- Email: [email protected]
Relationship between the site of thrombosis and the prevalence of pulmonary embolism in acute lower extremity deep venous thrombosis
Relationship between the site of thrombosis and the prevalence of pulmonary embolism in acute lower extremity deep venous thrombosis Chengwei Zhang, MD,a,b Qiao Li, MD,c Hang Yu, BD,b Fang Wang, BD,b Ziyi Lin, BD,b Weiwei Yin, BD,b Yijia Pan, BD,b Mengqi Wu, BD,b Weidong Xie, BD,b Xuehai Chen, MD,a and Naxin Liu, MD,a Zhejiang, China
ABSTRACT Objective: Lower extremity deep venous thrombosis (LEDVT) is common and can lead to pulmonary embolism (PE). Currently, the mechanism of how LEDVT causes PE is unclear. The aim of this study was to explore the relationship between the thrombus sites and PE in LEDVT patients. Methods: A retrospective study that included the medical data of 3101 patients aged >18 years who were diagnosed with LEDVT by duplex ultrasound was performed at The First Affiliated Hospital of Wenzhou Medical University from 2008 to 2017. The clinical information of the patients was collected. According to the thrombosis sites, the patients were divided into three groups. We determined the cumulative prevalence and prevalence rate of PE between the groups and used Cox proportional hazard regression models, which were stratified on matched sets, to calculate the hazard ratios (HRs) for all of the outcomes of interest. We focused on the relationship of proximal or isolated distal LEDVT with PE and also analyzed the relationship of the left side or right side of LEDVT with PE. Results: A total of 1629 (52.5%) patients had left LEDVT (group 1), 912 (29.4%) patients had right LEDVT (group 2), and 560 (18.1%) patients had bilateral LEDVT (group 3). The rate of PE was higher in group 2 than in group 1, although there were more patients suffering from LEDVT in group 1 than in group 2 (P < .001). The patients with proximal LEDVT in group 3 exhibited a greater risk of PE compared with those with isolated distal LEDVT (adjusted HR, 2.79; 95% confidence interval, 1.42-5.49). We also observed that the proportion of patients with proximal LEDVT who were receiving treatment was much higher than that of patients with distal LEDVT (P < .05). The patients with right LEDVT had a higher risk of PE than the patients with left LEDVT (adjusted HR, 1.60; 95% confidence interval, 1.15-2.21), and the patients with right LEDVT had more comorbidities, such as malignant neoplasms, hypertension, and diabetes (P < .001). Conclusions: Patients with proximal bilateral LEDVT had a higher likelihood for development of PE than did patients with distal LEDVT, which may be associated with inadequate therapy for proximal bilateral LEDVT. PE was more likely to develop with rightsided LEDVT because these patients had more comorbidities in our study. (J Vasc Surg: Venous and Lym Dis 2019;-:1-9.) Keywords: Lower extremity deep venous thrombosis (LEDVT); Pulmonary embolism (PE); Sites of thrombosis; Hospital length of stay (LOS); Therapy
Deep venous thrombosis (DVT) of the lower extremity is an extremely common disease. In China, the prevalence of lower extremity DVT (LEDVT) in the population is approximately 30/100,000, and the proportion is
From the Department of Pancreatitis Center,a and Department of Ultrasonography,c The First Affiliated Hospital of Wenzhou Medical University; and the Renji College of Wenzhou Medical University.b This project was sponsored by the Zhejiang Provincial Health Department Medical Support DisciplinedNutrition (11-ZC24), the Zhejiang Medical and Health Platform Project (Key Talents) (2014RCA014), the Natural Science Foundation of Zhejiang Province (LY16H030015), and the Wenzhou Municipal Science and Bureau (Y20120132). Author conflict of interest: none. Correspondence: Naxin Liu, MD, Department of Pancreatitis Center, The First Affiliated Hospital of Wenzhou Medical University, South Baixiang St, Wenzhou, Zhejiang 325000, China (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 2213-333X Copyright Ó 2019 by the Society for Vascular Surgery. Published by Elsevier Inc. https://doi.org/10.1016/j.jvsv.2019.11.010
increasing as the population ages.1 At present, the diagnosis of LEDVT primarily relies on the wide application of duplex ultrasound (DUS).2 DUS can indicate the site of the thrombus and other information that is helpful for the clinician. According to the site of the thrombus, physicians can choose suitable ways to prevent further development of thrombotic disease; different methods include anticoagulant, thrombolytic, and invasive treatment modalities. However, some LEDVT patients will still develop catastrophic pulmonary embolism (PE) in subsequent days because an unstable thrombus can easily detach and block the pulmonary circulation when it increases to a sufficient length and volume.3 It is well known that PE has been a leading cause of death in clinical patients, with an approximate 30% mortality rate.4 To prevent PE, it is important to identify the relevant factors of PE occurrence. It is generally accepted that PE is primarily related to the site of thrombosis in patients.5 Studies have demonstrated that patients with proximal (above-knee) LEDVT had a higher risk of having PE compared with patients with distal (below-knee) 1
2
Zhang et al
Journal of Vascular Surgery: Venous and Lymphatic Disorders ---
LEDVT6 and that patients with right-sided LEDVT were more likely to have PE than patients with left-sided LEDVT.7 These results demonstrated that anatomic location of the thrombus is linked to PE. Currently, many guidelines emphasize that the anatomy of LEDVT is important for the prevention and treatment of PE.8 However, the mechanism of how LEDVT develops into PE is still unclear, and more research in distinguishing between these disease conditions will provide a more effective treatment method for clinicians to prevent development of PE. In this study, we identified PE at different anatomic sites of LEDVT and analyzed the risk factors, such as therapy interventions and different comorbidities. We investigated the differences in the risk of PE between different anatomic sites, and we proposed a reasonable mechanism by which the prevalence of PE is related to the site of thrombosis.
METHODS Subjects. From January 2008 to August 2017, a total of 5017 patients with DVT who were diagnosed by DUS were enrolled in this study. We excluded 1178 DVT patients who did not have bilateral lower limb DUS diagnoses or who had diagnoses that were not clear on DUS. Moreover, to avoid the disturbance of the recurrence of LEDVT in our study, we excluded 571 patients who had a history of venous thrombosis in the hospital. In 3268 retained patients with acute LEDVT, the following cases were also removed to improve the data reliability: patients who had inaccurate diagnoses of PE or who had suffered PE before LEDVT was diagnosed (n ¼ 155); and patients aged <18 years (n ¼ 12; Fig 1). Finally, a total of 3101 cases were enrolled; in the enrolled patients, 184 patients were diagnosed as having PE by computed tomography pulmonary angiography (CTPA)9 during hospitalization. The
Fig 1. Flow diagram of the study showing the selection of patients with lower extremity deep venous thrombosis (LEDVT) who were included in the analysis. DUS, Duplex ultrasound; DVT, deep venous thrombosis; PE, pulmonary embolism.
2019
ARTICLE HIGHLIGHTS d
d
d
Type of Research: Single-center retrospective study Key Findings: In this retrospective study, patients with proximal lower extremity deep venous thrombosis (LEDVT) exhibited a greater risk of pulmonary embolism (PE; adjusted hazard ratio, 2.79; 95% confidence interval, 1.42-5.49) compared with those who had isolated distal LEDVT. Patients with right-sided LEDVT had a higher risk of PE than did patients with left-sided LEDVT (adjusted hazard ratio, 1.60; 95% confidence interval, 1.15-2.21). Take Home Message: Patients with bilateral proximal LEDVT had a higher likelihood of PE than did patients with bilateral distal LEDVT, which might be associated with inadequate therapy for bilateral proximal LEDVT. The patients with right-sided LEDVT were more likely to develop PE because they had more comorbidities in our study.
