3 exposure groups was PATIENTS AND METHODS defined as the start of follow-up (ie, index date). Patients were also allowed to cross-over to a different DMARD Data Source category at their first switching. Therefore, all the included We conducted a cohort study using the claims data from 3 patients in this study were required to have had at least 2 commercial US health plans (2001-2012)—WellPoint, rheumatoid arthritis diagnoses and at least 1 filled prescription United HealthCare, and Aetna—which insure primarily for a DMARD at the start of follow-up. A previous validation working adults and their family members across the United study showed that patients with rheumatoid arthritis can be States. These databases contain longitudinal claims inforidentified accurately using a combination of diagnosis codes mation, including medical diagnoses, procedures, hospitalfor rheumatoid arthritis and DMARD prescriptions in claims izations, physician visits, and pharmacy dispensing. data with a positive predictive value greater than 86%.16 Personal identifiers were removed from the dataset before For a given DMARD category, patients were followed up the analysis to protect subject confidentiality. Therefore, until discontinuing the drug or switching to a different patient informed consent was not required. The study proDMARD category (ie, “as treated” analysis), the occurrence tocol was approved by the Institutional Review Board of of venous thromboembolism, the loss of health plan eligiBrigham and Women’s Hospital. bility, the end of study period, or death. In the case of drug discontinuation, the exposure risk window for each patient Study Cohort treatment episode extended until 30 days after the expiration Adults aged 18 years or more with at least 2 visits, which of the supply of the last fill. Patients were allowed to enter were 7 to 365 days apart, coded with the International the study cohort up to 2 times. Classification of Diseases, 9th Revision, Clinical Modification code 714.xx, for rheumatoid arthritis, were identiOutcome Definition fied. To identify patients with newly diagnosed rheumatoid arthritis, patients were required to have a minimum of 12 We defined the venous thromboembolism event as a hosmonths of continuous insurance eligibility before the first pitalization for venous thromboembolism, either deep vein
Kim et al
Use of DMARDs and Venous Thromboembolism
thrombosis or pulmonary embolism, based on the primary discharge diagnosis code. The positive predictive value of a hospital discharge diagnosis code for venous thromboembolism listed in Supplementary Table 1, available online, in identifying venous thromboembolism cases was at least 93% in previous studies.17,18
Potential Confounders Variables potentially related to the initiation of DMARDs or risk factors for venous thromboembolism were assessed using data from the 12-month baseline period before the index date (ie, the date of the first DMARD dispensing or switching to another DMARD category). These variables included age; sex; comorbidities (eg, diabetes, obesity, chronic kidney disease, heart failure, cardiovascular disease, extremity fracture, and surgeries); medications, including oral contraceptives, steroids, and antiplatelet drugs; and health care use factors (Table 1).19,20 To quantify patients’ comorbidities at baseline, we also calculated a comorbidity score that combined 20 medical conditions included in both the Charlson Index and the Elixhauser system based on International Classification of Diseases, 9th Revision.21 This comorbidity score is a summative score and ranges from 2 to 26.21
