|Year : 2018 | Volume
| Issue : 5 | Page : 231-236
The risk of venous thromboembolism in patients with lower urinary tract symptoms
Kuo-Tsai Huang1, Wei-Yu Lin2, Cheng-Li Lin3, Chia-Hung Kao4
1 Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Chia-Yi, Taiwan
2 Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Chia-Yi; Chang Gung University of Science and Technology, Chia-Yi, Taiwan; Department of Medicine, Chang Gung University, Taoyuan, Taiwan
3 Management Office for Health Data, China Medical University Hospital; School of Medicine, China Medical University, Taichung, Taiwan
4 Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University; Department of Nuclear Medicine and PET Center, China Medical University Hospital; Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan
|Date of Web Publication||3-Sep-2018|
Department of Surgery, Division of Urology, Chang Gung Memorial Hospital, Chia-Yi 61363
Source of Support: None, Conflict of Interest: None
Objectives: Atherosclerosis may lead to chronic bladder ischemia, which eventually results in lower urinary tract symptoms (LUTS). Patients with venous thromboembolism (VTE) have a higher prevalence of atherosclerosis. Methods: A total of 31,559 patients had been diagnosed with or without LUTS between 2000 and 2010 in Taiwan National Health Insurance Research Database, each was enrolled in the LUTS and non-LUTS cohorts, respectively. The risk of VTE in LUTS and non-LUTS cohorts was calculated by Cox proportional hazards regression model. Results: After adjustment for age, sex, and comorbidities, the risk of subsequent VTE was 1.34-fold higher in the LUTS than in the non-LUTS cohort. The adjusted risk of VTE was highest in patients with LUTS with any comorbidity. The age-specific relative risk of VTE was significantly higher in patients aged ≥50 years, particularly in those aged 50–64 years, in the LUTS than in the non-LUTS cohort. Conclusions: LUTS is a risk factor for VTE. Physicians should consider the possibility of underlying VTE in patients aged ≥50 years having cardiovascular comorbidities.
Keywords: Atherosclerosis, cohort study, lower urinary tract symptoms, venous thromboembolism
|How to cite this article:|
Huang KT, Lin WY, Lin CL, Kao CH. The risk of venous thromboembolism in patients with lower urinary tract symptoms. Urol Sci 2018;29:231-6
| Introduction|| |
Venous thromboembolism (VTE) is a clinical challenge for health-care providers. VTE is highly prevalent and burdens the health economy. Cancer, trauma, surgery, medical illness, and pregnancy are the major risk factors for VTE, and a significant proportion (26%–47%) of VTE is currently classified as “unprovoked” in the absence of the aforementioned risk factors. Identifying preceding factors may substantially assist in developing new strategies for both primary and secondary prevention of VTE., Several studies have demonstrated the association between arterial (e.g., myocardial infarction and stroke) and venous (deep vein thrombosis and pulmonary embolism) thromboembolism in the last decade;,,, this association may be the result of shared risk factors.,
In 2008, approximately 45.2% of the population worldwide (4.3 billion) was affected by at least one of the lower urinary tract symptoms (LUTS). Atherosclerosis can lead to chronic bladder ischemia, which may be crucial in the development of LUTS.,,,, Since LUTS and VTE share certain risk factors, such as obesity, diabetes, smoking, hypertension, hyperlipidemia, and advanced age, we hypothesized that the presentation of LUTS is a sentinel symptom in patients with VTE.,,,,,,, To examine this hypothesis, a nationwide population-based cohort study was conducted in Taiwan to investigate whether LUTS precedes VTE.
| Methods|| |
The National Health Insurance (NHI) program, established in 1995, has provided health-care coverage to >99% of the 23 million population of in Taiwan since 1998. The National Health Research Institutes established and maintains the NHI Research Database (NHIRD) for facilitating research. The Longitudinal Health Insurance Database 2000 (LHID2000), a representative subset of the NHIRD containing the claims data of 1 million randomly selected NHI beneficiaries, was used as the data source. Data in the LHID2000 are deidentified for ensuring patient privacy. Diagnosis codes in the NHIRD are based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM).