Institutional Review Board at The First Affiliated Hospital of Wenzhou Medical University approved the use of the deidentified data for this study and waived consent. Data collection and definition of characteristics. We collected the following patient information: sex and age; time to diagnosis of LEDVT and PE; hospital length of stay (LOS); surgery history; underlying disease information; previous surgical conditions; accurate descriptions of the patients’ DUS diagnoses; therapy interventions for LEDVT; and sites of thrombus. We then divided patients into three groups according to the thrombus site: left-sided LEDVT (group 1), right-sided LEDVT (group 2), and bilateral LEDVT (group 3). First, we analyzed the differences of the characteristics of the three groups. Second, we explored the difference in the occurrence of PE in either the proximal or isolated distal LEDVT. Third, we explored the difference in the occurrence of PE on the left and right sides of the thrombus and analyzed the risk of PE in the different sites of thrombus. The lower extremity veins were divided into five segments10: calf veins, popliteal veins, femoral veins, common femoral veins, and iliac veins. Proximal DVT was defined as a venous thrombosis that was located in the popliteal vein, femoral vein, common femoral vein, or iliac vein; a distal (below-knee) DVT was defined as a venous thrombosis that was located in the calf veins, including the peroneal, posterior tibial, anterior tibial, and soleus muscle veins that are below the knee. Recent surgery was defined as patients with a surgery history of 3 months before the diagnosis of LEDVT; older surgery was defined as patients with a surgery history of >3 months before the diagnosis of LEDVT. The comorbidities consisted of seven diseases: malignant neoplasms, hypertension, diabetes, cardiopathy, renal insufficiency,
Journal of Vascular Surgery: Venous and Lymphatic Disorders Volume
-,
Number
Zhang et al
3
-
pulmonary infection, and cerebrovascular disease. Drug therapy involved the use of aspirin, heparin, vitamin K antagonists, new oral anticoagulants, and thrombolytic drugs. Non-drug therapy included the placement of a vena cava filter, graduated compression stockings, and physical thrombectomy. Treatment of patients began within an hour or two of DVT diagnosis. Our diagnosis criterion for LEDVT was based on the observation of lower limb deep vein intravascular shadows by DUS that included B-mode imaging and color Doppler flow imaging with or without probe compression.11,12 The diagnostic criterion for PE was the observation of pulmonary artery filling defect by CTPA. The length of LEDVT to PE was defined as the time from the LEDVT diagnosis by DUS to the PE diagnosis by CTPA. All these data were obtained from the electronic medical record of The First Affiliated Hospital of Wenzhou Medical University. All diagnoses and examinations were performed in the hospital. Data analysis. The data of the three groups were presented as numbers (percentages) for the categorical data, medians (interquartile ranges) for the nonnormally distributed continuous data, and means 6 standard deviations for the normally distributed continuous data. Mann-Whitney U tests were used to test the differences of LOS in cases in which the data were not normally distributed, whereas Student t-tests were used to test the differences of age when the data were normally distributed. The c2 test was used to test the significance of the differences in the frequencies between the groups. To compare the risks of PE between the patients with left distal LEDVT and right distal LEDVT, a Cox regression analysis was performed to assess the hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of PE in the different groups, and the calculated HRs were adjusted for age, sex, and comorbidities. A Kaplan-Meier curve was constructed to display non-PE rate for each group, and we estimated the differences by using the log-rank test. Statistical analyses were performed with the SPSS 22.0 statistical package software (IBM Corp, Armonk, NY). All of the statistical tests were performed at the two-tailed significance level of .05.
RESULTS Characteristics of enrolled patients. A total of 1629 (52.5%) patients had DVT in the left lower extremity, 912 (29.4%) in the right lower extremity, and 560 (18.1%) in the bilateral lower extremities (Table I). The number of male and female LEDVT patients was almost equal in the total number of patients (male, 1607; female, 1494), but the number of male patients was significantly higher than the number of female patients in group 2 (56.5% vs 43.5%; P < .001). The mean age was 61.2 6 17.2 years in group 1, 64.0 6 16.2 years in
group 2, and 70.6 6 13.2 years in group 3 (P < .001). The mean age of the non-PE LEDVT patients was 63.7 6 16.7 years, whereas the mean age of the patients with PE was 64.6 6 15.2 years (P < .001). We observed that the male patients had a higher risk of PE than the female patients (7.0% vs 5.0%; P < .01). Comorbidities, therapy, and LOS differences between the groups. Group 2 had a higher proportion of comorbidities than group 1 (group 2, 62.6%; group 1, 45.2%; P < .001), and group 3 patients had a higher proportion of comorbidities than patients with unilateral LEDVT (bilateral, 75.4%; unilateral, 51.5%; P < .001; Table I). These comorbidities included malignant neoplasms, hypertension, diabetes, cardiopathy, renal insufficiency, pulmonary infections, and cerebrovascular diseases. Among these comorbidities, LEDVT patients who had hypertension, cardiopathy, renal insufficiency, or pulmonary infections had a higher likelihood of being diagnosed with PE (7.2%, 8.0%, 11.7%, 11.0%; P < .05 for the four comorbidities). Patients with bilateral LEDVT had a higher likelihood of receiving both approaches (drug and non-drug therapy simultaneously) compared with patients with unilateral LEDVT (bilateral, 3.4%; unilateral, 1.8%; P < .05; Table I). The probability of the three groups without any treatment for LEDVT was similar (group 1, 6.4%; group 2, 6.6%; group 3, 5.5%; P > .05 for the three groups). We also observed that the patients who did not receive therapy for LEDVT had a conspicuously higher risk of PE than did those who received therapy for LEDVT (no therapy, 11.8%; therapy, 6.3%; P < .001). The median LOS of group 2 was significantly higher than that of group 1 (group 2, 12 days; group 1, 10 days; P < .001), and patients with bilateral LEDVT had a longer median LOS than that of patients with unilateral LEDVT (bilateral, 12 days; unilateral, 11 days; P < .001). Compared with LEDVT patients without PE, patients with PE had longer hospitalization times (without PE, 11 days; with PE, 14 days; P < .001). PE often caused prolonged LOS. PE differences between proximal LEDVT and isolated distal LEDVT patients. There was no difference in PE between the proximal LEDVT patients and the distal LEDVT patients (Table II). However, in group 3, proximal LEDVT patients exhibited a higher risk of PE than that of patients with isolated distal LEDVT (adjusted HR, 2.79; 95% CI, 1.42-5.49). In patients with unilateral LEDVT, the prevalence of PE was almost the same regardless of whether a thrombosis occurred at the proximal or distal site (proximal, 6.0%; distal, 5.7%; P > .05). Fig 2, A illustrates the cumulative prevalence of PE in comparing the proximal LEDVT patients with the isolated distal LEDVT patients. The prevalence of PE in patients with proximal LEDVT was significantly higher than that in patients with isolated distal LEDVT (log-rank test, P < .001).
4
Zhang et al
Journal of Vascular Surgery: Venous and Lymphatic Disorders ---
2019
Table I. Overall analysis of lower extremity deep venous thrombosis (LEDVT) of the lower limbs Left LEDVT (group 1; n ¼ 1629)
Right LEDVT (group 2; n ¼ 912)
P value
74 (4.5)
75 (8.2)
<.001d
149 (5.9)
521 (32.0)
442 (48.5)
<.001d
963 (37.9)
Male sex
800 (49.1)
515 (56.5)
<.001d
1315 (51.8)
Age, years
61.2 6 17.2
64.0 6 16.2
<.001d
62.2 6 16.9
Characteristics PEþ Isolated distal thrombosis
Unilateral LEDVT (group 1 þ group 2; n ¼ 2541)
Surgery history Recent
225 (13.8)
115 (12.6)
.393
340 (13.4)
Older
361 (22.2)
202 (22.1)
.995
563 (22.2)
Malignant neoplasm
167 (10.3)
138 (15.1)
<.001d
305 (12.0)
Hypertension
419 (25.7)
332 (36.4)
<.001d
751 (29.6)
Diabetes
180 (11.0)
145 (15.9)
<.001d
325 (12.8)
Cardiopathy
200 (12.3)
146 (16.0)
.009c
346 (13.6)
Comorbidity
Renal insufficiency
181 (11.1)
153 (16.8)
<.001
334 (13.1)
Pulmonary infection
199 (12.2)
176 (19.3)
<.001d
375 (14.8)
Cerebrovascular disease
262 (16.1)
185 (20.3)
.008c
447 (17.6)
737 (45.2)
571 (62.6)
<.001d
1308 (51.5) 2254 (88.7)
Patients with comorbidity
d
Therapy for LEDVT Drug therapy
1441 (88.5)
813 (89.1)
.600
Non-drug therapy
50 (3.1)
27 (3.0)
.878
77 (3.0)
Both approaches
34 (2.1)
12 (1.3)
.162
46 (1.8)
104 (6.4)
60 (6.6)
.848
Without any therapy for LEDVT Hospital LOS, days Time to diagnosis of PE, days In-hospital mortalitya
10 (7-15)
12 (7-16)
2 (2-4)
2 (1-3)
12 (0.7)
10 (1.1)
164 (6.5)
<.001
d
11 (7-15)
.060
2 (1-4)
.348
22 (0.9)
LOS, Length of stay; PE, pulmonary embolism. Categorical variables are presented as number (%). Continuous variables are presented as mean 6 standard deviation or median (interquartile range). Boldface entries indicate statistical significance. a Some patients in the face of impending death were discharged traditionally before they died, which caused the real mortality to be higher than the value. b P < .05. c P < .01. d P < .001.