Statistical Analyses We compared the baseline characteristics among initiators of each DMARD group. To control for potential confounders, we used propensity score (PS) methods.22 The PS, a balancing score, is the conditional probability of assignment to a particular drug or treatment given a vector of observed covariates.23 Multivariable logistic regression models that included all the baseline covariates, the index year, an indicator for a DMARD initiation versus switching, and the number of days between the first rheumatoid arthritis diagnosis and the index date were used to estimate the PS for 3 pairwise comparisons, defined as the predicted probability of a patient receiving biologic DMARD versus nonbiologic DMARD, biologic DMARD versus methotrexate, or methotrexate versus nonbiologic DMARD. Prior research showed that the inclusion of variables that are unrelated to the treatment but related to the outcome in the PS model would decrease the variance of an estimated treatment effect without increasing bias.24 For the primary analysis, patients were grouped into PS deciles after excluding those in the nonoverlapping parts of the PS distribution. We used asymmetric trimming with the cut-point at the 2.5th and 97.5th percentiles of the PS distribution in the exposed and unexposed for each comparison.25 Incidence rates of venous thromboembolism were calculated with 95% confidence intervals (CIs) in each group for each pairwise comparison. PS decilestratified Cox proportional hazard models compared the risk of venous thromboembolism between each DMARD comparison. For the secondary analysis, we used the nearest neighbor PS matching method within a “caliper” of 0.05 on the PS
539.e9 with a variable matching ratio of 1:1 to 1:7.26-28 To minimize potential confounding by differences in the follow-up time between the PS matched groups, we used the matched cohort methods, in which Cox regression models stratified by the PS matching set estimated the hazard ratio (HR) of venous thromboembolism from each comparison.29,30 Because patients could contribute more than 1 treatment episode, we calculated robust standard errors using the robust “sandwich” variance estimator.31 To examine the short- and long-term effect of DMARDs on venous thromboembolism, we also conducted a separate PS decilestratified Cox proportional hazards regression analysis for the follow-up period of 0 to 180 days, 181 to 365 days, 365 to 730 days, and 730 days or more. The proportional hazards assumption was tested using the Kolmogorov supremum test and was not violated in any models.32 All analyses were performed using SAS 9.2 statistical software (SAS Institute Inc, Cary, NC).
RESULTS Cohort Selection There were 272,613 patients with at least 1 diagnosis for rheumatoid arthritis with at least 12 months of continuous insurance eligibility in our databases. After applying exclusion criteria, our final cohort included 29,481 patients with newly diagnosed rheumatoid arthritis with 39,647 treatment episodes (5920 treatment episodes with biologic DMARDs, 17,614 treatment episodes with methotrexate, and 16,113 treatment episodes with nonbiologic DMARDs) before asymmetric trimming based on the pairwise PS distribution (Figure 1). Of these, 27% of biologic DMARD treatment episodes, 80% of methotrexate treatment episodes, and 86% of nonbiologic DMARD treatment episodes were new initiation. The mean (standard deviation) follow-up time was 1.0 (1.1) years for biologic DMARDs, 0.7 (0.8) year for methotrexate, and 0.6 (0.7) year for nonbiologic DMARDs. On average, patients contributed to 1.34 (standard deviation, 0.48) treatment episodes. In the secondary PS matched analysis, we compared 3794 treatment episodes with biologic DMARDs versus 12,204 nonbiologic DMARDs, 3794 treatment episodes with biologic DMARDs versus 12,204 with methotrexate, and 13,904 treatment episodes with methotrexate versus 16,113 nonbiologic DMARDs. The mean follow-up time was similar to the main cohort before asymmetric trimming.
