Clinical Characteristics and Outcomes of Venous Thromboembolisms According to an Out-of-Hospital vs. In-Hospital Onset　― From the COMMAND VTE Registry ―

Abstract

Background: Differences in the clinical characteristics and outcomes of venous thromboembolisms (VTEs) based on different clinical situations surrounding the onset might be important for directing appropriate treatment strategies, but have not yet been appropriately evaluated.

Methods and Results: The COMMAND VTE Registry is a multicenter registry enrolling 3,027 consecutive patients with acute symptomatic VTEs in Japan between January 2010 and August 2014. We divided the study population into 3 groups: Out-of-hospital onset (n=2,308), In-hospital onset with recent surgery (n=310), and In-hospital onset without recent surgery (n=374). Active cancer was most prevalent in the In-hospital onset without recent surgery group, and least in the Out-of-hospital onset group (Out-of-hospital onset group: 20%, In-hospital onset with recent surgery group: 26%, and In-hospital onset without recent surgery group: 38%, P<0.001). The cumulative 5-year incidence of recurrent VTEs did not significantly differ across the 3 groups (11.4%, 5.8%, and 8.7%, respectively; P=0.11). The cumulative 5-year incidences of major bleeding and all-cause death were highest in the In-hospital onset without recent surgery group (11.1%, 8.5%, and 23.3%, P<0.001; 26.8%, 24.9%, and 48.4%, P<0.001, respectively).

Conclusions: In the real-world VTE registry, the clinical characteristics and long-term outcomes substantially differed according to the clinical situation of VTE onset, suggesting the need for different treatment strategies for VTEs in different clinical settings.

Venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT), is a major health problem worldwide.¹ Recently, the number of patients clinically diagnosed with VTE in Japan was reported to be gradually increasing,² partly because of the increased prevalence of risk factors for VTEs, including surgery, old age, and active cancer, as well as an increased awareness of VTE. Surgery is a well-known transient risk factor for VTE, and VTE has been recognized as a serious perioperative complication and one of the main causes of in-hospital death.³ However, the incidence of perioperative PE has been reported as decreasing over time, partly because of the increasing administration of thromboprophylaxis for VTE in hospitals,⁴ suggesting that the clinical situation surrounding VTE onset is also changing.

The clinical characteristics and outcomes of VTE might differ according to the situation of its onset, and understanding the differences between out-of-hospital and in-hospital onset might be important in deciding on the appropriate treatment strategy in the daily clinical practice. However, there is a scarcity of data on the differences in the clinical characteristics and outcomes of VTE according to its onset. Therefore, we sought to evaluate the differences in clinical characteristics, management strategies, and outcomes in patients with VTE according to its onset in a large observational database in Japan.

Methods

Study Population

The COMMAND VTE (COntemporary ManageMent AND outcomes in patients with Venous ThromboEmbolism) Registry is a physician-initiated, multicenter retrospective cohort study enrolling consecutive patients with acute symptomatic VTE that was objectively confirmed by imaging examination (ultrasound, contrast-enhanced computed tomography, ventilation-perfusion lung scintigraphy, pulmonary angiography, or contrast venography) or by autopsy in 29 centers in Japan between January 2010 and August 2014.^5,6 The relevant review boards or ethics committees in all 29 participating centers (Supplementary Appendix 1) approved the research protocol. Written informed consent from each patient was waived because we used clinical information obtained in routine clinical practice, and no patient refused to participate in the study when contacted for follow-up. This method was concordant with the guidelines for epidemiological studies issued by the Ministry of Health, Labor, and Welfare in Japan.

We searched the hospitals’ databases for clinical diagnoses and imaging examinations, and enrolled consecutive patients who met the definition of an acute symptomatic VTE diagnosed within 31 days from symptom onset during the study period.⁷ The symptoms of VTE were defined as follows: sudden onset of dyspnea, pleuritic chest pain, substernal chest pain, cough, fever, hemoptysis, and syncope caused by a PE, and erythema, warmth, pain, swelling, tenderness, and pain upon dorsiflexion of the foot for a DVT.^8,9 Additionally, sudden onset abnormalities in the vital signs, such as a decrease in arterial oxygen saturation or hypotension, were also regarded as symptoms of a PE. The presence or absence of symptoms was evaluated at the time of the imaging studies.

