Characteristics and Management of Patients with Venous Thromboembolism: The GARFIELD-VTE Registry

Abstract Background Management of venous thromboembolism (VTE), encompassing both deep vein thrombosis (DVT) and pulmonary embolism (PE), varies worldwide. Methods The Global Anticoagulant Registry in the FIELD – Venous Thromboembolism (GARFIELD-VTE) is a prospective, observational study of 10,685 patients with objectively diagnosed VTE recruited from May 2014 to January 2017 at 417 sites in 28 countries. All patients are followed for at least 3 years. We describe the baseline characteristics of the study population and their management within 30 days of diagnosis. Results The median age was 60.2 years; 50.4% were male; 61.7% had DVT and 38.3% had PE ± DVT; and 32.3% were obese (body mass index ≥ 30 kg/m2). The most common risk factors were surgery (12.5%), hospitalization (12.0%) and trauma to the lower limbs (7.8%). At the time of VTE diagnosis, 10.1% had active cancer and 5.7% were chronically immobilized. Treatment for VTE was anticoagulant (AC) therapy alone in 90.9% of patients; 5.1% received thrombolytic and/or surgical/mechanical therapy ± AC and 4.0% received no therapy. Pre-diagnosis, 12.8% received AC therapy alone and 0.2% received thrombolytic and/or surgical/mechanical therapy ± AC. After diagnosis, parenteral AC therapy alone was administered in 17.6% of patients, and it was followed by a direct oral AC (DOAC) in 16.4% or a vitamin K antagonist (VKA) in 26.8%. DOACs alone were prescribed to 32.3% of patients, while 5.9% received VKA alone. Conclusion The initial findings from this global registry highlight the heterogeneity in characteristics and management of VTE patients. Prospective follow-up will reveal the impact of this heterogeneity on outcomes.


Introduction
Deep vein thrombosis (DVT) and pulmonary embolism (PE), collectively known as venous thromboembolism (VTE), are common causes of morbidity and mortality. VTE, which is the third most common cause of cardiovascular death after coronary heart disease and ischaemic stroke, is responsible for more than 500,000 deaths in the European Union, and up to 300,000 deaths in the United States each year. [1][2][3] The aetiology of VTE is multifactorial; patients may have an inherited predisposition to thrombosis, or VTE may be triggered by transient risk factors such as surgery or trauma, or by persistent risk factors such as cancer. 4 In approximately half of cases, VTE occurs in the absence of obvious provoking factors.
Anticoagulation therapy is the mainstay of VTE treatment, with only selected cases receiving thrombolytic or other reperfusion therapies. The changing clinical landscape of VTE treatment with the introduction of direct oral anticoagulants (DOACs) means that observational studies, beyond the clinical trial setting, are needed to provide insights into their impact on VTE treatment and clinical outcomes worldwide. The Global Anticoagulant Registry in the FIELD -Venous Thromboembolism (GARFIELD-VTE) is an on-going prospective study designed to observe initial and extended management strategies for a minimum of 36 months, in addition to economic and clinical outcomes in VTE patients treated according to local standard practices. 5 The purpose of this article is to describe the baseline characteristics of the study population and their initial management within 30 days of objective VTE diagnosis.

Methods Study Design and Participants
GARFIELD-VTE (ClinicalTrials.gov identifier: NCT02155491) is an on-going non-interventional, prospective, observational study of symptomatic or incidentally detected VTE in adults (! 18 years) who have been diagnosed and treated across a range of clinical settings, including the hospital (vascular medicine; internal medicine, including haematology and intensive care; cardiology; and emergency room) or general practice. The study is conducted at 417 sites in 28 countries worldwide and aims to capture the treatment patterns for acute VTE and the rate and nature of VTE recurrence, bleeding complications and all-cause mortality over 36 months of follow-up. As the registry aimed to record standard local practices, no specific treatments, tests or procedures were mandated by the study protocol. 5 Decisions to initiate, continue or change treatment were solely at the discretion of the treating physicians and the patients.
Eligible patients were required to have had an objective diagnosis of VTE (either first or recurrent episode, excluding superficial vein thrombosis) within 30 days of entry into the registry using the criteria outlined in the American College of Chest Physicians guidelines. 6 Patients with recurrent VTE must have completed treatment for the previous event before entry.
Centres were asked to only include patients in whom follow-up data could be collated either by the enrolling hospital or the associated primary care/outpatient clinic. Patients were recruited from centres representative of the various care settings for each country.