Patient Characteristics The baseline characteristics of the study cohort per DMARD group before asymmetric trimming are presented in Table 1. The mean age was 49 years for biologic DMARD and nonbiologic DMARD initiators and 51 years for methotrexate initiators. Overall baseline demographic factors, comorbidities, medication, and health care use were similar across the groups. However, the cumulative
539.e10 Table 1
The American Journal of Medicine, Vol 128, No 5, May 2015 Baseline Characteristics of the Study Cohort 12 Months Before Initiation of Disease-Modifying Antirheumatic Drugs
Treatment Episodes N (%) or mean SD Follow-up periods, y Demographic Age, y Female Comorbidities Comorbidity Index Diabetes Obesity Smoking Varicose vein Chronic kidney disease Liver disease Hypertension Cardiovascular disease Stroke Lung disease Heart failure Pregnancy Hyperlipidemia Extremity fractures Surgery, musculoskeletal Surgery, cardiovascular Surgery, intra-abdominal Medications Antiplatelet drugs Statins Hormone replacement therapy Oral contraceptives Non-oral contraceptives Recent steroid use† Cumulative steroid dose‡ (mg) NSAIDs Coxibs Opioids Health care use No. of total physician visits No. of hospitalizations Length of hospitalizations, d No. of prescription drugs No. of emergency department visits No. of ordered CRP tests No. of ordered ESR tests
Biologic DMARDs
Methotrexate
Nonbiologic DMARDs
5920
17,614
16,113
1.0 1.1
0.7 0.8
0.6 0.7
48.9 12.1 69.5*
50.7 11.9* 72.0*
49.2 12.3 76.4
0.3 1.1 695 (12) 393 (7) 601 (10) 54 (1) 137 (2) 303 (5) 2002 (34) 340 (6) 148 (3)* 825 (14)* 94 (2) 118 (2) 1962 (33)* 218 (4)* 292 (5)* 113 (2) 360 (6)
0.2 1.0* 2207 (13)* 1171 (7) 1755 (10) 195 (1) 331 (2)* 614 (3)* 6532 (36) 1140 (6) 555 (3) 2398 (14)* 281 (2) 305 (2)* 6420 (36) 513 (3) 754 (4)* 323 (2) 954 (5)*
0.3 1.2 1853 (12) 1048 (7) 1649 (10) 187 (1) 394 (2) 851 (5) 5648 (35) 972 (6) 540 (3) 2490 (15) 295 (2) 357 (2) 5759 (36) 513 (3) 620 (4) 288 (2) 1012 (6)
132 (2) 903 (15)* 415 (7)* 501 (8)* 65 (1) 2421 (41)* 596.0 1080.7* 3401 (57) 866 (15)* 3027 (51)*
476 (3) 3060 (17) 1388 (8)* 1276 (7)* 152 (1)* 7262 (41)* 361.8 751.7* 10,660 (61)* 2363 (13) 8676 (49)*
400 (2) 2704 (17) 1454 (9) 1566 (10) 201 (1) 5233 (32) 298.1 646.9 9098 (56) 2072 (13) 7715 (48)
12.1 7.5* 0.2 0.6 5.8 18.4 10.5 6.5* 0.4 1.0 1.7 1.9* 2.3 2.1*
9.8 0.2 7.1 9.0 0.4 0.9 1.4
6.6* 0.5* 36.9 6.2* 1.0 1.1* 1.3*
10.6 7.2 0.2 0.6 6.3 25.9 9.7 6.6 0.4 1.0 1.0 1.2 1.5 1.4
CRP ¼ C-reactive protein; DMARD ¼ disease-modifying antirheumatic drug; ESR ¼ erythrocyte sedimentation rate; NSAID ¼ non-selective non-steroidal anti-inflammatory drug; SD ¼ standard deviation. *P value is
Risk of Venous Thromboembolism in Patients with Rheumatoid Arthritis: Initiating Disease-Modifying Antirheumatic Drugs Seoyoung C. Kim, MD, MSCE, ScD,a,b,c Daniel H. Solomon, MD, MPH,a,b Jun Liu, MD, MPH,a Jessica M. Franklin, PhD,a Robert J. Glynn, ScD, PhD,a Sebastian Schneeweiss, MD, ScDa,c a Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Boston, Mass; bDivision of Rheumatology, Allergy and Immunology, Brigham and Women’s Hospital, Boston, Mass; cDepartment of Epidemiology, Harvard School of Public Health, Boston, Mass.