Therapy differences between proximal LEDVT and isolated distal LEDVT patients. In unilateral LEDVT, patients with isolated distal LEDVT received less treatment for their thromboembolism disease compared with patients with proximal LEDVT (proximal, 96.3%; distal, 89.1%; P < .001; Table III). In group 3 patients, the proportion of patients receiving antithrombotic therapy was almost the same for both proximal and distal LEDVT patients (proximal, 96.8%; distal, 93.3%; P > .05). PE differences between left-sided LEDVT and rightsided LEDVT patients. Right-sided LEDVT patients had longer median LOS values than left-sided LEDVT patients (right, 12 days; left, 10 days; P < .001; Table I). Patients with right-sided LEDVT were more likely to have PE than patients with left-sided LEDVT (adjusted HR, 1.69; 95% CI, 1.23-2.34; Table IV). Fig 2, B illustrates the
cumulative prevalence of PE in comparing the rightsided LEDVT patients with the left-sided LEDVT patients. The prevalence of PE was significantly higher for patients with right-sided LEDVT than for patients with left-sided LEDVT (log-rank test, P < .001). PE difference of single-segment LEDVT. Table IV shows that the patients with single-segment LEDVT and with the thrombus located in the calf veins and patients with right-sided LEDVT were more likely to have PE than patients with left-sided LEDVT (adjusted HR, 1.88; 95% CI, 1.08-3.26). Fig 2, C illustrates the cumulative prevalence of PE in comparing the right-sided LEDVT patients with the left-sided LEDVT patients. In patients with calf vein thrombosis, the prevalence of PE was significantly higher for patients with right-sided LEDVT than for those with left-sided LEDVT (log-rank test, P ¼ .007).
Zhang et al
Journal of Vascular Surgery: Venous and Lymphatic Disorders Volume
-,
Number
5
-
Table I. Continued. Bilateral LEDVT (group 3; n ¼ 560)
P value
Total (N ¼ 3101)
PEþ (n ¼ 184)
PE (n ¼ 2917)
P value
35 (6.3)
.726
184 (5.9)
e
e
e
372 (66.4)
<.001d
1335 (43.1)
69 (5.2)
1266
.117
292 (52.1)
.867
1607 (51.8)
113 (7.0)
1494
.007c
70.6 6 13.2
<.001d
63.7 6 16.6
63.7 6 16.7
64.6 6 15.2
24 (4.3)
<.001d
364 (13.3)
27 (7.4)
337
.202
144 (25.7)
.069
707 (21.3)
37 (5.2)
670
.370
114 (20.4)
<.001d
419 (13.5)
30 (7.2)
389
.253
244 (43.6)
<.001d
995 (32.1)
72 (7.2)
923
.035b
<.001d
119 (21.3)
<.001
d
444 (14.3)
33 (7.4)
411
119 (21.3)
<.001d
465 (15.0)
37 (8.0)
428
.045b
112 (20.0)
<.001d
446 (14.4)
52 (11.7)
394
<.001d
117 (20.9)
<.001
d
492 (15.9)
54 (11.0)
438
<.001d
135 (24.1)
<.001
d
582 (18.8)
28 (4.8)
554
.203
422 (75.4)
<.001d
1730 (55.8)
154 (8.9)
1576
<.001d
491 (87.7)
.490
2745 (88.5)
151 (5.5)
2592
.005c
19 (3.4)
.654
96 (3.1)
6 (6.3)
90
.894
19 (3.4)
.018b
65 (2.1)
3 (4.6)
62
.850
31 (5.5)
.418
195 (6.3)
23 (11.8)
172
<.001d
12 (8-16)
<.001
2 (1-4)
11 (7-15)
2 (1-5)
.948
6 (1.1)
.641
d
11 (7-15) 28 (0.9)
DISCUSSION It is well known that PE is one of the most serious complications associated with LEDVT. Few studies have examined the relationship between acute LEDVT and PE.13 In this study, we explored the potential factors associated with PE in patients with acute LEDVT. In this study, we observed that patients with proximal thrombus had similar risks of PE as patients who had only isolated distal thrombus (P > .05), which was against common sense that the probability of PE in patients with proximal LEDVT was higher than that in patients with distal LEDVT.5-8 We found that less concern of clinicians for distal thromboses might account for this phenomenon, and these clinicians did not adequately treat distal thromboses compared with proximal thromboses (Table III). Konstantinides et al14 observed that distal vein thromboses were stable and did not directly affect the occurrence of PE. The therapies for distal LEDVT
14 (11-18)
.149
<.001d
e
e
e
3 (1.6)
25 (0.9)
.500
were ignored, and sometimes these therapies were not adopted to avoid a significantly higher risk of bleeding.15,16 However, studies showed that a large number of proximal thrombi might originate from the continuation of distal vein embolism,17,18 and the prevalence of subsequent proximal LEDVT/PE in these distal patients was 7%.19 This suggests that we need to devote more attention to calf vein thrombus and to provide adequate treatment to avoid disease progression. In our data, among bilateral LEDVT cases but not unilateral LEDVT cases, patients with proximal thrombus had higher risk of PE than patients who had only isolated distal thrombus (P < .001). A review of our treatment options found that similar treatment strategies were adopted for the two groups. This result indirectly indicates that the treatment of bilateral LEDVT patients might not be enough and that more improvements should be made in the future.
Zhang et al
6
Journal of Vascular Surgery: Venous and Lymphatic Disorders ---
2019
Table II. Lower extremity deep venous thrombosis (LEDVT) patients with a thrombus that was proximal or isolated distal with pulmonary embolism (PE) Site of LEDVT
PEþ
PE
Adjusted HRa (95% CI)
P value
Left (group 1) Isolated distal Proximal
521 (39.1)
20 (3.8)
501
Reference
1108 (62.7)
54 (4.9)
1054
0.62 (0.37-1.05)
.780
Right (group 2) Isolated distal
442 (33.1)
35 (7.9)
407
Reference
Proximal
470 (26.6)
40 (8.5)
430
0.95 (0.60-1.50)
Isolated distal
372 (27.9)
14 (3.8)
358
Reference
Proximal
188 (10.6)
21 (11.2)
167
2.79 (1.42-5.49)
.820
Bilateral (group 3) <.001b
Unilateral (group 1 þ group 2) Isolated distal Proximal
963 (72.1)
55 (5.7)
908
Reference
1578 (89.4)
94 (6.0)
1484
0.83 (0.59-1.16)
.279
All Isolated distal
1335
69 (5.2)
1266
Reference
Proximal
1766
115 (6.5)
1651
1.34 (0.98-1.84)
.117
CI, Confidence interval; HR, hazard ratio. Values are reported as number (%). Boldface entries indicate statistical significance. a Multivariable analysis including age, sex, and comorbidities. b P < .001.
Fig 2. A, The cumulative prevalence of no pulmonary embolism (PE) in bilateral lower extremity deep venous thrombosis (LEDVT) patients with proximal LEDVT and isolated distal LEDVT. B, The cumulative prevalence of no PE in unilateral LEDVT patients with left-sided LEDVT and right-sided LEDVT. C, The cumulative prevalence of no PE in calf vein thrombosis patients with left-sided LEDVT and right-sided LEDVT. Standard error <10% for all time points up to cross.
In the left-sided and right-sided LEDVT patients, we observed that the number of patients with right-sided LEDVT was smaller than that of patients with left-sided LEDVT, which is similar to many previous studies.13,20 We observed that right-sided LEDVT patients were more likely to have PE than left-sided LEDVT patients, which resulted in right-sided LEDVT patients having a longer LOS. The current explanation for this phenomenon is the existence of May-Thurner syndrome resulting from stenosis of the left iliac vein. May-Thurner syndrome may predispose to DVT, but at the same time, the stenosis in the iliac vein may prevent PE from the DVT.13 In
other words, the presence of iliac stenosis may act as a partial filter, and thrombi are less likely to escape from the left iliac vein to the lungs. However, this explanation is insufficient. The number of individuals with comorbidities in the right-sided LEDVT cases was higher than that in the left-sided ones (Table I). This result was similar to the study of Narayan et al,21 but it was different from the study of Bikdeli et al.22 Some authors thought comorbidity to be an important cause of PE because comorbidity was associated with an increased risk of thrombosis. For example, in patients with a malignant tumor, the specific
Zhang et al
Journal of Vascular Surgery: Venous and Lymphatic Disorders Volume
-,
Number
7
-
Table III. Lower extremity deep venous thrombosis (LEDVT) patients with a thrombus that was proximal or isolated distal with therapy for LEDVT Therapy for LEDVT Drug therapy
P value
Non-drug therapy
P value
Both approaches
P value
With therapy for LEDVT
P value
521
429 (82.3)
<.001b
19 (3.6)
.354
12 (2.3)
.676
460 (88.3)
<.001b
1108
1012 (91.3)
Isolated distal
442
383 (86.7)
Proximal
470
430 (91.5)
963
812 (84.3)
1578
1442 (91.4)
Isolated distal
372
326 (87.6)
Proximal
188
165 (87.7)
Isolated distal
1335
1138 (85.2)
Proximal
1766
1607 (91.0)
Site of LEDVT Left Isolated distal Proximal
31 (2.8)
22 (2.0)
1065 (96.1)
Right .019a
12 (2.7)
.671
3 (2.3)
15 (3.2)
.178
398 (90.1)
9 (1.9)
<.001b
454 (96.6)
Unilateral Isolated distal Proximal
<.001b
31 (3.2)
.664
15 (1.6)
46 (2.9)
.455
858 (89.1)
31 (2.0)
<.001b
1519 (96.3)
Bilateral .964
9 (2.4)
.073
12 (3.2)
10 (5.3)
.759
347 (93.3)
7 (3.7)
.085
182 (96.8)
All <.001b
40 (3.0)
.781
56 (3.2)
27 (2.0)
.803
1205 (90.3)
38 (2.2)
<.001b
1701 (96.3)
Values are reported as number (%). Boldface entries indicate statistical significance. a P < .05. b P < .001.