We enrolled 3,027 consecutive patients with acute symptomatic VTEs after screening 19,634 consecutive patients with suspected VTEs for eligibility through chart reviews by the responsible physicians at each institution. Regarding the clinical situations surrounding the VTE onset, there were 2,308 patients with an out-of-hospital VTE onset regardless of recent surgery, and 719 with an in-hospital VTE onset. The patients with an in-hospital VTE onset were further classified according to the presence or absence of recent surgery before the onset of the VTE. We excluded 25 patients who developed VTEs in hospital more than 2 months after surgery, and 10 patients who developed VTEs during a re-hospitalization within 2 months after the surgery. Finally, the present study population consisted of 3 groups of patients classified according to the clinical situation surrounding VTE onset (Out-of-hospital onset group: n=2,308; In-hospital onset with recent surgery group: n=310; In-hospital onset without recent surgery group: n=374) (Figure 1).

Figure 1.

Study flow chart. VTE included both PE and/or DVT. DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism.

Data Collection and Definitions of Patients’ Characteristics

Data for the baseline characteristics were collected from the hospital charts or hospital databases according to prespecified definitions. The physicians at each institution were responsible for data entry into an electronic case report form in a web-based database system. Data were automatically checked for missing or contradictory input and values out of the expected range. Additional monitoring for the quality of the data was performed at the general office of the registry.

A simplified version of the PE severity index (sPESI) score was used to estimate the severity of the PEs. The sPESI score included the following variables: age >80 years, history of cancer, history of chronic cardiopulmonary disease, heart rate ≥110 beats/min, systolic blood pressure <100 mmHg, and arterial oxygen saturation <90% at the time of the diagnosis.¹⁰ Surgery included all surgeries with general or local anesthesia requiring hospitalization. The detailed definitions of the other patient characteristics are described in Supplementary Appendix 2.

Clinical Follow-up and Endpoints

Collection of the follow-up information was mainly conducted through review of hospital charts, and additional follow-up information was collected through contact with the patients, relatives, and/or referring physicians by phone and/or mail with questions regarding vital status, recurrent VTE, bleeding, invasive procedures, and the status of anticoagulation therapy.

Recurrent VTE was defined as PE and/or DVT with symptoms accompanied by confirmation of a new thrombus or exacerbation of the thrombus by objective imaging examinations or autopsy.¹¹ Major bleeding was defined as International Society of Thrombosis and Hemostasis (ISTH) major bleeding, which consisted of a reduction in the hemoglobin level by at least 2 g/dL, a transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ.¹² The independent clinical event committee (Supplementary Appendix 3), unaware of the patients’ characteristics, reviewed all study outcomes.

Statistical Analysis

We present the categorical variables as numbers and percentages, and continuous variables as the mean with the standard deviation or the median with the interquartile range based on their distribution. Categorical variables were compared using the chi-squared test when appropriate; otherwise, a Fisher’s exact test was used. Continuous variables were compared using a one-way analysis of variance or Kruskal-Wallis test based on their distribution. We used the Kaplan-Meier method to estimate the cumulative incidence and assessed the differences with a log-rank test. All statistical analyses were conducted using R software packages (version 3.5.0; R Development Core Team). All statistical analyses were two-tailed and P<0.05 was considered statistically significant.

Results

Patients’ Characteristics and Treatment Strategies

In the current study population, the mean age was 67 years, 61% were women, and the mean body weight and body mass index were 57.9 kg and 23.2 kg/m², respectively. The baseline characteristics substantially differed across the groups in several aspects (Table 1). Active cancer was most prevalent in the In-hospital onset without recent surgery group, and least prevalent in the Out-of-hospital onset group. Patients in the Out-of-hospital onset group presented with PEs most frequently, and the clinical severity of PEs was lowest in the Out-of-hospital onset group, which had the highest proportion of patients with sPESI score 0. In the Out-of-hospital onset group, the median time from onset to diagnosis was longest, and 80% of patients were admitted to an inpatient service for management of VTE, with a median duration of hospitalization of 16 days (Table 1). As for the types of surgery in the In-hospital onset with recent surgery group, orthopedic surgery was the most common (43%), followed by abdominal surgery (20%), and then neurosurgery (11%) (Figure 2). The distribution of the clinical situations surrounding VTE onset varied widely across the participating centers, and the proportion of an Out-of-hospital onset ranged from 43% to 95% (Figure 3).

