Incidence of Venous Thromboembolism in Patients Undergoing Major Esophageal Resection

Venous Thromboembolism (VTE) is a common post-operative complication that can result in
significant patient morbidity, mortality and health care resource utilization to treat the
resultant Pulmonary Embolus (PE) or Deep Vein Thrombosis (DVT) events. It is the third
leading cause of cardiovascular mortality. Due to the high burden of disease, VTE events are
actively prevented using mechanical and/or pharmaceutical prophylaxis interventions such as
compression stockings or a variety of anti-coagulants. Extensive literature identifies
incidence rates and provides guidelines regarding the use of prophylaxis measures in
orthopaedic and oncological surgery, but the literature in thoracic surgery is sparse at best
or conflicting with reported incidence of symptomatic events ranging from 5% to 14% after
esophagectomy. The current practice of VTE prophylaxis in thoracic surgery includes
administration of unfractionated or low molecular weight heparin (LMWH) starting in the
perioperative period and finishing at patient discharge, while prolonged thromboprophylaxis
in orthopaedic surgery beyond 10 to 14 days and up to 35 days has become the standard of
care. Such an approach has never been tested or validated in esophageal cancer patients
despite the substantial burden and high risk of VTE events in this population. There is a
clear need for well-designed studies aiming to define the extent of peri-operative VTE for
esophagectomy patients and additional contributing factors associated with VTE in those high
risk patients in order to inform best practice patterns. The investigators hypothesize that
the incidence and clinical burden of perioperative VTE events in esophagectomy patients are
substantial, and that VTE significantly contributes to peri-and post-operative morbidity and
mortality. Hence, it will be beneficial to explore the true incidence of VTE events and
evaluate the effectiveness of extended-duration, post-discharge prophylaxis for these
patients. The investigators also hypothesize that sub-groups of esophagectomy patients will
be at higher risk for VTE events and therefore might benefit more from extended-duration,
post-discharge prophylaxis, and perhaps from a more aggressive in-hospital regimen.

This prospective cohort study will involve patients undergoing major esophageal resection for
esophageal cancer at 9 tertiary care centres across Canada, 4 centres in the USA, and 1 site
in China. McMaster University at St. Joseph's Healthcare Hamilton will serve as the
Coordinating Centre as well as a study site. Recruitment will commence at each site until 177
patients are enrolled via consecutive convenience sampling. After undergoing esophagectomy,
all patients will receive both a peri-operative dose followed by post-operative LMWH VTE
prophylaxis for the remainder of their hospital stay. As per current VTE prophylaxis
guidelines, prophylaxis will be discontinued upon hospital discharge. VTE outcomes will be
assessed using Computed Tomography with pulmonary angiography protocol at 30 and 90 days and
bilateral venous Doppler ultrasounds at 30, 60 and 90 days after surgery. The role of D-Dimer
will be investigated peri-operatively up to post-operative day (POD) 3, at hospital discharge
or POD 10 (whichever is applicable), and at each imaging follow-up visit. A future second
phase study will be a randomized controlled trial that will evaluate the role of extended
duration thromboprophylaxis post-discharge in reducing the incidence of VTE in this patient
population. The proposed prospective cohort study to evaluate the incidence of VTE needs to
be conducted first, in order to optimize patient selection and determine the sample size for
the subsequent randomized controlled trial.

Inclusion Criteria:

1. Patients must be at least 18 years of age.

2. Patients may be of either gender.

3. Patients must be diagnosed with resectable esophageal cancer.

4. Patients must be undergoing an esophagectomy as either the first-line treatment or
after completion of neoadjuvant therapies.

5. Patients must receive VTE prophylaxis as per local institutional guidelines

6. Patients must be competent to understand and sign consent documents.

Exclusion Criteria:

1. All patients with known allergic or anaphylactic reaction to contrast dye, heparin, or
low molecular weight heparin (LMWH).

2. Patients must not be under current anticoagulation for venous thromboembolism or other
medical conditions.

3. Patients must not have known renal impairment, defined as creatinine clearance value
of less than 55ml/min/m2 as calculated by the Cockcroft-Gault method.

4. Patients with a history of, or ongoing liver disease, manifested as ascites or
previous peritoneal tapping for ascites.

5. Patients with known hepatic insufficiency, defined as international normalized ratio
(INR) >1.5.

6. Patients must not be pregnant or planning to become pregnant.

7. Patients must not have been diagnosed or treated for VTE in the past 3 months prior to
surgery.

8. Patients must not have a present or previous increased risk of haemorrhage.

9. Patients must not have known, objectively confirmed bleeding and clotting disorders
such as thrombophilia, von Willebrand's disease, hemophilia or otherwise active
bleeding.

10. Patients must not have a history of previous heparin-induced thrombocytopenia (HIT).

11. Platelet count must be above 75,000, but transient, recovered thrombocytopenia
associated with chemotherapy will not be a basis for exclusion.

12. Patients must not have previously inserted inferior vena cava (IVC) filter.