ABSTRACT OBJECTIVES: Recent research suggests that rheumatoid arthritis increases the risk of venous thromboembolism. This study compared the risk of venous thromboembolism in patients with newly diagnosed rheumatoid arthritis initiating a biologic disease-modifying antirheumatic drug (DMARD) with those initiating methotrexate or a nonbiologic DMARD. METHODS: We conducted a population-based cohort study using US insurance claims data (2001-2012). Three mutually exclusive, hierarchical DMARD groups were used: (1) a biologic DMARD with and without nonbiologic DMARDs; (2) methotrexate without a biologic DMARD; or (3) nonbiologic DMARDs without a biologic DMARD or methotrexate. We calculated the incidence rates of venous thromboembolism. Cox proportional hazard models stratified by propensity score (PS) deciles after asymmetric PS trimming were used for 3 pairwise comparisons, controlling for potential confounders at baseline. RESULTS: We identified 29,481 patients with rheumatoid arthritis with 39,647 treatment episodes. From the pairwise comparison after asymmetric PS trimming, the incidence rate of hospitalization for venous thromboembolism per 1000 person-years was 5.5 in biologic DMARD initiators versus 4.4 in nonbiologic DMARD initiators and 4.8 in biologic DMARD initiators versus 3.5 in methotrexate initiators. The PS decile-stratified hazard ratio of venous thromboembolism associated with biologic DMARDs was 1.83 (95% confidence interval [CI], 0.91-3.66) versus nonbiologic DMARDs and 1.39 (95% CI, 0.73-2.63) versus methotrexate. The hazard ratio of venous thromboembolism in biologic DMARD initiators was the highest in the first 180 days versus nonbiologic DMARD initiators (2.48; 95% CI, 1.14-5.39) or methotrexate initiators (1.80; 95% CI, 0.90-3.62). CONCLUSIONS: The absolute risk for venous thromboembolism was low in patients with newly diagnosed rheumatoid arthritis. Initiation of a biologic DMARD seems to be associated with an increased short-term risk of hospitalization for venous thromboembolism compared with initiation of a nonbiologic DMARD or methotrexate. Ó 2015 Elsevier Inc. All rights reserved. The American Journal of Medicine (2015) 128, 539.e7-539.e17 KEYWORDS: Disease-modifying antirheumatic drugs; Rheumatoid arthritis; Venous thromboembolism
Several studies recently showed that patients with rheumatoid arthritis have a 1.5 to 6 times increased risk of venous Funding: See last page of article. Conflict of Interest: See last page of article. Authorship: See last page of article. Requests for reprints should be addressed to Seoyoung C. Kim, MD, ScD, MSCE, 1620 Tremont St, Suite 3030, Boston MA 02120. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2014.11.025
thromboembolism, including pulmonary embolism and deep vein thrombosis.1-5 It is thought that active systemic inflammation may lead to the development of venous thromboembolism because inflammatory cytokines such as interleukin-6, interleukin-8, and tumor necrosis factor (TNF)-a activate coagulation pathways and thus alter thrombotic tendency.6,7 To date, limited evidence is available on whether treatment of rheumatoid arthritis with any
539.e8
The American Journal of Medicine, Vol 128, No 5, May 2015
disease-modifying antirheumatic drugs (DMARDs) or a rheumatoid arthritis diagnosis and to be free of any DMARD specific type of DMARD, such as biologic DMARDs dispensing any time before their first rheumatoid arthritis including TNF-a inhibitors, increases or decreases the risk diagnosis. Patients were also required to have less than of venous thromboembolism. Although several studies 365 days between the first rheumatoid arthritis diagnosis and report cases of venous thromboembolism or peripheral the first DMARD dispensing. Subjects with malignancies, thrombosis after treatment with TNF-a inhibitors for rheuprior venous thromboembolism, or dispensing for an matoid arthritis or other inflamanticoagulant any time before their matory diseases,8-12 a few small index date were excluded CLINICAL SIGNIFICANCE studies found that TNF-a (Supplementary Table 1, blockade with infliximab in paavailable online). Initiation of a biologic diseasetients with rheumatoid arthritis modifying antirheumatic drug (DMARD) decreases inflammatory and coagseems to be associated with an increased Disease-Modifying ulation markers and reduces the short-term risk of hospitalization for 13,14 Antirheumatic Drug inhibition of fibrinolysis. venous thromboembolism compared Furthermore, a cohort study Exposures with initiation of a nonbiologic DMARD based