Table IV. Segment and side of lower extremity deep venous thrombosis (LEDVT) associated with pulmonary embolism (PE) Site of LEDVT
PEþ
PE
Adjusted HRa (95% CI)
P value
Segment 1, calf vein Left
521 (32.0)
20 (3.8)
501
Reference
Right
442 (48.5)
35 (7.9)
407
1.95 (1.13-3.38)
.017b
Segment 2, popliteal vein Left
44 (2.7)
2 (4.5)
42
Reference
Right
34 (3.7)
6 (17.6)
28
e
.067
Segment 3, femoral vein Left
67 (4.1)
3 (4.5)
64
Reference
Right
34 (3.7)
0 (e)
34
e
0 (e)
e
.663
Segment 4, common femoral vein Left Right
e
Reference
38 (4.2)
4 (10.5)
34
e
Left
47 (2.9)
4 (8.5)
43
Reference
Right
16 (1.8)
2 (12.5)
14
e
e
Segment 5, iliac vein .627
Two or more segments Left
950 (58.3)
45 (4.7)
905
Reference
Right
348 (38.2)
28 (8.0)
320
e
Left
1629
74 (4.5)
1555
Reference
Right
912
75 (8.2)
837
1.69 (1.23-2.34)
.275
All
CI, Confidence interval; HR, hazard ratio. Values are reported as number (%). Boldface entries indicate statistical significance. a Multivariable analysis including age, sex, and comorbidities. b P < .05. c P < .01.
.001c
8
Zhang et al
Journal of Vascular Surgery: Venous and Lymphatic Disorders ---
procoagulant substances and the inflammatory responses of the host cells were significantly increased, which increased the probability of thrombosis22,23; and some patients with heart failure often had increased venous stasis and venous pressure, which facilitated the occurrence of DVT.20 We speculate that the main reason for the occurrence of PE in right-sided LEDVT patients is that these patients have a higher likelihood of comorbidities. To reduce the prevalence of PE in patients with right-sided LEDVT, the key is to treat the comorbidities actively. Several limitations of our study should be considered. First, we were not definitively sure that the PE in patients originated from the legs rather than from the pelvis or other sites of the vein. To investigate the source of the embolus, more venous examinations are needed to find details. Second, not enough attention was paid to the efficacy of new oral anticoagulants and thrombus removal, and whether our data were affected by new therapies in the last 10 years remains in doubt. Third, some patients did not receive treatment because of their physicians’ subjective criteria, such as abnormal coagulant function or stable thrombus, which led to no treatment. Fourth, different physicians had different criteria to use computed tomography angiography for PE diagnosis, and we did not know how many PE patients had been missed. Last, our data came from a single-center study, and we need multicenter studies from which the results can be generalized.
CONCLUSIONS Among bilateral LEDVT patients but not unilateral LEDVT patients, the probability of PE was significantly increased in patients with proximal LEDVT compared with patients with distal LEDVT, and this result may be associated with inadequate therapy for proximal bilateral LEDVT. The probability of PE occurring on the left side of the thrombus was significantly lower than the probability of PE occurring on the right side of the thrombus, especially in calf DVT patients, and the main reason may be that patients with right-sided LEDVT experience more comorbidities.
AUTHOR CONTRIBUTIONS Conception and design: CZ, QL, HY, FW, ZL, WY, YP, MW, WX, XC, NL Analysis and interpretation: CZ, XC, NL Data collection: CZ, QL, HY, FW, ZL, WY, YP, MW, WX, XC, NL Writing the article: CZ, QL, HY, FW, ZL, WY, YP, MW, WX, XC, NL Critical revision of the article: CZ, XC, NL Final approval of the article: CZ, QL, HY, FW, ZL, WY, YP, MW, WX, XC, NL Statistical analysis: CZ, XC, NL Obtained funding: Not applicable Overall responsibility: CZ
2019
REFERENCES 1. Law Y, Chan YC, Cheng SW. Epidemiological updates of venous thromboembolism in a Chinese population. Asian J Surg 2018;41:176-82. 2. Adams K, Sheth SA, Meyr AJ. The reliability of venous duplex ultrasound and clinical findings for the diagnosis of lower extremity deep venous thrombosis. J Am Podiatr Med Assoc 2016;106:12. 3. Cogo A, Lensing AW, Prandoni P, Hirsh J. Distribution of thrombosis in patients with symptomatic deep vein thrombosis. Implications for simplifying the diagnostic process with compression ultrasound. Arch Intern Med 1993;153: 2777-80. 4. Claus K, Angelika R. Principle mechanisms underlying venous thromboembolism: epidemiology, risk factors, pathophysiology and pathogenesis. Respiration 2003;70: 7-30. 5. Georgiev M. Regarding “Nomenclature of the veins of the lower limbs: an international interdisciplinary consensus statement. J Vasc Surg 2004;39:1144. 6. Yamaki T, Hamahata A, Soejima K, Kono T, Nozaki M, Sakurai H. Factors predicting development of postthrombotic syndrome in patients with a first episode of deep vein thrombosis: preliminary report. Eur J Vasc Endovasc Surg 2011;41:126-33. 7. Mebazaa A, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, et al. Predicting the risk of venous thromboembolism in patients hospitalized with heart failure. Circulation 2014;130:410. 8. Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014;35:3033-69. 3069a-k. 9. Dwyer KH, Rempell JS, Stone MB. Diagnosing centrally located pulmonary embolisms in the emergency department using point-of-care ultrasound. Am J Emerg Med 2016;68:S135. 10. De Maeseneer MG, Bochanen N, van Rooijen G, Neglén P. Analysis of 1,338 patients with acute lower limb deep venous thrombosis (DVT) supports the inadequacy of the term "proximal DVT. Eur J Vasc Endovasc Surg 2016;51: 415-20. 11. Wells PS, Carolyn O, Steve D, Dean F, Huyen T. Does this patient have deep vein thrombosis? JAMA 1998;279:1094. 12. Kearon C, Ginsberg JS, Hirsh J. The role of venous ultrasonography in the diagnosis of suspected deep venous thrombosis and pulmonary embolism. Ann Intern Med 1998;129:1044-9. 13. Widimský J Sr, Aschermann M. [New ESC guidelines on the diagnosis and management of acute pulmonary embolism]. Vnitr Lek 2015;61:236-43. 14. Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, et al. Corrigendum to: 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2015;36:2666. 15. Galanaud JP, Khau VK, Boubakri C, Böge G, Laroche JP, Quéré I. [Calf vein thrombosis: to treat or not to treat? Epidemiology, management and problematics]. J Mal Vasc 2007;32:225-8. 16. Righini M, Galanaud JP, Guenneguez H, Brisot D, Diard A, Faisse P, et al. Anticoagulant therapy for symptomatic calf deep vein thrombosis (CACTUS): a randomised, double-blind, placebo-controlled trial. Lancet Haematol 2016;3:e556-62. 17. Pham XB, de Virgilio C. Significance of isolated calf vein thrombosisdfurther evidence. JAMA Surg 2016;151:e161799. 18. Ro A, Kageyama N. Clinical significance of the soleal vein and related drainage veins, in calf vein thrombosis in
Journal of Vascular Surgery: Venous and Lymphatic Disorders Volume
-,
Number
Zhang et al
9
-
autopsy cases with massive pulmonary thromboembolism. Ann Vasc Dis 2016;9:15-21. 19. Ro A, Kageyama N, Tanifuji T, Fukunaga T. Pulmonary thromboembolism: overview and update from medicolegal aspects. Leg Med (Tokyo) 2008;10:57-71. 20. Alexandre M, Spiro TE, Büller HR, Lloyd H, Dayi H, Russell H, et al. Predicting the risk of venous thromboembolism in patients hospitalized with heart failure. Circulation 2014;130:410. 21. Narayan A, Eng J, Carmi L, McGrane S, Ahmed M, Sharrett AR, et al. Iliac vein compression as risk factor for leftversus right-sided deep venous thrombosis: case-control study. Radiology 2012;265:949-57.
