DOI: 10.1111/eci.12502

ORIGINAL ARTICLE Multiple sclerosis increases the risk of venous thromboembolism: a nationwide cohort analysis Wei-Sheng Chung*,†,‡, Cheng-Li Lin§, Tzung-Chang Tsai¶, Wu-Huei Hsu** and Chia-Hung Kao**,†† * Department of Internal Medicine, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan, †Department of Health Services Administration, China Medical University, Taichung, Taiwan, ‡Department of Healthcare Administration, Central Taiwan University of Science and Technology, Taichung, Taiwan, §Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan, ¶Department of Neurology, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan, **Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan, ††Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan

ABSTRACT Objectives The purpose of this study was to evaluate the effects of multiple sclerosis (MS) on the risk of venous thromboembolism (VTE) development. Methods We identified patients diagnosed with MS in Taiwan between 1998 and 2010 using the National Health Insurance Research Database and the Catastrophic Illness Patient Database (RCIPD). Each MS patient was frequency matched to 4 controls according to age, sex and the year of MS registration to the RCIPD. Patients with a history of VTE and incomplete information of age and sex were excluded. All patients were followed up from the index year until VTE diagnosis, loss to follow-up or the end of 2010. We calculated the hazard ratios (HRs) and 95% confidence intervals (CIs) of VTE in the MS and comparison cohorts using Cox proportional hazards regression models. Results We followed up 1238 MS patients and 4952 comparison patients for approximately 6437 and 27 595 person-years, respectively. After adjusting for age, sex and comorbidities, the MS patients exhibited a 6
87-fold increased risk of VTE compared with the control patients. Women with MS were associated with an 11
1-fold increased risk of VTE development compared with the non-MS women (95% CI: 2
70–45
5). The MS patients aged < 50 years exhibited a 14
8-fold increased risk of developing VTE compared with age-matched patients in the comparison cohort (95% CI: 2
99–73
4). The risk of VTE development increased with the duration of hospitalization stay. Conclusion MS patients are associated with significantly greater risk of developing VTE compared with non-MS patients. Keywords Catastrophic Illness Patient Database, multiple sclerosis (MS), National Health Insurance Research Database, venous thromboembolism (VTE). Eur J Clin Invest 2015; 45 (12): 1228–1233

Introduction Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease associated with damage to the insulating covers of nerve cells in the brain and spinal cord. This damage destroys the myelin and axons to various extents, leading to autonomic, visual, motor and sensory problems [1]. The course of MS can be fluctuating and unpredictable. In most patients, the disease is initially characterized by episodes of reversible neurological deficits, often followed by progressive neurological deterioration. The most widely accepted

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theory is that MS begins as an inflammatory autoimmune disorder mediated by autoreactive lymphocytes [2,3]. Subsequently, the disease is dominated by microglial activation and chronic neurodegeneration [1]. Most studies on MS have focused on treatment taxonomy and methods to improve the quality of life of MS patients [4–7]. Deep vein thrombosis (DVT) is a condition associated with the formation of blood clots in the deep vein, with thrombus predominantly occurring in the legs. DVT represents a serious problem because these blood clots can travel through the bloodstream to the pulmonary arteries and obstruct the

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MULTIPLE SCLEROSIS AND VENOUS THROMBOEMBOLISM

pulmonary blood flow. Pulmonary thromboembolism (PE) is a potentially life-threatening disorder. Together, DVT and PE constitute venous thromboembolism (VTE), which has a 30-day case fatality rate of 11%–30% [8–10]. According to the Virchow’s triad, VTE is a condition that results from altered blood coagulation, stasis or abnormalities in the vessel wall [11,12]. Previous studies have identified multiple risk factors for VTE, including age, previous VTE episodes and cerebrovascular disease (CVA) [13–15]. Diabetes, leg fractures, major surgery and certain cancers are also associated with increased risk of VTE [16–19]. Although autoimmune disorders are not traditionally considered risk factors for VTE, recent studies have indicated associations between autoimmune diseases and the risk of VTE development [20,21]. However, previous research on the risk of VTE in MS patients is limited. Therefore, we conducted a nationwide longitudinal cohort analysis to investigate the effects of MS on the risk of VTE development in Taiwan.