Table 1. Characteristics of Patients With VTE

	Out-of-hospital onset (n=2,308)	In-hospital onset with recent surgery (n=310)	In-hospital onset without recent surgery (n=374)	P value
Baseline characteristics
Age (years)	66.9±15.5	69.0±14.5	66.8±15.5	0.07
Female	1,378 (60%)	221 (71%)	238 (64%)	<0.001
Body weight (kg)	58.5±14.0	57.0±13.7	55.0±11.8	<0.001
Body mass index (kg/m2)	23.3±4.4	23.6±4.9	22.4±3.9	<0.001
Body mass index ≥30 kg/m2	126 (5.5%)	25 (8.1%)	17 (4.6%)	0.11
Comorbidities
Hypertension	893 (39%)	122 (39%)	133 (36%)	0.48
Diabetes mellitus	266 (12%)	40 (13%)	75 (20%)	<0.001
Dyslipidemia	479 (21%)	61 (20%)	61 (16%)	0.14
Chronic kidney disease	444 (19%)	48 (16%)	78 (21%)	0.18
Dialysis	7 (0.3%)	2 (0.6%)	11 (2.9%)	<0.001
Liver cirrhosis	15 (0.6%)	5 (1.6%)	6 (1.6%)	0.06
History of cancer	643 (28%)	113 (37%)	163 (44%)	<0.001
Active cancer at diagnosis	458 (20%)	81 (26%)	141 (38%)	<0.001
Chronic lung disease	203 (8.8%)	24 (7.7%)	40 (11%)	0.36
Heart failure	65 (2.8%)	13 (4.2%)	20 (5.3%)	0.02
History of myocardial infarction	33 (1.4%)	7 (2.3%)	12 (3.2%)	0.04
History of stroke	167 (7.2%)	27 (8.7%)	70 (19%)	<0.001
Atrial fibrillation	81 (3.5%)	15 (4.8%)	30 (8.0%)	<0.001
Connective tissue disease	177 (7.7%)	11 (3.5%)	54 (14%)	<0.001
Varicose vein	115 (5.0%)	14 (4.5%)	9 (2.4%)	0.09
History of VTE	152 (6.6%)	6 (1.9%)	18 (4.8%)	0.003
History of major bleeding	111 (4.8%)	38 (12%)	76 (20%)	<0.001
Transient risk factors for VTE	541 (23%)	310 (100%)	209 (56%)	<0.001
Unprovoked VTE	1,373 (60%)	0 (0%)	66 (18%)	<0.001
Presentation
PE with or without DVT	1,352 (59%)	153 (49%)	193 (52%)	<0.001
Hypoxemia	648/1,352 (48%)	99/153 (65%)	112/193 (58%)	0.32
Shock	128/1,352 (9.5%)	30/153 (20%)	24/193 (12%)	0.02
Cardiac arrest/collapse	58/1,352 (4.3%)	14/153 (9.2%)	8/193 (4.1%)	0.10
sPESI score 0	331/1,352 (24%)	27/153 (18%)	24/193 (12%)	<0.001
sPESI score ≥1	1,021/1,352 (76%)	126/153 (82%)	169/193 (88%)	<0.001
DVT only	956 (41%)	157 (51%)	181 (48%)	<0.001
Proximal DVT	684/956 (72%)	94/157 (60%)	126/181 (70%)	<0.001
Onset-to-diagnosis (days)	5 (2–10)	1 (0–3)	2 (1–5)	<0.001
Hospitalization	1,847 (80%)	–	–	–
Length of hospital stay (days)	16 (11–23)	–	–	–
Hospitalization with PE	1,221/1,352 (90%)	–	–	–
Length of hospital stay (days)	17 (12–24)	–	–	–
Hospitalization with DVT	626/956 (65%)	–	–	–
Length of hospital stay (days)	15 (10–21)	–	–	–
Laboratory tests at diagnosis
Anemia (n=2,977)	1,055 (46%)	263 (85%)	283 (76%)	<0.001
Thrombocytopenia (n=2,977)	115 (5.0%)	12 (3.9%)	36 (9.7%)	0.005
D-dimer (μg/mL) (n=2,820)	9.5 (4.7–19.0)	15.0 (8.5–26.2)	13.4 (6.1–29.3)	<0.001
Thrombophilia	133 (5.8%)	7 (2.3%)	5 (1.3%)	<0.001
eGFR (mL/min/1.73 m2) (n=2,966)	66.1 (50.6–82.5)	75.6 (57.5–91.1)	72.0 (54.1–94.1)	<0.001