Data Collection
Data collected on unselected eligible patients are submitted to the registry-coordinating centre (eClinicalHealth Services, Stirling, United Kingdom) electronically via a secure website, and are analysed by the Thrombosis Research Institute, London, United Kingdom. The completeness and accuracy of data collected from medical records are checked by the registry-coordinating centre and the source data are verified in 10% of all cases.
For the first VTE event recorded in the registry, and for each subsequent VTE event, the following information is captured: patient characteristics, medical history, predisposing risk factors, provoking risk factors (within the previous 3 months), symptoms, nature of VTE (extent and location) and date and method of diagnosis. The use of pre-test probability scores and measurement of D-dimer was captured in DVT patients only. The use of echocardiography and prognostic markers (troponin, brain natriuretic peptide [BNP]) were recorded for PE patients. For patients with a prior episode of VTE, data are recorded before entry into the registry on the nature of this VTE, the time since this episode as well as associated complications. The care settings for the management of the patient are defined according to specialty, location and medical insurance. Routinely performed tests are documented (haemoglobin, chronically immobilized. Treatment for VTE was anticoagulant (AC) therapy alone in 90.9% of patients; 5.1% received thrombolytic and/or surgical/mechanical therapy AE AC and 4.0% received no therapy. Pre-diagnosis, 12.8% received AC therapy alone and 0.2% received thrombolytic and/or surgical/mechanical therapy AE AC. After diagnosis, parenteral AC therapy alone was administered in 17.6% of patients, and it was followed by a direct oral AC (DOAC) in 16.4% or a vitamin K antagonist (VKA) in 26.8%. DOACs alone were prescribed to 32.3% of patients, while 5.9% received VKA alone. Conclusion The initial findings from this global registry highlight the heterogeneity in characteristics and management of VTE patients. Prospective follow-up will reveal the impact of this heterogeneity on outcomes.
Thrombosis and Haemostasis Vol. 119 No. 2/2019 platelet count, international normalized ratio and creatinine). Relevant medications taken before and after VTE diagnosis are described. Patients are followed prospectively for a minimum of 36 months.

Ethics Statement
The registry is being conducted in accordance with the Declaration of Helsinki, guidelines from the International Conference on Harmonisation on Good Clinical and Pharmacoepidemiological Practice and adheres to all applicable national laws and regulations. Independent ethics committee for each participating country and the hospital-based institutional review board approved the design of the registry. All patients provided written informed consent to participate.

Statistical Analyses
These analyses describe data collected at baseline, that is, within 30 days before or after VTE diagnosis. Only patients with objectively confirmed VTE were included in the analyses. Active cancer was defined as cancer that was treated 90 days before and up to 30 days after VTE diagnosis. History of cancer was defined as a cancer diagnosis > 90 days before the diagnosis of VTE, and not currently being treated. Haemoglobin was categorized as low (< 13.5 g/dL for males and < 12 g/dL for females), normal (13.5-17.5 g/dL for males, 12-15.5 g/dL for females) or high (> 17.5 g/dL for males, > 15.5 g/dL for females). Thrombocytopaenia and thrombocytosis were categorized as platelet counts < 150 Â 10 9 /L and > 450 Â 10 9 /L, respectively. Continuous variables are presented as median AE interquartile range (IQR), and categorical variables are presented as frequency and percentage. Patients with missing values were not removed from the study (available case analysis). Percentages are calculated using available data. Statistical analysis was performed using SAS software version 9.1.3 (SAS Institute Inc., Cary, North Carolina, United States).