Methods Data sources The universal National Health Insurance (NHI) programme was implemented in Taiwan in 1995. It covers nearly 99% of the country’s 23
74 million residents and is contracted with 97% of the healthcare institutions for comprehensive health care [22]. In this study, a longitudinal analysis of a nationwide population-based cohort in Taiwan was conducted using the National Health Insurance Research Database (NHIRD). Details of the NHIRD have been published previously [21,23]. Insurance reimbursement claims used in this study were derived from the NHIRD, which is available for public access. To ensure confidentiality, all personal identification numbers are encrypted prior to release of the database to the public. For this study, we used a subset of the NHIRD containing healthcare data including files of inpatients claims, the Registry for Catastrophic Illness Patient Database (RCIPD) and registry of beneficiaries. This study was evaluated and approved by the Institutional Review Board of China Medical University and Hospital (CMU-REC-101-012). The International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) was used to define the diagnosis disease codes.

Study participants After examination of the medical claims, 1257 patients with a new diagnosis of MS (ICD-9-CM 340) were identified from RCIPD during 1998–2010. Patients with a history of DVT (ICD9-CM 453
8) or PE (ICD-9-CM 415
1 excluding iatrogenic PE ICD-9-CM 415
11) prior to the index date (n = 11) or missing information for age or sex were excluded (n = 8). The

remaining 1238 patients with MS were included in the MS cohort. The diagnostic criteria of MS included clinical and paraclinical laboratory assessments using magnetic resonance imaging (MRI) to demonstrate the dissemination of lesions of the central nervous system (CNS) in space and time and to exclude alternative diagnoses [24–26]. In Taiwan’s NHI program, MS is defined as a catastrophic disease. According to the regulations of the NHI program, insured beneficiaries with a catastrophic disease can apply for a catastrophic disease certificate to exempt them from copayment for their MS-related medical care. The Bureau of the NHI strictly reviews the applications and examines each applicant’s medical records, and laboratory and image studies. The MS patients’ dates of registration to the RCIPD were defined as their index dates for estimations of durations of follow-up. For each MS patient, 4 control patients were randomly selected from the whole insured population without MS and applied the same exclusion criteria used in selecting MS cohort. The index date for control patients was a randomly appointed month and day with the same index year of the matched MS cases. The non-MS controls were frequency matched with the MS patients by age (every 5year span), sex and the year of MS registration to the RCIPD. The same exclusion criteria were also applied to non-MS controls. Finally, a total of 1238 patients with MS and 4952 patients with non-MS were included in this study.

Outcome definition Follow-up began on the index date and continued until the diagnosis of VTE, withdrawal from the NHI program or the end of 2010. VTE was identified using the hospital discharge diagnosis. Pre-existing comorbidities included hypertension (ICD-9-CM 401-405), diabetes (ICD-9-CM 250), hyperlipidemia (ICD-9-CM 272), CVA (ICD-9-CM 430-438), lower leg fracture or surgery (ICD-9-CM 820-823 and procedure codes 81
51, 81
52, 81
53, 81
54), and cancer (ICD-9-CM 140-208).

Statistical analysis All statistical analyses were performed using the SAS package (Version 9.3 for Windows; SAS Institute, Inc., Cary, NC, USA). A 2-tailed P value < .05 was considered significant. Distributions of sex, age (≤ 34 year, 35–49 year, and ≥ 50 year) and comorbidities were compared between the MS and non-MS cohorts and examined using the chi-square test. The mean ages of both cohorts were measured and compared using the t-test. The follow-up times were used to estimate the incidence density rates of VTE in both cohorts. The MS cohort to non-MS cohort incidence rate ratio (IRR) and the 95% confidence intervals (CI) of VTE were estimated using the Poisson regression model. Multivariable Cox proportional hazard regression models were used to calculate the hazard ratios (HRs), with stratification based on age, sex, the presence of comorbidity and