22. Bikdeli B, Sharif-Kashani B, Bikdeli B, Valle R, Falga C, RieraMestre A, et al. Impact of thrombus sidedness on presentation and outcomes of patients with proximal lower extremity deep vein thrombosis. Semin Thromb Hemost 2018;44:341-7. 23. Rickles FR, Falanga A. Molecular basis for the relationship between thrombosis and cancer. Thromb Res 2001;102: V215-24.
Submitted Aug 5, 2019; accepted Nov 25, 2019.
ABSTRACT Objective: Lower extremity deep venous thrombosis (LEDVT) is common and can lead to pulmonary embolism (PE). Currently, the mechanism of how LEDVT causes PE is unclear. The aim of this study was to explore the relationship between the thrombus sites and PE in LEDVT patients. Methods: A retrospective study that included the medical data of 3101 patients aged >18 years who were diagnosed with LEDVT by duplex ultrasound was performed at The First Affiliated Hospital of Wenzhou Medical University from 2008 to 2017. The clinical information of the patients was collected. According to the thrombosis sites, the patients were divided into three groups. We determined the cumulative prevalence and prevalence rate of PE between the groups and used Cox proportional hazard regression models, which were stratified on matched sets, to calculate the hazard ratios (HRs) for all of the outcomes of interest. We focused on the relationship of proximal or isolated distal LEDVT with PE and also analyzed the relationship of the left side or right side of LEDVT with PE. Results: A total of 1629 (52.5%) patients had left LEDVT (group 1), 912 (29.4%) patients had right LEDVT (group 2), and 560 (18.1%) patients had bilateral LEDVT (group 3). The rate of PE was higher in group 2 than in group 1, although there were more patients suffering from LEDVT in group 1 than in group 2 (P < .001). The patients with proximal LEDVT in group 3 exhibited a greater risk of PE compared with those with isolated distal LEDVT (adjusted HR, 2.79; 95% confidence interval, 1.42-5.49). We also observed that the proportion of patients with proximal LEDVT who were receiving treatment was much higher than that of patients with distal LEDVT (P < .05). The patients with right LEDVT had a higher risk of PE than the patients with left LEDVT (adjusted HR, 1.60; 95% confidence interval, 1.15-2.21), and the patients with right LEDVT had more comorbidities, such as malignant neoplasms, hypertension, and diabetes (P < .001). Conclusions: Patients with proximal bilateral LEDVT had a higher likelihood for development of PE than did patients with distal LEDVT, which may be associated with inadequate therapy for proximal bilateral LEDVT. PE was more likely to develop with rightsided LEDVT because these patients had more comorbidities in our study. (J Vasc Surg: Venous and Lym Dis 2019;-:1-9.) Keywords: Lower extremity deep venous thrombosis (LEDVT); Pulmonary embolism (PE); Sites of thrombosis; Hospital length of stay (LOS); Therapy
Deep venous thrombosis (DVT) of the lower extremity is an extremely common disease. In China, the prevalence of lower extremity DVT (LEDVT) in the population is approximately 30/100,000, and the proportion is
From the Department of Pancreatitis Center,a and Department of Ultrasonography,c The First Affiliated Hospital of Wenzhou Medical University; and the Renji College of Wenzhou Medical University.b This project was sponsored by the Zhejiang Provincial Health Department Medical Support DisciplinedNutrition (11-ZC24), the Zhejiang Medical and Health Platform Project (Key Talents) (2014RCA014), the Natural Science Foundation of Zhejiang Province (LY16H030015), and the Wenzhou Municipal Science and Bureau (Y20120132). Author conflict of interest: none. Correspondence: Naxin Liu, MD, Department of Pancreatitis Center, The First Affiliated Hospital of Wenzhou Medical University, South Baixiang St, Wenzhou, Zhejiang 325000, China (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 2213-333X Copyright Ó 2019 by the Society for Vascular Surgery. Published by Elsevier Inc. https://doi.org/10.1016/j.jvsv.2019.11.010
increasing as the population ages.1 At present, the diagnosis of LEDVT primarily relies on the wide application of duplex ultrasound (DUS).2 DUS can indicate the site of the thrombus and other information that is helpful for the clinician. According to the site of the thrombus, physicians can choose suitable ways to prevent further development of thrombotic disease; different methods include anticoagulant, thrombolytic, and invasive treatment modalities. However, some LEDVT patients will still develop catastrophic pulmonary embolism (PE) in subsequent days because an unstable thrombus can easily detach and block the pulmonary circulation when it increases to a sufficient length and volume.3 It is well known that PE has been a leading cause of death in clinical patients, with an approximate 30% mortality rate.4 To prevent PE, it is important to identify the relevant factors of PE occurrence. It is generally accepted that PE is primarily related to the site of thrombosis in patients.5 Studies have demonstrated that patients with proximal (above-knee) LEDVT had a higher risk of having PE compared with patients with distal (below-knee) 1
2
Zhang et al
Journal of Vascular Surgery: Venous and Lymphatic Disorders ---
LEDVT6 and that patients with right-sided LEDVT were more likely to have PE than patients with left-sided LEDVT.7 These results demonstrated that anatomic location of the thrombus is linked to PE. Currently, many guidelines emphasize that the anatomy of LEDVT is important for the prevention and treatment of PE.8 However, the mechanism of how LEDVT develops into PE is still unclear, and more research in distinguishing between these disease conditions will provide a more effective treatment method for clinicians to prevent development of PE. In this study, we identified PE at different anatomic sites of LEDVT and analyzed the risk factors, such as therapy interventions and different comorbidities. We investigated the differences in the risk of PE between different anatomic sites, and we proposed a reasonable mechanism by which the prevalence of PE is related to the site of thrombosis.
METHODS Subjects. From January 2008 to August 2017, a total of 5017 patients with DVT who were diagnosed by DUS were enrolled in this study. We excluded 1178 DVT patients who did not have bilateral lower limb DUS diagnoses or who had diagnoses that were not clear on DUS. Moreover, to avoid the disturbance of the recurrence of LEDVT in our study, we excluded 571 patients who had a history of venous thrombosis in the hospital. In 3268 retained patients with acute LEDVT, the following cases were also removed to improve the data reliability: patients who had inaccurate diagnoses of PE or who had suffered PE before LEDVT was diagnosed (n ¼ 155); and patients aged <18 years (n ¼ 12; Fig 1). Finally, a total of 3101 cases were enrolled; in the enrolled patients, 184 patients were diagnosed as having PE by computed tomography pulmonary angiography (CTPA)9 during hospitalization. The
Fig 1. Flow diagram of the study showing the selection of patients with lower extremity deep venous thrombosis (LEDVT) who were included in the analysis. DUS, Duplex ultrasound; DVT, deep venous thrombosis; PE, pulmonary embolism.
2019
ARTICLE HIGHLIGHTS d
d
d
Type of Research: Single-center retrospective study Key Findings: In this retrospective study, patients with proximal lower extremity deep venous thrombosis (LEDVT) exhibited a greater risk of pulmonary embolism (PE; adjusted hazard ratio, 2.79; 95% confidence interval, 1.42-5.49) compared with those who had isolated distal LEDVT. Patients with right-sided LEDVT had a higher risk of PE than did patients with left-sided LEDVT (adjusted hazard ratio, 1.60; 95% confidence interval, 1.15-2.21). Take Home Message: Patients with bilateral proximal LEDVT had a higher likelihood of PE than did patients with bilateral distal LEDVT, which might be associated with inadequate therapy for bilateral proximal LEDVT. The patients with right-sided LEDVT were more likely to develop PE because they had more comorbidities in our study.