on the British Society for We defined 3 mutually exclusive, or methotrexate. Rheumatology Biologics Register hierarchical groups of DMARDs: (BSRBR) showed no significant (1) a biologic DMARD with and The absolute risk of hospitalization for association between TNF-a inwithout methotrexate or other venous thromboembolism was low in hibitors and venous thromboemnonbiologic DMARDs; (2) methpatients with rheumatoid arthritis initibolism in patients with rheumatoid otrexate with and without other ating biologic DMARDs or nonbiologic arthritis.15 nonbiologic DMARDs; or (3) 1 or DMARDs. On the basis of the potential more nonbiologic DMARDs other link between DMARD treatment than methotrexate (Supplementary and thrombosis, we examined the Table 2, available online). risk of incident venous thromboembolism in patients with Subjects in the methotrexate group could not simultaneously newly diagnosed rheumatoid arthritis initiating a biologic use a biologic DMARD; however, they could use other DMARD, methotrexate, or other nonbiologic DMARDs. In nonbiologic DMARDs (eg, triple therapy). The nonbiologic addition, we investigated both short- and long-term risks of DMARD group could not simultaneously use a biologic venous thromboembolism associated with the use of specific DMARD or methotrexate, but they could start more than 1 DMARD treatment. other nonbiologic DMARD at the index date (eg, concurrent use of hydroxychloroquine and leflunomide). The date of initiating a DMARD in 1 of these 3 exposure groups was PATIENTS AND METHODS defined as the start of follow-up (ie, index date). Patients were also allowed to cross-over to a different DMARD Data Source category at their first switching. Therefore, all the included We conducted a cohort study using the claims data from 3 patients in this study were required to have had at least 2 commercial US health plans (2001-2012)—WellPoint, rheumatoid arthritis diagnoses and at least 1 filled prescription United HealthCare, and Aetna—which insure primarily for a DMARD at the start of follow-up. A previous validation working adults and their family members across the United study showed that patients with rheumatoid arthritis can be States. These databases contain longitudinal claims inforidentified accurately using a combination of diagnosis codes mation, including medical diagnoses, procedures, hospitalfor rheumatoid arthritis and DMARD prescriptions in claims izations, physician visits, and pharmacy dispensing. data with a positive predictive value greater than 86%.16 Personal identifiers were removed from the dataset before For a given DMARD category, patients were followed up the analysis to protect subject confidentiality. Therefore, until discontinuing the drug or switching to a different patient informed consent was not required. The study proDMARD category (ie, “as treated” analysis), the occurrence tocol was approved by the Institutional Review Board of of venous thromboembolism, the loss of health plan eligiBrigham and Women’s Hospital. bility, the end of study period, or death. In the case of drug discontinuation, the exposure risk window for each patient Study Cohort treatment episode extended until 30 days after the expiration Adults aged 18 years or more with at least 2 visits, which of the supply of the last fill. Patients were allowed to enter were 7 to 365 days apart, coded with the International the study cohort up to 2 times. Classification of Diseases, 9th Revision, Clinical Modification code 714.xx, for rheumatoid arthritis, were identiOutcome Definition fied. To identify patients with newly diagnosed rheumatoid arthritis, patients were required to have a minimum of 12 We defined the venous thromboembolism event as a hosmonths of continuous insurance eligibility before the first pitalization for venous thromboembolism, either deep vein
Kim et al
Use of DMARDs and Venous Thromboembolism
thrombosis or pulmonary embolism, based on the primary discharge diagnosis code. The positive predictive value of a hospital discharge diagnosis code for venous thromboembolism listed in Supplementary Table 1, available online, in identifying venous thromboembolism cases was at least 93% in previous studies.17,18