Data availability statement
The dataset used in this study is held by the Taiwan Ministry of Health and Welfare (MOHW). The MOHW must approve our application to access this data. Any researcher interested in accessing this dataset can submit an application form to the MOHW requesting access. Please contact the staff of MOHW (Email: firstname.lastname@example.org) for further assistance. Taiwan MOHW Address: No. 488, Sec. 6, Zhongxiao E. Rd., Nangang Dist., Taipei City 115, Taiwan (R. O. C.). Phone: +886-2-8590-6848. All relevant data are within the paper.
The NHIRD encrypts patient personal information to protect privacy and provides researchers with anonymous identification numbers associated with relevant claims information, including sex, date of birth, medical services received, and prescriptions. Therefore, patient consent is not required to access the NHIRD. This study was approved to fulfill the condition for exemption by the Institutional Review Board (IRB) of China Medical University (CMUH104-REC2-115-CR1). The IRB also specifically waived the consent requirement.
Patients older than 20 years diagnosed with LUTS (ICD-9-CM codes 596.51, 788.4, 625.6, 788.32, 788.31, 788.36, 788.43, 788.33, 788.2, 788.6, 788.35, and 600) between 2000 and 2011 were included in the LUTS cohort. The date of LUTS diagnosis was designated the index date. Individuals younger than 20 years and those with a history of VTE (415.1, 453.8 excluding iatrogenic pulmonary embolism, 415.11) at the baseline, and those without information on age and sex were excluded from both cohorts. Patients without LUTS randomly chosen from the LHID2000 formed the non-LUTS cohort: For each patient in the LUTS cohort, one control–frequency-matched by age (5-year spans), sex, year of LUTS diagnosis, comorbidities of hypertension (ICD-9-CM codes 401–405), diabetes (250), hyperlipidemia (272), cerebrovascular disease (430–438), heart failure (428), lower leg fracture or surgery (820–823 and procedure codes 81.51, 81.52, 81.53, and 81.54), and all cancers (140–208)–was included in the non-LUTS cohort.
The LUTS and non-LUTS cohorts were followed until VTE diagnosis, withdrawal from the NHI program, or December 31, 2011, whichever occurred earlier.
Chi-square test and t-test were used to analyze differences between the LUTS and non-LUTS cohorts for categorical and continuous variables, respectively. The cumulative incidence curves of VTE in the two cohorts were plotted using the Kaplan–Meier method, and the differences were tested using log-rank test. The incidence density of VTE was calculated for different risk factors and stratified by age, sex, and comorbidity. Unavailable and multivariable Cox proportional hazards regression analysis was used to assess the hazard ratio (HR) and 95% confidence interval (CI) of VTE associated with LUTS compared with non-LUTS cohort. A multivariable model was used to estimate the adjusted HR (aHR) after controlling for covariates, namely, age, sex, and comorbidities of hypertension, diabetes, hyperlipidemia, CVA, heart failure, and all cancers. All statistical analyses were performed using SAS 9.4 software (SAS Institute, Cary, NC, USA). The level of significance was set at 0.05 (2-tailed test).
| Results|| |
In total, 31,559 patients each were included in the LUTS and non-LUTS cohorts [Table 1]. The mean age in the LUTS and non-LUTS cohorts was 59.9 years (standard deviation [SD] = 15.5) and 60.1 (SD = 14.9) years, respectively. Distributions of sex and comorbidities were similar in both cohorts. Approximately 70% of the members of both cohorts were male, and the most prevalent comorbidities were hypertension (approximately 41%), hyperlipidemia (20.2%), and diabetes (11.2%). The mean follow-up periods in the LUTS and non-LUTS cohorts were 5.34 and 6.23 years, respectively. The results of the Kaplan–Meier plot revealed that the LUTS cohort had a higher cumulative incidence of VTE than did the non-LUTS cohort (log-rank test P < 0.001) [Figure 1]. The incidence density was 1.31 and 0.96/10,000 person-years in the LUTS and non-LUTS cohorts, respectively [Table 2]. The multivariable Cox method estimated that the aHR of developing VTE was 1.34 (95% CI = 1.12–1.61) in the LUTS cohort compared with the non-LUTS cohort.