Categorical variables are presented as numbers and percentages. Continuous variables are presented as the mean and standard deviation, or the median and interquartile range based on their distribution. Categorical variables were compared with the chi-square test when appropriate; otherwise, Fisher’s exact test was used. Continuous variables were compared using one-way analysis of variance or the Kruskal-Wallis test based on their distribution. Chronic kidney disease was diagnosed if there was persistent proteinuria or if the estimated glomerular filtration rate (eGFR) was <60 mL/min/1.73 m² for more than 3 months. The eGFR data were calculated using the equation reported by the Japan Association of Chronic Kidney Disease Initiative [men: 194*Scr^−1.094*age^−0.287, women: 194*Scr^−1.094*age^−0.287*0.739]. The sPESI score included the following variables: age >80 years, history of cancer, history of chronic cardiopulmonary disease, heart rate ≥110 beats/min, systolic blood pressure <100 mmHg, and arterial oxygen saturation <90% at the time of the diagnosis. Anemia was diagnosed if hemoglobin was <13 g/dL for men and <12 g/dL for women. Thrombocytopenia was diagnosed if platelets were <100×10⁹/L. Thrombophilia included a protein C deficiency, protein S deficiency, antithrombin deficiency, and antiphospholipid syndrome. DVT, deep vein thrombosis; PE, pulmonary embolism; sPESI, simplified pulmonary embolism severity index; VTE, venous thromboembolism.

Figure 2.

Distribution of the types of surgery associated with venous thromboembolism in the current study.

Figure 3.

Distribution of the situation surrounding VTE onset according to the participating centers, classified as Out-of-hospital onset, In-hospital-onset with recent surgery, and In-hospital-onset without recent surgery. VTE included pulmonary embolism and/or deep vein thrombosis. VTE, venous thromboembolism.

Patients in the Out-of-hospital onset group received initial parenteral anticoagulation therapy least frequently, but received thrombolysis treatment most frequently (Table 2). The prevalence of inferior vena cava filter use, ventilator support, or percutaneous cardiopulmonary support did not significantly differ across the 3 groups. Anticoagulation therapy beyond the acute phase was implemented most frequently in the Out-of-hospital onset group.