Institutional Review Board at The First Affiliated Hospital of Wenzhou Medical University approved the use of the deidentified data for this study and waived consent. Data collection and definition of characteristics. We collected the following patient information: sex and age; time to diagnosis of LEDVT and PE; hospital length of stay (LOS); surgery history; underlying disease information; previous surgical conditions; accurate descriptions of the patients’ DUS diagnoses; therapy interventions for LEDVT; and sites of thrombus. We then divided patients into three groups according to the thrombus site: left-sided LEDVT (group 1), right-sided LEDVT (group 2), and bilateral LEDVT (group 3). First, we analyzed the differences of the characteristics of the three groups. Second, we explored the difference in the occurrence of PE in either the proximal or isolated distal LEDVT. Third, we explored the difference in the occurrence of PE on the left and right sides of the thrombus and analyzed the risk of PE in the different sites of thrombus. The lower extremity veins were divided into five segments10: calf veins, popliteal veins, femoral veins, common femoral veins, and iliac veins. Proximal DVT was defined as a venous thrombosis that was located in the popliteal vein, femoral vein, common femoral vein, or iliac vein; a distal (below-knee) DVT was defined as a venous thrombosis that was located in the calf veins, including the peroneal, posterior tibial, anterior tibial, and soleus muscle veins that are below the knee. Recent surgery was defined as patients with a surgery history of 3 months before the diagnosis of LEDVT; older surgery was defined as patients with a surgery history of >3 months before the diagnosis of LEDVT. The comorbidities consisted of seven diseases: malignant neoplasms, hypertension, diabetes, cardiopathy, renal insufficiency,
Journal of Vascular Surgery: Venous and Lymphatic Disorders Volume
-,
Number
Zhang et al
3
-
pulmonary infection, and cerebrovascular disease. Drug therapy involved the use of aspirin, heparin, vitamin K antagonists, new oral anticoagulants, and thrombolytic drugs. Non-drug therapy included the placement of a vena cava filter, graduated compression stockings, and physical thrombectomy. Treatment of patients began within an hour or two of DVT diagnosis. Our diagnosis criterion for LEDVT was based on the observation of lower limb deep vein intravascular shadows by DUS that included B-mode imaging and color Doppler flow imaging with or without probe compression.11,12 The diagnostic criterion for PE was the observation of pulmonary artery filling defect by CTPA. The length of LEDVT to PE was defined as the time from the LEDVT diagnosis by DUS to the PE diagnosis by CTPA. All these data were obtained from the electronic medical record of The First Affiliated Hospital of Wenzhou Medical University. All diagnoses and examinations were performed in the hospital. Data analysis. The data of the three groups were presented as numbers (percentages) for the categorical data, medians (interquartile ranges) for the nonnormally distributed continuous data, and means 6 standard deviations for the normally distributed continuous data. Mann-Whitney U tests were used to test the differences of LOS in cases in which the data were not normally distributed, whereas Student t-tests were used to test the differences of age when the data were normally distributed. The c2 test was used to test the significance of the differences in the frequencies between the groups. To compare the risks of PE between the patients with left distal LEDVT and right distal LEDVT, a Cox regression analysis was performed to assess the hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of PE in the different groups, and the calculated HRs were adjusted for age, sex, and comorbidities. A Kaplan-Meier curve was constructed to display non-PE rate for each group, and we estimated the differences by using the log-rank test. Statistical analyses were performed with the SPSS 22.0 statistical package software (IBM Corp, Armonk, NY). All of the statistical tests were performed at the two-tailed significance level of .05.
RESULTS Characteristics of enrolled patients. A total of 1629 (52.5%) patients had DVT in the left lower extremity, 912 (29.4%) in the right lower extremity, and 560 (18.1%) in the bilateral lower extremities (Table I). The number of male and female LEDVT patients was almost equal in the total number of patients (male, 1607; female, 1494), but the number of male patients was significantly higher than the number of female patients in group 2 (56.5% vs 43.5%; P < .001). The mean age was 61.2 6 17.2 years in group 1, 64.0 6 16.2 years in
group 2, and 70.6 6 13.2 years in group 3 (P < .001). The mean age of the non-PE LEDVT patients was 63.7 6 16.7 years, whereas the mean age of the patients with PE was 64.6 6 15.2 years (P < .001). We observed that the male patients had a higher risk of PE than the female patients (7.0% vs 5.0%; P < .01). Comorbidities, therapy, and LOS differences between the groups. Group 2 had a higher proportion of comorbidities than group 1 (group 2, 62.6%; group 1, 45.2%; P < .001), and group 3 patients had a higher proportion of comorbidities than patients with unilateral LEDVT (bilateral, 75.4%; unilateral, 51.5%; P < .001; Table I). These comorbidities included malignant neoplasms, hypertension, diabetes, cardiopathy, renal insufficiency, pulmonary infections, and cerebrovascular diseases. Among these comorbidities, LEDVT patients who had hypertension, cardiopathy, renal insufficiency, or pulmonary infections had a higher likelihood of being diagnosed with PE (7.2%, 8.0%, 11.7%, 11.0%; P < .05 for the four comorbidities). Patients with bilateral LEDVT had a higher likelihood of receiving both approaches (drug and non-drug therapy simultaneously) compared with patients with unilateral LEDVT (bilateral, 3.4%; unilateral, 1.8%; P < .05; Table I). The probability of the three groups without any treatment for LEDVT was similar (group 1, 6.4%; group 2, 6.6%; group 3, 5.5%; P > .05 for the three groups). We also observed that the patients who did not receive therapy for LEDVT had a conspicuously higher risk of PE than did those who received therapy for LEDVT (no therapy, 11.8%; therapy, 6.3%; P < .001). The median LOS of group 2 was significantly higher than that of group 1 (group 2, 12 days; group 1, 10 days; P < .001), and patients with bilateral LEDVT had a longer median LOS than that of patients with unilateral LEDVT (bilateral, 12 days; unilateral, 11 days; P < .001). Compared with LEDVT patients without PE, patients with PE had longer hospitalization times (without PE, 11 days; with PE, 14 days; P < .001). PE often caused prolonged LOS. PE differences between proximal LEDVT and isolated distal LEDVT patients. There was no difference in PE between the proximal LEDVT patients and the distal LEDVT patients (Table II). However, in group 3, proximal LEDVT patients exhibited a higher risk of PE than that of patients with isolated distal LEDVT (adjusted HR, 2.79; 95% CI, 1.42-5.49). In patients with unilateral LEDVT, the prevalence of PE was almost the same regardless of whether a thrombosis occurred at the proximal or distal site (proximal, 6.0%; distal, 5.7%; P > .05). Fig 2, A illustrates the cumulative prevalence of PE in comparing the proximal LEDVT patients with the isolated distal LEDVT patients. The prevalence of PE in patients with proximal LEDVT was significantly higher than that in patients with isolated distal LEDVT (log-rank test, P < .001).
4
Zhang et al
Journal of Vascular Surgery: Venous and Lymphatic Disorders ---
2019
Table I. Overall analysis of lower extremity deep venous thrombosis (LEDVT) of the lower limbs Left LEDVT (group 1; n ¼ 1629)
Right LEDVT (group 2; n ¼ 912)
P value
74 (4.5)
75 (8.2)
<.001d
149 (5.9)
521 (32.0)
442 (48.5)
<.001d
963 (37.9)
Male sex
800 (49.1)
515 (56.5)
<.001d
1315 (51.8)
Age, years
61.2 6 17.2
64.0 6 16.2
<.001d
62.2 6 16.9
Characteristics PEþ Isolated distal thrombosis
Unilateral LEDVT (group 1 þ group 2; n ¼ 2541)
Surgery history Recent
225 (13.8)
115 (12.6)
.393
340 (13.4)
Older
361 (22.2)
202 (22.1)
.995
563 (22.2)
Malignant neoplasm
167 (10.3)
138 (15.1)
<.001d
305 (12.0)
Hypertension
419 (25.7)
332 (36.4)
<.001d
751 (29.6)
Diabetes
180 (11.0)
145 (15.9)
<.001d
325 (12.8)
Cardiopathy
200 (12.3)
146 (16.0)
.009c
346 (13.6)
Comorbidity
Renal insufficiency
181 (11.1)
153 (16.8)
<.001
334 (13.1)
Pulmonary infection
199 (12.2)
176 (19.3)
<.001d
375 (14.8)
Cerebrovascular disease
262 (16.1)
185 (20.3)
.008c
447 (17.6)
737 (45.2)
571 (62.6)
<.001d
1308 (51.5) 2254 (88.7)
Patients with comorbidity
d
Therapy for LEDVT Drug therapy
1441 (88.5)
813 (89.1)
.600
Non-drug therapy
50 (3.1)
27 (3.0)
.878
77 (3.0)
Both approaches
34 (2.1)
12 (1.3)
.162
46 (1.8)
104 (6.4)
60 (6.6)
.848
Without any therapy for LEDVT Hospital LOS, days Time to diagnosis of PE, days In-hospital mortalitya
10 (7-15)
12 (7-16)
2 (2-4)
2 (1-3)
12 (0.7)
10 (1.1)
164 (6.5)
<.001
d
11 (7-15)
.060
2 (1-4)
.348
22 (0.9)
LOS, Length of stay; PE, pulmonary embolism. Categorical variables are presented as number (%). Continuous variables are presented as mean 6 standard deviation or median (interquartile range). Boldface entries indicate statistical significance. a Some patients in the face of impending death were discharged traditionally before they died, which caused the real mortality to be higher than the value. b P < .05. c P < .01. d P < .001.