|Table 1: Demographic characteristics and comorbidities in cohorts with and without lower urinary tract symptoms|
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|Figure 1: Cumulative incidence comparison of venous thromboembolism for patients with (dashed line) or without (solid line) lower urinary tract symptoms|
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|Table 2: Incidence and hazard ratio for venous thromboembolism and venous thromboembolism-associated risk factor|
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Compared with patients aged ≤49 years, the risk of VTE development was 3.36- and 7.04-fold higher in patients aged 50–64 years (95% CI = 2.18–5.16) and ≥65 years (95% CI = 4.63–10.7), respectively. The risk of VTE was 1.32-fold higher for women than for men (95% CI = 1.08–1.62) and was higher in patients with the comorbidities of hypertension (aHR = 1.43, 95% CI = 1.16–1.75), heart failure (aHR = 2.10, 95% CI = 1.52–2.90), and all cancers (aHR = 2.53, 95% CI = 1.72–3.71). The incidence density of VTE increased with age in both cohorts [Table 3]; however, the age-specific relative risk of VTE in the LUTS cohort was higher for patients aged 50–64 years (aHR = 1.61, 95% CI = 1.11–2.23) ≥65 years (aHR = 1.36, 95% CI = 1.09–1.69) compared with the non-LUTS cohort. The sex-specific relative risk of VTE for LUTS cohort compared with the non-LUTS cohort was significant for both women (aHR = 1.45, 95% CI = 1.03–2.03) and men (aHR = 1.32, 95% CI = 1.06–1.64). Moreover, compared with the non-LUTS cohort, the LUTS cohort was associated with a significantly higher risk of VTE (aHR = 1.41, 95% CI = 1.14–1.74) in patients having any one of the evaluated comorbidities.
|Table 3: Incidence of venous thromboembolism by age, sex, and comorbidity and Cox model measured hazards ratio for patients with lower urinary tract symptoms compared those without lower urinary tract symptoms|
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| Discussion|| |
VTE is highly prevalent, substantially burdens the health economy, and can complicate the course of a disease; it might also be encountered in the absence of precipitating disorders. Identifying predictive symptoms of VTE enables early intervention and can decrease the incidence of complications, which is crucial for patients without regular and adequate medical assessments of VTE risk factors because VTE is a clinical challenge for all medical practitioners.
LUTS could be the initial manifestation of underlying vascular disease because LUTS, cardiovascular disease (CVD), peripheral artery occlusive disease (PAOD), and VTE share certain risk factors, such as obesity, tobacco use, physical inactivity, diabetes, hypertension, and hyperlipidemia.,,, The association of LUTS with CVD remains controversial.,,,, The relationship between LUTS and PAOD has been reported in animal studies and cohort observations. In animal models, atherosclerosis has induced pelvic ischemia and has resulted in the functional and structural alteration of bladder muscles.,,, Anatomically, vascular supply to the lower urinary tract is primarily from the iliac arteries. Therefore, atherosclerotic obstructive changes distal to the aortic bifurcation can affect blood flow in the distal vasculature and lower urinary tract., Bladder ischemia can precede PAOD because of the easy obstruction caused by atherosclerosis in most distal arterial branches.