Table 2. Treatment Strategies for VTE

	Out-of-hospital onset (n=2,308)	In-hospital onset with recent surgery (n=310)	In-hospital onset without recent surgery (n=374)	P value
Treatment in the acute phase
Initial parenteral anticoagulation therapy	1,899 (82%)	271 (87%)	335 (90%)	<0.001
Thrombolysis	383 (20%)	21 (7.7%)	22 (6.6%)	<0.001
Inferior vena cava filter use	529 (23%)	65 (21%)	96 (26%)	0.33
Ventilator support	73 (3.2%)	11 (3.5%)	7 (1.9%)	0.35
Percutaneous cardiopulmonary support	30 (1.3%)	5 (1.6%)	3 (0.8%)	0.60
Concomitant medications
Corticosteroids	237 (10%)	17 (5.5%)	89 (24%)	<0.001
Nonsteroidal anti-inflammatory drugs	202 (8.8%)	46 (15%)	45 (12%)	<0.001
Proton pump inhibitors/H2-blockers	992 (43%)	124 (40%)	203 (54%)	<0.001
Statins	349 (15%)	39 (13%)	44 (12%)	0.14
Antiplatelet agents	233 (10%)	27 (8.7%)	42 (11%)	0.55
Anticoagulation therapy beyond the acute phase	2,172 (94%)	279 (90%)	324 (87%)	<0.001
Direct oral anticoagulant	53/2,172 (2.4%)	15/279 (5.4%)	10/324 (3.1%)	0.002
Heparin	35/2,172 (1.6%)	2/279 (0.7%)	12/324 (3.7%)
Warfarin	2,084/2,172 (96%)	262/279 (94%)	302/324 (93%)
TTR for INR 1.5–2.5 (%) (n=2,483)	73.2 (47.0–92.0)	70.8 (44.3–89.2)	67.9 (39.4–88.2)	0.046
TTR for INR 2.0–3.0 (%) (n=2,483)	31.2 (9.1–56.9)	27.4 (2.4–50.1)	30.7 (7.4–55.9)	0.04
Duration of anticoagulation (days)	642 (188–1,286)	245 (103–951)	273 (89–975)	<0.001

Categorical variables are presented as numbers and percentages. Continuous variables are presented as the median and interquartile range. Categorical variables were compared with the chi-square test when appropriate; otherwise, Fisher’s exact test was used. Continuous variables were compared using the Kruskal-Wallis test. INR, international normalized ratio; TTR, time in therapeutic range; VTE, venous thromboembolism.

Clinical Outcomes

The cumulative 5-year incidence of recurrent VTE did not significantly differ across the 3 groups (Out-of-hospital onset group: 11.4%; In-hospital onset with recent surgery group: 5.8%; In-hospital onset without recent surgery group; 8.7%, P=0.11), although it was numerically higher in the Out-of-hospital onset group than in the other 2 groups (Figure 4A). The cumulative 5-year incidence of major bleeding was highest in the In-hospital onset without recent surgery group (11.1%, 8.5%, and 23.3%, respectively; P<0.001) (Figure 4B). The cumulative 5-year incidence of all-cause death was also highest in the In-hospital onset without recent surgery group (26.8%, 24.9%, and 48.4%, respectively; P<0.001) (Figure 4C).

Figure 4.

Kaplan-Meier curves for clinical outcomes of VTE. (A) Recurrent VTE, (B) major bleeding, and (C) all-cause death. VTE included pulmonary embolism and/or deep vein thrombosis. VTE, venous thromboembolism.

Discussion

The main findings of the current study were: (1) approximately three-quarters of the patients developed VTE out of hospital, and the clinical characteristics substantially differed according to the clinical situation of VTE onset; (2) the Out-of-hospital onset group received initial parenteral anticoagulation therapy least frequently, but received anticoagulation therapy beyond the acute phase most frequently; (3) the long-term risk for recurrent VTE did not significantly differ according to the clinical situation of VTE onset, but the long-term risk for major bleeding and death was highest in the In-hospital onset without recent surgery group.

A previous study by questionnaire survey in Japan reported that the proportions of patients developing VTE out of hospital among all patients with VTE had increased from 49% in 2000–2003 to 70% in 2011.² Consistent with that report, the current study showed a high proportion of patients developing VTE out of hospital (76%). This could be partly because more attention has been paid to the prevention of in-hospital VTE, leading to a decreased relative proportion of VTE in the hospital setting. Considering the high proportion of patients developing VTE out of hospital in current real-world clinical practice, we should recognize VTE as a disease rather than an adverse event during hospitalization, which we frequently encounter not only in the in-hospital setting, but also in the out-of-hospital setting. The current study also showed that the distribution of the clinical situation surrounding VTE onset varied widely across the participating centers. The differences in the target patients at each institution might have greatly affected this variation, suggesting the need for different approaches to the diagnosis, treatment, and prevention of VTE at each institution.