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the severity of MS. The multivariable models simultaneously adjusted for age, sex and comorbidities of hypertension, diabetes, hyperlipidemia, CVA, lower leg fracture or surgery, and cancer. The Kaplan–Meier method was applied to estimate the VTE-free rates, and the log-rank test was used to examine the statistical significance of the differences between the 2 cohorts. In further analysis, we have addressed the attributable risk and 95% CI from MS. The risk of VTE associated with the length of stay due to MS was also assessed. The length of stay was defined as the total duration of hospitalization stay for MS during the follow-up period divided by the entire duration of follow-up in years. We further classified the length of stay into the first tertile ≤ 2
47 day/year, the second tertile 2
47–12
45 day/year and the third tertile > 12
45 day/year.

Results Characteristics of the study participants Table 1 displays the demographic characteristics and comorbidities of the 2 cohorts. The MS cohort contained 1238 patients, and the non-MS cohort contained 4952 control Table 1 Comparisons in demographic characteristics and comorbidities in patient with and without multiple sclerosis Multiple sclerosis

patients, identified from 1998 to 2010. Most participants were women (n = 941, 76
0% in both cohorts) and aged < 50 years (n = 983, 79
4% in both cohorts) (Table 1). The mean ages of the MS and non-MS cohorts were 37
8  13
9 and 37
9  14
0 years, respectively. The MS patients were more likely to have hypertension (8
40% vs. 2
34%), diabetes (4
93% vs. 1
45%), hyperlipidemia (5
82% vs. 0
71%), CVA (10
5% vs. 0
77%) and cancer (1
78% vs. 0
65%) than the control patients were. The mean duration of follow-up was 5
20  3
58 years in the MS cohort and 5
58  3
65 years in the non-MS cohort (P = .001, data not shown).

The risk of VTE in the MS and non-MS cohorts In total, 8 MS patients were diagnosed with VTE, yielding an incidence of 12
4 per 10 000 person-years, whereas 5 cases of VTE occurred in the comparison cohort, yielding an incidence of 1
81 per 10 000 person-years, with an adjusted HR of 6
87 (95% CI = 2
13–22
2). According to the sex-specific HR, women MS patients exhibited an 11
1-fold higher risk of developing VTE compared with non-MS women (adjusted HR = 11
1, 95% CI = 2
70–45
5). Compared with age-matched non-MS patients, the younger MS patients (≤ 49 year) had an IRR of 12
5 (95% CI = 9
96–15
6) and an adjusted HR of 14
8 (95% CI = 2
99– 73
4). In patients without comorbidity, the incidence of VTE was 20
7-fold higher in the MS cohort than in the non-MS cohort (15
5 vs. 0
75 per 10 000 person-years), with an adjusted HR of 23
8 (95% CI = 5
03–113
0) (Table 2). As shown in Fig. 1, the VTE-free rate was 1
16% lower in the MS cohort than in the non-MS cohort (98
7% vs. 99
9%; P < .0001) at the end of follow-up. We further stratified the length of stay of MS and observed an increasing trend in the association between the length of stay of MS and VTE risk (≤ 2
47 day/year: adjusted HR = 1
54, 95% CI: 0
17–13
6; 2
47–12
45 day/year: adjusted HR = 11
0, 95% CI: 2
51–48
6; > 12
45 day/year: adjusted HR = 16
0, 95% CI: 4
01–63
5) (Table 3).

No (N = 4952)

Yes (N = 1238)

P value

Women

3764 (76
0)

941 (76
0)

0
99

Men

1188 (24
0)

297 (24
0)

≤ 34

2280 (46
0)

570 (46
0)

35–49

1652 (33
4)

413 (33
4)

Attributable risks and 95% CIs

≥ 50

1020 (20
6)

255 (20
6)

Age, mean  SD*

37
9  14
0

37
8  13
9

The 52
5% of the VTE incidence in the MS cohort would be eliminated if the MS exposure were eliminated (95% CI = 11
7%–78
1%). In other words, the excess VTE due to MS was 52
5%.