To the best of our knowledge, this study is thefirst to investigate the association of LUTS with VTE. The NHIRD facilitates retrospective investigations of the association of LUTS with subsequent VTE. In both the LUTS and non-LUTS cohorts, 70% of the patients were men aged >60 years (41.6%). Patients diagnosed with BPH were also included in the study. Although the risk of VTE was 1.32-fold higher for women than for men (95% CI = 1.08–1.62), the sex-specific risk of VTE for the LUTS cohort relative to the non-LUTS cohort was significantly higher in both women (aHR = 1.47, 95% CI = 1.03–2.03) and men (aHR = 1.32, 95% CI = 1.06–1.64). In addition, the LUTS cohort was associated with a significantly higher risk of VTE compared with the non-LUTS cohort (aHR = 1.41, 95% CI = 1.14–1.74) in patients with any one of the assessed comorbidities. The age-specific relative risk of VTE was higher in patients aged 50–64 years (aHR = 1.61; 95% CI = 1.11–2.23) and ≥65 years (aHR = 1.36; 95% CI = 1.09–1.69) in the LUTS cohort as compared with the non-LUTS cohort. Therefore, clinicians should consider the possibility of underlying VTE in patients with LUTS aged >49 years and with any cardiovascular comorbidity.
This was thefirst nationwide population-based cohort longitudinal study conducted in Taiwan for assessing the risk of VTE development in patients with LUTS. This study has several limitations. First, the ICD-9-CM diagnostic codes used in the study may be incorrect, and information on the accuracy of these codes for LUTS is lacking. LUTS is possibly undercoded in the NHI because the diagnosis is symptomatic, which might have resulted in the underestimation of the effect of LUTS on subsequent PAOD.
Second, the diagnoses of LUTS, VTE, and other comorbidities were based on ICD-9-CM codes, which may have been misclassified. However, the use of ICD-9-CM codes for diagnosing chronic diseases has been validated in previous national cohort studies., 25, ,,, In addition, the NHI is a universal health insurance program and the doctors are reimbursed by administrative specialists; therefore, a peer-review system was established to reduce false positives. Moreover, the NHI Bureau of Taiwan reviews charts, verifies medical charges, and imposes heavy penalties for inappropriate charges and malpractice. These practices are assumed to ensure accurate coding.,
Third, The NHIRD lacks information on some critical cardiovascular risk factors such as smoking, obesity, increased body mass index (BMI), alcohol consumption, lack of exercise, and dietary habits. Nevertheless, risk factors such as hypertension, diabetes, and hyperlipidemia were included in the study to account for the influence of BMI and obesity. To minimize the potential confounding effect of smoking, we adjusted for smoking-related diseases such as COPD, asthma, and stroke, as was the case in previous studies., Considering these limitations, a high prevalence of LUTS should be considered a sentinel symptom in patients with occult VTE.
The implications of this study are substantial. With the availability of effective pharmacotherapy, an increasing number of patients are seeking treatment for LUTS. In 2008, approximately 45.2% of the population worldwide (4.3 billion) was affected by at least one LUTS, with an age-related increase in both sexes., In our study, incidences of VTE over a 65-year-old man in the LUTs and non-LUTs was 2.3/10,000 and 1.7/10,000, respectively. It suggests that patients with LUTS have an approximately 1.34-fold higher risk of subsequent VTE than do individuals without LUTS. Thus, the initial presentation of patients with LUTS, particularly of those aged ≥50 years or with any comorbidity, should prompt the evaluating physician to screen for standard VTE risk factors and intervention for VTE should be accordingly initiated. The occult symptoms in patient with VTE should be underestimated in current era who was treated as LUTS and our result provides objective evidence to remind physician evaluating LUTs and its comorbidities, especially who are candidate for invasive procedure.
| Conclusions|| |
This study concluded that LUTS is associated with subsequent VTE, particularly in patients aged ≥50 years having cardiovascular comorbidities. Physicians should consider the possibility of VTE in patients with LUTS. Additional studies on disease screening and early intervention are warranted to prevent the subsequent complications of VTE in patients with LUTS. The clinical significance of the findings should be more addressed.
This study is supported in part by Taiwan MOHW Clinical Trial and Research Center of Excellence (MOHW106-TDU-B-212-113004), China Medical University Hospital, Academia Sinica Taiwan Biobank Stroke Biosignature Project (BM10501010037), NRPB Stroke Clinical Trial Consortium (MOST105-2325-B-039-003), Tseng-Lien Lin Foundation, Taichung, Taiwan, Taiwan Brain Disease Foundation, Taipei, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan. 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.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kyrle PA, Eichinger S. Deep vein thrombosis. Lancet 2005;365:1163-74.