In the era of warfarin, patients with acute VTE needed to be treated with heparin intravenously followed by warfarin in hospital. However, in the era of direct oral anticoagulants (DOACs) for VTE, some are used as a single-drug approach without administering intravenous anticoagulants, which is more suitable for early hospital discharge or home treatment.^13–15 Furthermore, patients with a relatively-low-risk for PE could also be treated with DOACs without hospitalization.¹⁶ The current study showed that 90% of patients developing PEs out of hospital were admitted to hospital, although approximately one-quarter of the patients with PEs who were at a low risk (sPESI score 0) could be candidates for early hospital discharge or home treatment. The current study also showed that patients developing VTE out of hospital least frequently received initial parenteral anticoagulation therapy, suggesting that some of them who received initial oral anticoagulation therapy with warfarin could be good candidates for home treatment with DOACs.

In the current study, the Out-of-hospital onset group received thrombolysis most frequently, although they had a lower clinical severity of the PEs, and there was a discrepancy between clinical severity and the antithrombotic treatment strategy. This could be partly because of the differences in the patients’ characteristics. The Out-of-hospital onset group had a lower risk of bleeding, including anemia, active cancer, and a history of major bleeding, and they tended to receive more aggressive antithrombotic therapy, whereas the In-hospital onset group had a higher risk of bleeding, and they tended not to receive aggressive antithrombotic therapy.

Regarding the long-term clinical outcomes, previous studies reported that surgery-provoked VTEs had a lower risk of recurrence than nonsurgical provoked or unprovoked VTEs,^17–19 and cancer-associated VTEs compared with non-cancer-associated VTEs were associated with a higher risk for recurrent VTE, major bleeding, and all-cause death.^20–26 In the current study, the long-term risk of patients in the In-hospital onset with recent surgery group did not differ from that in the other 2 groups, which might be explained by the relatively high prevalence of a cancer history in this group. Further, the patients in the In-hospital onset without recent surgery group compared with the other 2 groups were associated with a substantially higher long-term risk for major bleeding and death, which might be explained by the higher prevalence of active cancer and other comorbidities such as strokes, connective tissue disease, atrial fibrillation, etc.

Study Limitations

First, the patient demographics, practice patterns, and medical therapy, as well as the clinical outcomes of patients with VTEs in Japan may differ from those outside Japan. Second, the current study was conducted before the introduction of DOACs for VTE in Japan.²⁷ Thus, the results should be interpreted with caution as to whether they can be extrapolated to patients treated with DOACs. Third, the current study population included some patients with atrial fibrillation, which could have had some influence on the anticoagulation treatment strategies and clinical outcomes. Thus, we analyzed the relevant treatment strategies and clinical outcomes among the groups after excluding 126 patients with atrial fibrillation. As a result, we had almost similar results for the relevant treatment strategies and clinical outcomes, except for slightly shorter duration of anticoagulation with a similar reduction (Supplementary Table, Supplementary Figure).

Conclusions

In the current real-world VTE registry, the clinical characteristics and long-term outcomes substantially differed according to the clinical situations surrounding the VTE onset, suggesting the need for different treatment strategies for VTEs in different clinical settings.

Acknowledgments

We appreciate the support and collaboration of the co-investigators participating in the COMMAND VTE Registry. We are indebted to the independent clinical research organization (Research Institute for Production Development, Kyoto, Japan) for technical support. We also express our gratitude to Mr. John Martin for his grammatical assistance.

Conflicts of Interest

Dr. Yamashita received lecture fees from Daiichi-Sankyo, Bristol-Myers Squibb, and Bayer Healthcare. Dr. Morimoto received lecture fees from Mitsubishi Tanabe Pharma and Pfizer Japan, and consultant fees from Asahi Kasei, Bristol-Myers Squibb, and Boston Scientific. Dr. Akao received lecture fees from Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Bayer Healthcare, and Daiichi-Sankyo. Dr. Kimura received a research grant from Daiichi-Sankyo. All other authors report that they have no relationships relevant to this paper to disclose.

Funding

The COMMAND VTE Registry is supported by an independent clinical research organization (Research Institute for Production Development, Kyoto, Japan) and research funding from Mitsubishi Tanabe Pharma Corporation. The research funding had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data, and preparation, review, or approval of the manuscript.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-18-1314

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