Discussion
This large, on-going global registry provides a unique perspective of baseline characteristics and initial management of more than 10,000 patients with acute VTE from 28 countries.
Baseline characteristics such as average age, BMI and gender ratio of patients in this study are comparable to those reported in other VTE registries. 7,8 The distribution of risk factors confirms the importance of hospital-acquired VTE, since over one-third of VTE events were associated with hospitalization, surgery, trauma or acute medical illness. These events are potentially preventable with appropriate thromboprophylaxis, thus highlighting the need for continuous education on VTE prevention in hospitals. 9,10 This study provides a contemporary picture of the diagnostic strategies used in routine clinical practice, confirming that compression ultrasound and CT pulmonary angiography represent the standard of practice for the diagnosis of DVT and PE, respectively. However, contrast venography or impedance plethysmography is still used for diagnosis of DVT in a small number of cases, and ventilation perfusion lung scanning, once the standard of practice for PE diagnosis, is now used in only 10% of patients. Surprisingly, only a minority of DVT patients underwent measurement of D-dimer and/or evaluation of pretest probability prior to imaging and only a small number of PE patients had measurement of troponin or BNP, despite recommendations from international clinical guidelines. 6,11 Unfortunately, information on D-dimer and on the use of pre-test probability was not collected for PE patients.
Surprisingly, only the minority of patients (27%) were entirely treated as outpatients, despite evidence to support this approach in particular for patients with DVT. However, these rates may substantially vary across countries and future analyses will address geographic variations in the management patterns of VTE.
A minority of VTE patients enrolled in this registry received reperfusion therapy. Reperfusion was more frequently used in PE than in DVT patients, and the rate of use may vary according to specialists and countries. Overall, IVC filters were placed in a small minority of patients. A small number of DVT and PE patients received compression therapy alone, AP therapy or no therapy at all. This may be due to the presence of isolated distal Haemoglobin was categorized as low (< 13.5 for males, < 12 for females), medium (13.5-17.5 for males, 12-15.5 for females) or high (> 17.5 for males, > 15.5 for females). Thrombocytopaenia and thrombocytosis was categorized as < 150 Â 10 9 /L and > 450 Â 10 9 /L, respectively. Provoking and predisposing risk factors were not mutually exclusive. A total of 4,096 (38.3%) patients had no provoking and no predisposing factors. Data  DVT, isolated sub-segmental PE or a major contraindication to AC treatment, such as concomitant active bleeding.
Most patients were treated with ACs, with DOACs prescribed in nearly 50%. This finding is consistent with a change in treatment patterns. Results from the RIETE registry published in 2013 reported that over 90% of patients with VTE were treated with low-molecular-weight heparin, and approximately two-thirds received VKAs. 12 In the GAR-FIELD-VTE registry, which enrolled patients between 2014 and early 2017, parenteral treatment was used in 60.8%, and almost one-third of patients only received a DOAC. This change in VTE management reflects recent recommendations from clinical guidelines, since DOACs are now suggested as the firstline therapy for the treatment of VTE in patients without active cancer. 6 The results of observational studies have confirmed the safety and effectiveness of rivaroxaban for the treatment of VTE, 13 and the GARFIELD-VTE registry will provide an opportunity to see whether these findings can be confirmed in a larger and more diverse population. In addition to these changes in treatment patterns, GARFIELD-VTE shows that there is substantial heterogeneity in the treatment of VTE patients. This heterogeneity may be explained by different patient characteristics, which highlight the need for an individualized therapeutic approach and by differences in health systems across countries.
In summary, this large, global registry describes the baseline characteristics and current management strategies in a broad cross-section of 10,685 VTE patients across 28 countries. The effect of these management patterns in relation to patient outcomes will become apparent in follow-up data.

Limitations
Due to the observational nature of this study, GARFIELD-VTE is subject to certain limitations, including the collection of non-randomized data and incomplete data collection. Selection bias may have occurred as only patients for whom follow-up data could be collected were included in the study. The presence of missing data is unsurprising, given the random selection of sites (some of which have minimal clinical research experience) and the range of care settings. However, the amount of missing data is small.  What is known about this topic?
• Venous thromboembolism is a leading cause of morbidity and mortality worldwide, which can largely be prevented by anticoagulation therapy. • The optimal treatment strategy depends on the severity of the presentation, the presence or absence of risk factors and comorbidities such as cancer, anaemia or renal insufficiency. • The availability of newer therapeutic strategies, such as direct oral anticoagulants (DOACs) has led to a rapid change in the management of VTE patients.
What does this paper add?
• This study provides a perspective on the demographics, characteristics, diagnosis and initial treatment within 30 days of diagnosis for over 10,000 VTE patients from a diverse range of clinical settings and countries. • We provide a contemporary picture of the diagnostic and therapeutic strategies used in routine clinical practice globally. • The wide heterogeneity in baseline characteristics of VTE patients highlights the need for an individualized therapeutic approach.

Note
The lead authors affirm that the manuscript is an honest, accurate and transparent account of the study being reported; that no important aspects of the study have been omitted.

Ethical Approval
Independent ethics committee and hospital-based institutional review board approvals were obtained, as necessary, for the registry protocol.