Heit JA. Venous thromboembolism epidemiology: Implications for prevention and management. Semin Thromb Hemost 2002;28 Suppl 2:3-13.
Bai J, Ding X, Du X, Zhao X, Wang Z, Ma Z, et al.
Diabetes is associated with increased risk of venous thromboembolism: A systematic review and meta-analysis. Thromb Res 2015;135:90-5.
Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, et al.
Prevention of venous thromboembolism: The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004;126:338S-400S.
Eliasson A, Bergqvist D, Björck M, Acosta S, Sternby NH, Ogren M, et al.
Incidence and risk of venous thromboembolism in patients with verified arterial thrombosis: A population study based on 23,796 consecutive autopsies. J Thromb Haemost 2006;4:1897-902.
Lind C, Flinterman LE, Enga KF, Severinsen MT, Kristensen SR, Braekkan SK, et al.
Impact of incident venous thromboembolism on risk of arterial thrombotic diseases. Circulation 2014;129:855-63.
Prandoni P, Bilora F, Marchiori A, Bernardi E, Petrobelli F, Lensing AW, et al.
An association between atherosclerosis and venous thrombosis. N Engl J Med 2003;348:1435-41.
Sørensen HT, Horvath-Puho E, Pedersen L, Baron JA, Prandoni P. Venous thromboembolism and subsequent hospitalisation due to acute arterial cardiovascular events: A 20-year cohort study. Lancet 2007;370:1773-9.
Ageno W, Becattini C, Brighton T, Selby R, Kamphuisen PW. Cardiovascular risk factors and venous thromboembolism: A meta-analysis. Circulation 2008;117:93-102.
Andersson KE, Nomiya M, Sawada N, Yamaguchi O. Pharmacological treatment of chronic pelvic ischemia. Ther Adv Urol 2014;6:105-14.
Andersson KE. Storage and voiding symptoms: Pathophysiologic aspects. Urology 2003;62:3-10.
Kaplan SA. Male pelvic health: A urological call to arms. J Urol 2006;176:2351-2.
Mariappan P, Chong WL. Prevalence and correlations of lower urinary tract symptoms, erectile dysfunction and incontinence in men from a multiethnic asian population: Results of a regional population-based survey and comparison with industrialized nations. BJU Int 2006;98:1264-8.
Ponholzer A, Temml C, Wehrberger C, Marszalek M, Madersbacher S. The association between vascular risk factors and lower urinary tract symptoms in both sexes. Eur Urol 2006;50:581-6.
Yamaguchi O, Nomiya M, Andersson KE. Functional consequences of chronic bladder ischemia. Neurourol Urodyn 2014;33:54-8.
Karatas OF, Bayrak O, Cimentepe E, Unal D. An insidious risk factor for cardiovascular disease: Benign prostatic hyperplasia. Int J Cardiol 2010;144:452.
Kupelian V, Araujo AB, Wittert GA, McKinlay JB. Association of moderate to severe lower urinary tract symptoms with incident type 2 diabetes and heart disease. J Urol 2015;193:581-6.
Ng CF, Wong A, Li ML, Chan SY, Mak SK, Wong WS, et al.
The prevalence of cardiovascular risk factors in male patients who have lower urinary tract symptoms. Hong Kong Med J 2007;13:421-6.
Sandfeldt L, Hahn RG. Cardiovascular risk factors correlate with prostate size in men with bladder outlet obstruction. BJU Int 2003;92:64-8.
Su TW, Chou TY, Jou HJ, Yang PY, Lin CL, Sung FC, et al.
Peripheral arterial disease and spinal cord injury: A Retrospective nationwide cohort study. Medicine (Baltimore) 2015;94:e1655.
Katz DL. Lifestyle and dietary modification for prevention of heart failure. Med Clin North Am 2004;88:1295-320, xii.
Horvei LD, Brækkan SK, Mathiesen EB, Njølstad I, Wilsgaard T, Hansen JB, et al.