Potential Confounders Variables potentially related to the initiation of DMARDs or risk factors for venous thromboembolism were assessed using data from the 12-month baseline period before the index date (ie, the date of the first DMARD dispensing or switching to another DMARD category). These variables included age; sex; comorbidities (eg, diabetes, obesity, chronic kidney disease, heart failure, cardiovascular disease, extremity fracture, and surgeries); medications, including oral contraceptives, steroids, and antiplatelet drugs; and health care use factors (Table 1).19,20 To quantify patients’ comorbidities at baseline, we also calculated a comorbidity score that combined 20 medical conditions included in both the Charlson Index and the Elixhauser system based on International Classification of Diseases, 9th Revision.21 This comorbidity score is a summative score and ranges from 2 to 26.21
Statistical Analyses We compared the baseline characteristics among initiators of each DMARD group. To control for potential confounders, we used propensity score (PS) methods.22 The PS, a balancing score, is the conditional probability of assignment to a particular drug or treatment given a vector of observed covariates.23 Multivariable logistic regression models that included all the baseline covariates, the index year, an indicator for a DMARD initiation versus switching, and the number of days between the first rheumatoid arthritis diagnosis and the index date were used to estimate the PS for 3 pairwise comparisons, defined as the predicted probability of a patient receiving biologic DMARD versus nonbiologic DMARD, biologic DMARD versus methotrexate, or methotrexate versus nonbiologic DMARD. Prior research showed that the inclusion of variables that are unrelated to the treatment but related to the outcome in the PS model would decrease the variance of an estimated treatment effect without increasing bias.24 For the primary analysis, patients were grouped into PS deciles after excluding those in the nonoverlapping parts of the PS distribution. We used asymmetric trimming with the cut-point at the 2.5th and 97.5th percentiles of the PS distribution in the exposed and unexposed for each comparison.25 Incidence rates of venous thromboembolism were calculated with 95% confidence intervals (CIs) in each group for each pairwise comparison. PS decilestratified Cox proportional hazard models compared the risk of venous thromboembolism between each DMARD comparison. For the secondary analysis, we used the nearest neighbor PS matching method within a “caliper” of 0.05 on the PS
539.e9 with a variable matching ratio of 1:1 to 1:7.26-28 To minimize potential confounding by differences in the follow-up time between the PS matched groups, we used the matched cohort methods, in which Cox regression models stratified by the PS matching set estimated the hazard ratio (HR) of venous thromboembolism from each comparison.29,30 Because patients could contribute more than 1 treatment episode, we calculated robust standard errors using the robust “sandwich” variance estimator.31 To examine the short- and long-term effect of DMARDs on venous thromboembolism, we also conducted a separate PS decilestratified Cox proportional hazards regression analysis for the follow-up period of 0 to 180 days, 181 to 365 days, 365 to 730 days, and 730 days or more. The proportional hazards assumption was tested using the Kolmogorov supremum test and was not violated in any models.32 All analyses were performed using SAS 9.2 statistical software (SAS Institute Inc, Cary, NC).
RESULTS Cohort Selection There were 272,613 patients with at least 1 diagnosis for rheumatoid arthritis with at least 12 months of continuous insurance eligibility in our databases. After applying exclusion criteria, our final cohort included 29,481 patients with newly diagnosed rheumatoid arthritis with 39,647 treatment episodes (5920 treatment episodes with biologic DMARDs, 17,614 treatment episodes with methotrexate, and 16,113 treatment episodes with nonbiologic DMARDs) before asymmetric trimming based on the pairwise PS distribution (Figure 1). Of these, 27% of biologic DMARD treatment episodes, 80% of methotrexate treatment episodes, and 86% of nonbiologic DMARD treatment episodes were new initiation. The mean (standard deviation) follow-up time was 1.0 (1.1) years for biologic DMARDs, 0.7 (0.8) year for methotrexate, and 0.6 (0.7) year for nonbiologic DMARDs. On average, patients contributed to 1.34 (standard deviation, 0.48) treatment episodes. In the secondary PS matched analysis, we compared 3794 treatment episodes with biologic DMARDs versus 12,204 nonbiologic DMARDs, 3794 treatment episodes with biologic DMARDs versus 12,204 with methotrexate, and 13,904 treatment episodes with methotrexate versus 16,113 nonbiologic DMARDs. The mean follow-up time was similar to the main cohort before asymmetric trimming.