Gender

Age stratified 0
99

0
85

Comorbidity 116 (2
34)

104 (8
40)

< 0
0001

Diabetes

72 (1
45)

61 (4
93)

< 0
0001

Discussion

Hyperlipidemia

35 (0
71)

72 (5
82)

< 0
0001

CVA

38 (0
77)

130 (10
5)

< 0
0001

Lower leg fracture or surgery

37 (0
75)

7 (0
57)

Cancer

32 (0
65)

22 (1
78)

In previous studies, the prevalence of MS was 1
9 per 100 000 people in Taiwan, which was lower than the prevalence of 100– 300 per 100 000 people identified in western countries [27,28]. In this nationwide population-based cohort study, we observed that the MS patients exhibited a 6
87-fold increased risk of VTE compared with the non-MS patients after adjusting for age, sex and comorbidities. Ramapogalan et al. evaluated patients

Hypertension

Chi-square test, *t-test.

1230

0
50 0
0001

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MULTIPLE SCLEROSIS AND VENOUS THROMBOEMBOLISM

Table 2 Comparison of incidence densities of venous thromboembolism and hazard ratio between with and without multiple sclerosis by demographic characteristics and comorbidity Multiple sclerosis No

Yes Rate†

Event

PY

Rate†

IRR (95% CI)

1
81

8

6437

12
4

6
87 (5
71, 8
27)***

6
87 (2
13, 22
2)**

21062

1
42

7

4877

14
4

10
1 (8
06, 12
6)***

11
1 (2
70, 45
5)***

2

6572

3
04

1

1560

2
11 (1
42, 3
13)***

3
09 (0
27, 35
1)

2

22179

0
90

6

5333

11
3

12
5 (9
96, 15
6)***

14
8 (2
99, 73
4)**

3

5454

5
50

2

1105

18
1

3
29 (2
17, 4
99)***

2
18 (0
28, 16
7)

No

2

26644

0
75

8

5157

15
5

20
7 (16
5, 25
9)***

23
8 (5
03, 113
0)***

Yes

3

990

30
3

0

1281

Event

PY

5

27634

Women

3

Men

All

Adjusted HR‡ (95% CI)

Gender

6
41

Stratify age ≤ 49 ≥ 50 §

Comorbidity

0
00

–

–

†

Rate, incidence rate, per 10 000 person-years; IRR, incidence rate ratio; ‡Adjusted HR: multiple analysis including age, gender and comorbidities; *P < 0
05, **P < 0
01, ***P < 0
001. § Comorbidity: Patients with any one of the comorbidities hypertension, diabetes, hyperlipidemia, CVA, lower leg fracture or surgery, and cancer were classified as the comorbidity group.

PY

Rate†

Adjusted HR‡ (95% CI)

5

27634

1
81

1(Reference)

T1

1

3810

2
62

1
54 (0
17, 13
6)

T2

3

1471

20
4

11
0 (2
51, 48
6)**

T3

4

1156

34
6

16
0 (4
01, 63
5)***

0·995

Length of stay Non-MS

Event

0·990

MS

Without multiple sclerosis With multiple sclerosis Log-rank test: P-value < 0·001

0·985

p for trend

< 0
0001

† Rate, incidence rate, per 1000 person-years; T1, first tertile ≤ 2
47 day/year; T2, second tertile 2
47–12
45 day/year; T3, third tertile > 12
45 day/year. Length of stay = (total length of hospital stay due to multiple sclerosis during the follow-up duration)  (length of follow-up duration). ‡ Adjusted HR: multiple analysis including age, gender and comorbidities; **P < 0
01, ***P < 0
001.

0·980

Probability free of venous thromboembolism

1·000

Table 3 Incidence and hazard ratio for venous thromboembolism stratified by the length of stay due to multiple sclerosis

0

2

4

6

8

10

12

14

Years

Figure 1 Probability free of venous thromboembolism for patients with (dashed line) or without (solid line) multiple sclerosis.

admitted to hospitals in England with various immune-mediated diseases and observed that the MS patients were associated with a 2
14-fold higher risk of developing VTE

compared with the control patients [20]. However, the authors did not adjust for comorbid medical illnesses when calculating the risk of VTE. Christensen et al. used data from the Danish National Registry of Patients to identify that MS was associated with increased risk of VTE, but the absolute risk of VTE was low [29]. The discrepancies in these studies’ findings might reflect true variations in disease occurrence among various populations and different environmental exposure [30–32].