Obesity measures and risk of venous thromboembolism and myocardial infarction. Eur J Epidemiol 2014;29:821-30.
Bouwman II, Blanker MH, Schouten BW, Bohnen AM, Nijman RJ, van der Heide WK, et al.
Are lower urinary tract symptoms associated with cardiovascular disease in the dutch general population? Results from the Krimpen study. World J Urol 2015;33:669-76.
Bouwman II, Voskamp MJ, Kollen BJ, Nijman RJ, van der Heide WK, Blanker MH, et al.
Do lower urinary tract symptoms predict cardiovascular diseases in older men? A systematic review and meta-analysis. World J Urol 2015;33:1911-20.
Lin HJ, Weng SF, Yang CM, Wu MP. Risk of hospitalization for acute cardiovascular events among subjects with lower urinary tract symptoms: A nationwide population-based study. PLoS One 2013;8:e66661.
Thompson IM, Tangen CM, Goodman PJ, Probstfield JL, Moinpour CM, Coltman CA, et al.
Erectile dysfunction and subsequent cardiovascular disease. JAMA 2005;294:2996-3002.
Wehrberger C, Temml C, Gutjahr G, Berger I, Rauchenwald M, Ponholzer A, et al.
Is there an association between lower urinary tract symptoms and cardiovascular risk in men? A cross sectional and longitudinal analysis. Urology 2011;78:1063-7.
Azadzoi KM. Effect of chronic ischemia on bladder structure and function. Adv Exp Med Biol 2003;539:271-80.
Bschleipfer T, Dannenmaier AK, Illig C, Kreisel M, Gattenlöhner S, Langheinrich AC, et al.
Systemic atherosclerosis causes detrusor overactivity: Functional and morphological changes in hyperlipoproteinemic apoE-/-LDLR-/- mice. J Urol 2015;193:345-51.
Nomiya M, Yamaguchi O, Andersson KE, Sagawa K, Aikawa K, Shishido K, et al.
The effect of atherosclerosis-induced chronic bladder ischemia on bladder function in the rat. Neurourol Urodyn 2012;31:195-200.
Chen YC, Lin HY, Li CY, Lee MS, Su YC. A nationwide cohort study suggests that hepatitis C virus infection is associated with increased risk of chronic kidney disease. Kidney Int 2014;85:1200-7.
Chou TY, Su TW, Jou HJ, Yang PY, Chen HJ, Muo CH, et al.
Increased risk of peripheral arterial disease after hip replacement: An 11-year retrospective population-based cohort study. Medicine (Baltimore) 2015;94:e870.
Lin TY, Chen YG, Lin CL, Huang WS, Kao CH. Inflammatory bowel disease increases the risk of peripheral arterial disease: A Nationwide cohort study. Medicine (Baltimore) 2015;94:e2381.
Sheu JJ, Kang JH, Lin HC, Lin HC. Hyperthyroidism and risk of ischemic stroke in young adults: A 5-year follow-up study. Stroke 2010;41:961-6.
Lim YP, Lin CL, Hung DZ, Ma WC, Lin YN, Kao CH, et al.
Increased risk of deep vein thrombosis and pulmonary thromboembolism in patients with organophosphate intoxication: A nationwide prospective cohort study. Medicine (Baltimore) 2015;94:e341.
Shen CH, Lin TY, Huang WY, Chen HJ, Kao CH. Pneumoconiosis increases the risk of peripheral arterial disease: A nationwide population-based study. Medicine (Baltimore) 2015;94:e911.
Yeh CC, Wang HH, Chou YC, Hu CJ, Chou WH, Chen TL, et al.
High risk of gastrointestinal hemorrhage in patients with epilepsy: A nationwide cohort study. Mayo Clin Proc 2013;88:1091-8.
Irwin DE, Kopp ZS, Agatep B, Milsom I, Abrams P. Worldwide prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction. BJU Int 2011;108:1132-8.
[Table 1], [Table 2], [Table 3]