Therapy differences between proximal LEDVT and isolated distal LEDVT patients. In unilateral LEDVT, patients with isolated distal LEDVT received less treatment for their thromboembolism disease compared with patients with proximal LEDVT (proximal, 96.3%; distal, 89.1%; P < .001; Table III). In group 3 patients, the proportion of patients receiving antithrombotic therapy was almost the same for both proximal and distal LEDVT patients (proximal, 96.8%; distal, 93.3%; P > .05). PE differences between left-sided LEDVT and rightsided LEDVT patients. Right-sided LEDVT patients had longer median LOS values than left-sided LEDVT patients (right, 12 days; left, 10 days; P < .001; Table I). Patients with right-sided LEDVT were more likely to have PE than patients with left-sided LEDVT (adjusted HR, 1.69; 95% CI, 1.23-2.34; Table IV). Fig 2, B illustrates the
cumulative prevalence of PE in comparing the rightsided LEDVT patients with the left-sided LEDVT patients. The prevalence of PE was significantly higher for patients with right-sided LEDVT than for patients with left-sided LEDVT (log-rank test, P < .001). PE difference of single-segment LEDVT. Table IV shows that the patients with single-segment LEDVT and with the thrombus located in the calf veins and patients with right-sided LEDVT were more likely to have PE than patients with left-sided LEDVT (adjusted HR, 1.88; 95% CI, 1.08-3.26). Fig 2, C illustrates the cumulative prevalence of PE in comparing the right-sided LEDVT patients with the left-sided LEDVT patients. In patients with calf vein thrombosis, the prevalence of PE was significantly higher for patients with right-sided LEDVT than for those with left-sided LEDVT (log-rank test, P ¼ .007).
Zhang et al
Journal of Vascular Surgery: Venous and Lymphatic Disorders Volume
-,
Number
5
-
Table I. Continued. Bilateral LEDVT (group 3; n ¼ 560)
P value
Total (N ¼ 3101)
PEþ (n ¼ 184)
PE (n ¼ 2917)
P value
35 (6.3)
.726
184 (5.9)
e
e
e
372 (66.4)
<.001d
1335 (43.1)
69 (5.2)
1266
.117
292 (52.1)
.867
1607 (51.8)
113 (7.0)
1494
.007c
70.6 6 13.2
<.001d
63.7 6 16.6
63.7 6 16.7
64.6 6 15.2
24 (4.3)
<.001d
364 (13.3)
27 (7.4)
337
.202
144 (25.7)
.069
707 (21.3)
37 (5.2)
670
.370
114 (20.4)
<.001d
419 (13.5)
30 (7.2)
389
.253
244 (43.6)
<.001d
995 (32.1)
72 (7.2)
923
.035b
<.001d
119 (21.3)
<.001
d
444 (14.3)
33 (7.4)
411
119 (21.3)
<.001d
465 (15.0)
37 (8.0)
428
.045b
112 (20.0)
<.001d
446 (14.4)
52 (11.7)
394
<.001d
117 (20.9)
<.001
d
492 (15.9)
54 (11.0)
438
<.001d
135 (24.1)
<.001
d
582 (18.8)
28 (4.8)
554
.203
422 (75.4)
<.001d
1730 (55.8)
154 (8.9)
1576
<.001d
491 (87.7)
.490
2745 (88.5)
151 (5.5)
2592
.005c
19 (3.4)
.654
96 (3.1)
6 (6.3)
90
.894
19 (3.4)
.018b
65 (2.1)
3 (4.6)
62
.850
31 (5.5)
.418
195 (6.3)
23 (11.8)
172
<.001d
12 (8-16)
<.001
2 (1-4)
11 (7-15)
2 (1-5)
.948
6 (1.1)
.641
d
11 (7-15) 28 (0.9)
DISCUSSION It is well known that PE is one of the most serious complications associated with LEDVT. Few studies have examined the relationship between acute LEDVT and PE.13 In this study, we explored the potential factors associated with PE in patients with acute LEDVT. In this study, we observed that patients with proximal thrombus had similar risks of PE as patients who had only isolated distal thrombus (P > .05), which was against common sense that the probability of PE in patients with proximal LEDVT was higher than that in patients with distal LEDVT.5-8 We found that less concern of clinicians for distal thromboses might account for this phenomenon, and these clinicians did not adequately treat distal thromboses compared with proximal thromboses (Table III). Konstantinides et al14 observed that distal vein thromboses were stable and did not directly affect the occurrence of PE. The therapies for distal LEDVT
14 (11-18)
.149
<.001d
e
e
e
3 (1.6)
25 (0.9)
.500
were ignored, and sometimes these therapies were not adopted to avoid a significantly higher risk of bleeding.15,16 However, studies showed that a large number of proximal thrombi might originate from the continuation of distal vein embolism,17,18 and the prevalence of subsequent proximal LEDVT/PE in these distal patients was 7%.19 This suggests that we need to devote more attention to calf vein thrombus and to provide adequate treatment to avoid disease progression. In our data, among bilateral LEDVT cases but not unilateral LEDVT cases, patients with proximal thrombus had higher risk of PE than patients who had only isolated distal thrombus (P < .001). A review of our treatment options found that similar treatment strategies were adopted for the two groups. This result indirectly indicates that the treatment of bilateral LEDVT patients might not be enough and that more improvements should be made in the future.
Zhang et al
6
Journal of Vascular Surgery: Venous and Lymphatic Disorders ---
2019
Table II. Lower extremity deep venous thrombosis (LEDVT) patients with a thrombus that was proximal or isolated distal with pulmonary embolism (PE) Site of LEDVT
PEþ
PE
Adjusted HRa (95% CI)
P value
Left (group 1) Isolated distal Proximal
521 (39.1)
20 (3.8)
501
Reference
1108 (62.7)
54 (4.9)
1054
0.62 (0.37-1.05)
.780
Right (group 2) Isolated distal
442 (33.1)
35 (7.9)
407
Reference
Proximal
470 (26.6)
40 (8.5)
430
0.95 (0.60-1.50)
Isolated distal
372 (27.9)
14 (3.8)
358
Reference
Proximal
188 (10.6)
21 (11.2)
167
2.79 (1.42-5.49)
.820
Bilateral (group 3) <.001b
Unilateral (group 1 þ group 2) Isolated distal Proximal
963 (72.1)
55 (5.7)
908
Reference
1578 (89.4)
94 (6.0)
1484
0.83 (0.59-1.16)
.279
All Isolated distal
1335
69 (5.2)
1266
Reference
Proximal
1766
115 (6.5)
1651
1.34 (0.98-1.84)
.117
CI, Confidence interval; HR, hazard ratio. Values are reported as number (%). Boldface entries indicate statistical significance. a Multivariable analysis including age, sex, and comorbidities. b P < .001.
Fig 2. A, The cumulative prevalence of no pulmonary embolism (PE) in bilateral lower extremity deep venous thrombosis (LEDVT) patients with proximal LEDVT and isolated distal LEDVT. B, The cumulative prevalence of no PE in unilateral LEDVT patients with left-sided LEDVT and right-sided LEDVT. C, The cumulative prevalence of no PE in calf vein thrombosis patients with left-sided LEDVT and right-sided LEDVT. Standard error <10% for all time points up to cross.
In the left-sided and right-sided LEDVT patients, we observed that the number of patients with right-sided LEDVT was smaller than that of patients with left-sided LEDVT, which is similar to many previous studies.13,20 We observed that right-sided LEDVT patients were more likely to have PE than left-sided LEDVT patients, which resulted in right-sided LEDVT patients having a longer LOS. The current explanation for this phenomenon is the existence of May-Thurner syndrome resulting from stenosis of the left iliac vein. May-Thurner syndrome may predispose to DVT, but at the same time, the stenosis in the iliac vein may prevent PE from the DVT.13 In
other words, the presence of iliac stenosis may act as a partial filter, and thrombi are less likely to escape from the left iliac vein to the lungs. However, this explanation is insufficient. The number of individuals with comorbidities in the right-sided LEDVT cases was higher than that in the left-sided ones (Table I). This result was similar to the study of Narayan et al,21 but it was different from the study of Bikdeli et al.22 Some authors thought comorbidity to be an important cause of PE because comorbidity was associated with an increased risk of thrombosis. For example, in patients with a malignant tumor, the specific
Zhang et al
Journal of Vascular Surgery: Venous and Lymphatic Disorders Volume
-,
Number
7
-
Table III. Lower extremity deep venous thrombosis (LEDVT) patients with a thrombus that was proximal or isolated distal with therapy for LEDVT Therapy for LEDVT Drug therapy
P value
Non-drug therapy
P value
Both approaches
P value
With therapy for LEDVT
P value
521
429 (82.3)
<.001b
19 (3.6)
.354
12 (2.3)
.676
460 (88.3)
<.001b
1108
1012 (91.3)
Isolated distal
442
383 (86.7)
Proximal
470
430 (91.5)
963
812 (84.3)
1578
1442 (91.4)
Isolated distal
372
326 (87.6)
Proximal
188
165 (87.7)
Isolated distal
1335
1138 (85.2)
Proximal
1766
1607 (91.0)
Site of LEDVT Left Isolated distal Proximal
31 (2.8)
22 (2.0)
1065 (96.1)
Right .019a
12 (2.7)
.671
3 (2.3)
15 (3.2)
.178
398 (90.1)
9 (1.9)
<.001b
454 (96.6)
Unilateral Isolated distal Proximal
<.001b
31 (3.2)
.664
15 (1.6)
46 (2.9)
.455
858 (89.1)
31 (2.0)
<.001b
1519 (96.3)
Bilateral .964
9 (2.4)
.073
12 (3.2)
10 (5.3)
.759
347 (93.3)
7 (3.7)
.085
182 (96.8)
All <.001b
40 (3.0)
.781
56 (3.2)
27 (2.0)
.803
1205 (90.3)
38 (2.2)
<.001b
1701 (96.3)
Values are reported as number (%). Boldface entries indicate statistical significance. a P < .05. b P < .001.