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Although the MS patients in this study had a higher prevalence of comorbidities and coexistent conditions associated with the development of VTE than the comparison cohort, MS remains an independent risk factor for developing VTE after adjusting for covariates. Reduced limb mobility caused by MS might affect venous stasis because MS is a chronic neurodegenerative disorder [33]. The inflammatory mediators associated with prothrombotic factors and endothelial dysfunction are involved in the development of atherosclerosis and thrombosis [20,34]. Therefore, chronic inflammation might induce arterial, venous and microvascular thrombosis [35]. In this study, the majority of the MS patients were women. These women exhibited an 11
1-fold increased risk of developing VTE compared with the non-MS women after adjusting for covariates. This finding is consistent with those of previous studies [36]. Nearly, 80% of the MS patients were aged ≤ 49 years and displayed a 14
8-fold increased risk of VTE development compared with age-matched members of the non-MS cohort after adjusting for covariates. Because of pregnancy, differing hormonal status and distinct social roles, the effects of MS on women of reproductive age are substantial. Our findings emphasize the requirement for a multidisciplinary approach for the management of the potential risk factors for VTE among MS patients. In our study, the adjusted HR of VTE development increased with the duration of hospitalization stay. Therefore, the length of stay for MS-related hospitalization may be associated with MS severity and longer time in bed, which is associated with increased risk of VTE development. Ramagopalan et al. also suggested that people admitted to hospitals for autoimmune disorders might be associated with increased risk of subsequent VTE [20]. The strength of our study is its nationwide population-based longitudinal analysis of the risk of VTE in Asian MS patients. In addition, the diagnoses of all MS cases identified in the NHIRD claims data were confirmed by the RCIPD, which establishes a high level of reliability for our data. Because each resident in Taiwan is assigned a unique personal identification number, every patient could be traced through the records of the NHI programme for the entire follow-up period. However, several limitations should also be considered when interpreting our findings. First, the NHRID does not provide detailed information on cigarette smoking, body mass index and physical activity, which are all potential confounding factors. The absence of drug data, such as hormone replacement therapy, contraceptive drugs, glucocorticosteroid treatments and disease-modifying therapies, could also have potentially influenced our study’s primary outcomes. In conclusion, our nationwide population-based cohort study results indicate that MS patients are associated with a 6
87-fold increased risk of VTE development compared with non-MS

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patients. A multidisciplinary team should guide the assessment, treatment and holistic care of MS patients. Future studies on the biological mechanisms of MS are warranted to fully elucidate the contribution of the disease to the development of VTE.

Author contributions Conception/Design: Wei-Sheng Chung, Chia-Hung Kao. Provision of study material or patients: Cheng-Li Lin, ChiaHung Kao. Collection and/or assembly of data: Wei-Sheng Chung, Cheng-Li Lin, Chia-Hung Kao. Data analysis and interpretation: Wei-Sheng Chung, Cheng-Li Lin, Chia-Hung Kao. Manuscript writing: All authors. Final approval of manuscript: All authors. Acknowledgements This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW104-TDU-B-212-113002); China Medical University Hospital, Academia Sinica Taiwan Biobank, Stroke Biosignature Project (BM104010092); NRPB Stroke Clinical Trial Consortium (MOST 103-2325-B-039 -006); Tseng-Lien Lin Foundation, Taichung, Taiwan; Taiwan Brain Disease Foundation, Taipei, Taiwan; Katsuzo and Kiyo Aoshima Memorial Funds, Japan; and CMU under the Aim for Top University Plan of the Ministry of Education, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. No additional external funding received for this study. Conflict of interest All authors state that they have no conflict of interests. Address Department of Internal Medicine, Taichung Hospital, Ministry of Health and Welfare, Sanmin Rd., Taichung 403, Taiwan (WeiSheng Chung); Department of Health Services Administration, China Medical University, Xueshi Rd., Taichung 404, Taiwan (Wei-Sheng Chung); Department of Healthcare Administration, Central Taiwan University of Science and Technology, Buzi Rd., Taichung 406, Taiwan (Wei-Sheng Chung); Management Office for Health Data, China Medical University Hospital, Xueshi Rd., Taichung 404, Taiwan (Cheng-Li Lin); Department of Neurology, Taichung Hospital, Ministry of Health and Welfare, Sanmin Rd., Taichung 403, Taiwan (Tzung-Chang Tsai); Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Xueshi Rd., Taichung 404, Taiwan (Wu-Huei Hsu, Chia-Hung Kao); Department of Nuclear Medicine and PET Center, China Medical University Hospital, Xueshi Rd., Taichung 404, Taiwan (Chia-Hung Kao).