Patient Characteristics The baseline characteristics of the study cohort per DMARD group before asymmetric trimming are presented in Table 1. The mean age was 49 years for biologic DMARD and nonbiologic DMARD initiators and 51 years for methotrexate initiators. Overall baseline demographic factors, comorbidities, medication, and health care use were similar across the groups. However, the cumulative
539.e10 Table 1
The American Journal of Medicine, Vol 128, No 5, May 2015 Baseline Characteristics of the Study Cohort 12 Months Before Initiation of Disease-Modifying Antirheumatic Drugs
Treatment Episodes N (%) or mean SD Follow-up periods, y Demographic Age, y Female Comorbidities Comorbidity Index Diabetes Obesity Smoking Varicose vein Chronic kidney disease Liver disease Hypertension Cardiovascular disease Stroke Lung disease Heart failure Pregnancy Hyperlipidemia Extremity fractures Surgery, musculoskeletal Surgery, cardiovascular Surgery, intra-abdominal Medications Antiplatelet drugs Statins Hormone replacement therapy Oral contraceptives Non-oral contraceptives Recent steroid use† Cumulative steroid dose‡ (mg) NSAIDs Coxibs Opioids Health care use No. of total physician visits No. of hospitalizations Length of hospitalizations, d No. of prescription drugs No. of emergency department visits No. of ordered CRP tests No. of ordered ESR tests
Biologic DMARDs
Methotrexate
Nonbiologic DMARDs
5920
17,614
16,113
1.0 1.1
0.7 0.8
0.6 0.7
48.9 12.1 69.5*
50.7 11.9* 72.0*
49.2 12.3 76.4
0.3 1.1 695 (12) 393 (7) 601 (10) 54 (1) 137 (2) 303 (5) 2002 (34) 340 (6) 148 (3)* 825 (14)* 94 (2) 118 (2) 1962 (33)* 218 (4)* 292 (5)* 113 (2) 360 (6)
0.2 1.0* 2207 (13)* 1171 (7) 1755 (10) 195 (1) 331 (2)* 614 (3)* 6532 (36) 1140 (6) 555 (3) 2398 (14)* 281 (2) 305 (2)* 6420 (36) 513 (3) 754 (4)* 323 (2) 954 (5)*
0.3 1.2 1853 (12) 1048 (7) 1649 (10) 187 (1) 394 (2) 851 (5) 5648 (35) 972 (6) 540 (3) 2490 (15) 295 (2) 357 (2) 5759 (36) 513 (3) 620 (4) 288 (2) 1012 (6)
132 (2) 903 (15)* 415 (7)* 501 (8)* 65 (1) 2421 (41)* 596.0 1080.7* 3401 (57) 866 (15)* 3027 (51)*
476 (3) 3060 (17) 1388 (8)* 1276 (7)* 152 (1)* 7262 (41)* 361.8 751.7* 10,660 (61)* 2363 (13) 8676 (49)*
400 (2) 2704 (17) 1454 (9) 1566 (10) 201 (1) 5233 (32) 298.1 646.9 9098 (56) 2072 (13) 7715 (48)
12.1 7.5* 0.2 0.6 5.8 18.4 10.5 6.5* 0.4 1.0 1.7 1.9* 2.3 2.1*
9.8 0.2 7.1 9.0 0.4 0.9 1.4
6.6* 0.5* 36.9 6.2* 1.0 1.1* 1.3*
10.6 7.2 0.2 0.6 6.3 25.9 9.7 6.6 0.4 1.0 1.0 1.2 1.5 1.4
CRP ¼ C-reactive protein; DMARD ¼ disease-modifying antirheumatic drug; ESR ¼ erythrocyte sedimentation rate; NSAID ¼ non-selective non-steroidal anti-inflammatory drug; SD ¼ standard deviation. *P value is