Table IV. Segment and side of lower extremity deep venous thrombosis (LEDVT) associated with pulmonary embolism (PE) Site of LEDVT
PEþ
PE
Adjusted HRa (95% CI)
P value
Segment 1, calf vein Left
521 (32.0)
20 (3.8)
501
Reference
Right
442 (48.5)
35 (7.9)
407
1.95 (1.13-3.38)
.017b
Segment 2, popliteal vein Left
44 (2.7)
2 (4.5)
42
Reference
Right
34 (3.7)
6 (17.6)
28
e
.067
Segment 3, femoral vein Left
67 (4.1)
3 (4.5)
64
Reference
Right
34 (3.7)
0 (e)
34
e
0 (e)
e
.663
Segment 4, common femoral vein Left Right
e
Reference
38 (4.2)
4 (10.5)
34
e
Left
47 (2.9)
4 (8.5)
43
Reference
Right
16 (1.8)
2 (12.5)
14
e
e
Segment 5, iliac vein .627
Two or more segments Left
950 (58.3)
45 (4.7)
905
Reference
Right
348 (38.2)
28 (8.0)
320
e
Left
1629
74 (4.5)
1555
Reference
Right
912
75 (8.2)
837
1.69 (1.23-2.34)
.275
All
CI, Confidence interval; HR, hazard ratio. Values are reported as number (%). Boldface entries indicate statistical significance. a Multivariable analysis including age, sex, and comorbidities. b P < .05. c P < .01.
.001c
8
Zhang et al
Journal of Vascular Surgery: Venous and Lymphatic Disorders ---
procoagulant substances and the inflammatory responses of the host cells were significantly increased, which increased the probability of thrombosis22,23; and some patients with heart failure often had increased venous stasis and venous pressure, which facilitated the occurrence of DVT.20 We speculate that the main reason for the occurrence of PE in right-sided LEDVT patients is that these patients have a higher likelihood of comorbidities. To reduce the prevalence of PE in patients with right-sided LEDVT, the key is to treat the comorbidities actively. Several limitations of our study should be considered. First, we were not definitively sure that the PE in patients originated from the legs rather than from the pelvis or other sites of the vein. To investigate the source of the embolus, more venous examinations are needed to find details. Second, not enough attention was paid to the efficacy of new oral anticoagulants and thrombus removal, and whether our data were affected by new therapies in the last 10 years remains in doubt. Third, some patients did not receive treatment because of their physicians’ subjective criteria, such as abnormal coagulant function or stable thrombus, which led to no treatment. Fourth, different physicians had different criteria to use computed tomography angiography for PE diagnosis, and we did not know how many PE patients had been missed. Last, our data came from a single-center study, and we need multicenter studies from which the results can be generalized.
CONCLUSIONS Among bilateral LEDVT patients but not unilateral LEDVT patients, the probability of PE was significantly increased in patients with proximal LEDVT compared with patients with distal LEDVT, and this result may be associated with inadequate therapy for proximal bilateral LEDVT. The probability of PE occurring on the left side of the thrombus was significantly lower than the probability of PE occurring on the right side of the thrombus, especially in calf DVT patients, and the main reason may be that patients with right-sided LEDVT experience more comorbidities.
AUTHOR CONTRIBUTIONS Conception and design: CZ, QL, HY, FW, ZL, WY, YP, MW, WX, XC, NL Analysis and interpretation: CZ, XC, NL Data collection: CZ, QL, HY, FW, ZL, WY, YP, MW, WX, XC, NL Writing the article: CZ, QL, HY, FW, ZL, WY, YP, MW, WX, XC, NL Critical revision of the article: CZ, XC, NL Final approval of the article: CZ, QL, HY, FW, ZL, WY, YP, MW, WX, XC, NL Statistical analysis: CZ, XC, NL Obtained funding: Not applicable Overall responsibility: CZ
2019
REFERENCES 1. Law Y, Chan YC, Cheng SW. Epidemiological updates of venous thromboembolism in a Chinese population. Asian J Surg 2018;41:176-82. 2. Adams K, Sheth SA, Meyr AJ. The reliability of venous duplex ultrasound and clinical findings for the diagnosis of lower extremity deep venous thrombosis. J Am Podiatr Med Assoc 2016;106:12. 3. Cogo A, Lensing AW, Prandoni P, Hirsh J. Distribution of thrombosis in patients with symptomatic deep vein thrombosis. Implications for simplifying the diagnostic process with compression ultrasound. Arch Intern Med 1993;153: 2777-80. 4. Claus K, Angelika R. Principle mechanisms underlying venous thromboembolism: epidemiology, risk factors, pathophysiology and pathogenesis. Respiration 2003;70: 7-30. 5. Georgiev M. Regarding “Nomenclature of the veins of the lower limbs: an international interdisciplinary consensus statement. J Vasc Surg 2004;39:1144. 6. Yamaki T, Hamahata A, Soejima K, Kono T, Nozaki M, Sakurai H. Factors predicting development of postthrombotic syndrome in patients with a first episode of deep vein thrombosis: preliminary report. Eur J Vasc Endovasc Surg 2011;41:126-33. 7. Mebazaa A, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, et al. Predicting the risk of venous thromboembolism in patients hospitalized with heart failure. Circulation 2014;130:410. 8. Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014;35:3033-69. 3069a-k. 9. Dwyer KH, Rempell JS, Stone MB. Diagnosing centrally located pulmonary embolisms in the emergency department using point-of-care ultrasound. Am J Emerg Med 2016;68:S135. 10. De Maeseneer MG, Bochanen N, van Rooijen G, Neglén P. Analysis of 1,338 patients with acute lower limb deep venous thrombosis (DVT) supports the inadequacy of the term "proximal DVT. Eur J Vasc Endovasc Surg 2016;51: 415-20. 11. Wells PS, Carolyn O, Steve D, Dean F, Huyen T. Does this patient have deep vein thrombosis? JAMA 1998;279:1094. 12. Kearon C, Ginsberg JS, Hirsh J. The role of venous ultrasonography in the diagnosis of suspected deep venous thrombosis and pulmonary embolism. Ann Intern Med 1998;129:1044-9. 13. Widimský J Sr, Aschermann M. [New ESC guidelines on the diagnosis and management of acute pulmonary embolism]. Vnitr Lek 2015;61:236-43. 14. Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, et al. Corrigendum to: 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2015;36:2666. 15. Galanaud JP, Khau VK, Boubakri C, Böge G, Laroche JP, Quéré I. [Calf vein thrombosis: to treat or not to treat? Epidemiology, management and problematics]. J Mal Vasc 2007;32:225-8. 16. Righini M, Galanaud JP, Guenneguez H, Brisot D, Diard A, Faisse P, et al. Anticoagulant therapy for symptomatic calf deep vein thrombosis (CACTUS): a randomised, double-blind, placebo-controlled trial. Lancet Haematol 2016;3:e556-62. 17. Pham XB, de Virgilio C. Significance of isolated calf vein thrombosisdfurther evidence. JAMA Surg 2016;151:e161799. 18. Ro A, Kageyama N. Clinical significance of the soleal vein and related drainage veins, in calf vein thrombosis in
Journal of Vascular Surgery: Venous and Lymphatic Disorders Volume
-,
Number
Zhang et al
9
-
autopsy cases with massive pulmonary thromboembolism. Ann Vasc Dis 2016;9:15-21. 19. Ro A, Kageyama N, Tanifuji T, Fukunaga T. Pulmonary thromboembolism: overview and update from medicolegal aspects. Leg Med (Tokyo) 2008;10:57-71. 20. Alexandre M, Spiro TE, Büller HR, Lloyd H, Dayi H, Russell H, et al. Predicting the risk of venous thromboembolism in patients hospitalized with heart failure. Circulation 2014;130:410. 21. Narayan A, Eng J, Carmi L, McGrane S, Ahmed M, Sharrett AR, et al. Iliac vein compression as risk factor for leftversus right-sided deep venous thrombosis: case-control study. Radiology 2012;265:949-57.
22. Bikdeli B, Sharif-Kashani B, Bikdeli B, Valle R, Falga C, RieraMestre A, et al. Impact of thrombus sidedness on presentation and outcomes of patients with proximal lower extremity deep vein thrombosis. Semin Thromb Hemost 2018;44:341-7. 23. Rickles FR, Falanga A. Molecular basis for the relationship between thrombosis and cancer. Thromb Res 2001;102: V215-24.
Submitted Aug 5, 2019; accepted Nov 25, 2019.