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MULTIPLE SCLEROSIS AND VENOUS THROMBOEMBOLISM

Correspondence to: Chia-Hung Kao, Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 404, Taiwan. Tel.: +886 4 22052121x7412; fax.: +886 4 22336174; e-mail: [email protected] Received 29 May 2015; accepted 7 June 2015 References 1 Compston A, Coles A. Multiple sclerosis. Lancet 2008;372:1502–17. 2 Weiner HL. Multiple sclerosis is an inflammatory T-cell-mediated autoimmune disease. Arch Neurol 2004;61:1613–5. 3 Roach ES. Is multiple sclerosis an autoimmune disorder? Arch Neurol 2004;61:1615–6. 4 Dhib-Jalbut S, Marks S. Interferon-beta mechanisms of action in multiple sclerosis. Neurology 2010;74(Suppl 1):S17–24. 5 Bielekova B, Becker BL. Monoclonal antibodies in MS: mechanisms of action. Neurology 2010;74(Suppl 1):S31–40. 6 Sadiq SA, Simon EV, Puccio LM. Intrathecal methotrexate treatment in multiple sclerosis. J Neurol 2010;257:1806–11. 7 Goldenberg MM. Multiple sclerosis review. P T 2012;37:175-84. 8 Cushman M, Tsai AW, White RH, Heckbert SR, Rosamond WD, Enright P et al. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. Am J Med 2004;117:19–25. 9 Heit JA. Venous thromboembolism: disease burden, outcomes and risk factors. J Thromb Haemost 2005;3:1611–7. 10 Cohen AT, Tapson VF, Bergmann JF, Goldhaber SZ, Kakkar AK, Deslandes B et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet 2008;371:387–94. 11 Esmon CT. Basic mechanisms and pathogenesis of venous thrombosis. Blood Rev 2009;23:225–9. 12 Reitsma PH, Versteeg HH, Middeldorp S. Mechanistic view of risk factors for venous thromboembolism. Arterioscler Thromb Vasc Biol 2012;32:563–8. 13 Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation 2003;107:I9–16. 14 Lobo JL, Jime´nez D,Teresa Orue M, Grau E, Naufall D, Madridano O, et al. Recurrent venous thromboembolism during coumarin therapy. Data from the computerised registry of patients with venous thromboembolism. Br J Haematol 2007;138:400–3. 15 Bembenek J, Karlinski M, Kobayashi A, Czlonkowska A. Early stroke-related deep venous thrombosis: risk factors and influence on outcome. J Thromb Thrombolysis 2011;32:96–102. 16 Piazza G, Goldhaber SZ, Kroll A, Goldberg RJ, Emery C, Spencer FA. Venous thromboembolism in patients with diabetes mellitus. Am J Med 2012;125:709–16. 17 Tien WC, Kao HY, Tu YK, Chiu HC, Lee KT, Shi HY. A populationbased study of prevalence and hospital charges in total hip and knee replacement. Int Orthop 2009;33:949–54. 18 Falck-Ytter Y, Francis CW, Johanson NA, Curley C, Dahl OE, Schulman S et al. Prevention of VTE in orthopedic surgery patients: antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e278S–325S.

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