Extended Low-Molecular Weight Heparin VTE Prophylaxis in Thoracic Surgery

Extended Low-Molecular Weight Heparin VTE Prophylaxis in the Thoracic Surgery Population, a Prospective, Randomized Controlled Study

After any surgery, there is a risk of venous thromboembolism (VTE), including Deep Vein Thrombosis (DVT) in the major veins of the legs and Pulmonary Embolus (PE) in the lungs. These clots are usually prevented by the administration of low-molecular-weight heparin, a blood thinner that prevents clotting. In most surgical specialties like thoracic or vascular surgery, this treatment is used until patients are discharged from the hospital. However, in orthopaedic surgery, there is strong evidence that longer term preventative treatment up to 35 days after hospital discharge helps to reduce VTE occurrences. In thoracic surgery, there is an even greater risk of developing PE because of the surgical stress, the common presence of cancer and direct damage to blood vessels in the lung during surgery. Despite the potential utility, the use of extended VTE prevention has never been evaluated in the thoracic surgery population. If extended treatment prevents clots, more patients will avoid complications related to VTE. There is currently very limited information available on the incidence of venous thromboembolism (VTE) in patients undergoing lung cancer resection and the utility of extended thromboprophylaxis (ET) in this patient population. Furthermore, in contrast to patients undergoing orthopaedic surgery where ET has become standard of care, duration of thromboprophylaxis is not well defined in this patient population. Therefore, there is a clear need to systematically evaluate the effects of extended VTE prophylaxis on the incidence of VTE in the post-op population.

Study Overview

• Status: Completed
• Conditions: Lung Neoplasms; Venous Thromboembolism; Pulmonary Embolism
• Intervention / Treatment: Drug: LMWH: Dalteparin; Other: Placebo

Detailed Description

There is currently very limited information available on the incidence of venous thromboembolism (VTE) in patients undergoing lung cancer resection and the utility of extended thromboprophylaxis (ET) in this patient population. Furthermore, in contrast to patients undergoing orthopaedic surgery where ET has become standard of care, duration of thromboprophylaxis is not well defined in this patient population. Therefore, there is a clear need to systematically evaluate the effects of extended VTE prophylaxis on the incidence of VTE in the post-op population.

As a pilot study, the primary outcome will involve feasibility measures. The investigators aim to measure the proportion of recruitment within each centre, compliance, loss to follow-up, and tolerability of the intervention, defined as the number and severity of per-defined adverse events. The primary outcome of interest for the future full-scale trial is the 30-day incidence rate of VTE following extended 30-day prophylaxis (defined as pulmonary emboli or deep venous thromboembolism of the lower limb as detected by CT (Computed Tomography) pulmonary angiography and full leg Doppler ultrasound, respectively) following lung resection for malignancies.

The proposed pilot project is a multicenter blinded placebo-controlled randomized controlled pilot clinical trial assessing the feasibility and effectiveness of extended-duration VTE prophylaxis (30 days post-operatively) vs. short-term prophylaxis restricted to in-hospital stay with outpatient injected placebo, in patients undergoing lung resection for lung cancer or metastatic disease. All patients will receive both a peri-operative dose followed by postoperative VTE prophylaxis for the duration of their hospital stay. Those who were randomized to prolonged prophylaxis will continue the same dosage regime for an overall of 30 days, whereas the control group will receive placebo injections for the same duration of time.

• Study Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 4A6
      • St. Joseph's Healthcare Hamilton
    • Toronto, Ontario, Canada, M5G 2C4
      • Toronto General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients must be at least 18 years of age.
2. Patient may be of either gender.
3. Patients must be diagnosed with resectable lung cancer or metastatic lung disease eligible to complete metastasectomy.
4. Patients must be undergoing one of the following surgeries: segmentectomy, wedge resection, lobectomy, bilobectomy or pneumonectomy.
5. Patients must be competent to understand 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 estimated glomerular filtration rate of less than 30ml/min/m2 as calculated by the Cockcroft-Gault method) either pre-operatively or as identified based on blood work obtained prior to the scheduled 30-day post-operative scan.
4. Patients must not have known hepatic failure, with international normalized ratio (INR) of >1.5.
5. Patients with history of, or ongoing liver disease, manifested as ascites or previous peritoneal tapping for ascites.
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 known, objectively confirmed bleeding disorder.
9. Patients must not have a present or previous increase risk of haemorrhage.
10. Patients must not have a history of previous heparin induced thrombocytopenia.
11. Baseline platelet count <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 filter.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LMWH: Dalteparin; Consenting patients undergoing lung resection will receive standard postoperative thromboprophylaxis in hospital until the time of discharge. Subsequently, patients will be administered LMWH for duration of 30 days as outpatients.	Drug: LMWH: Dalteparin; Dalteparin is a low-molecular weight heparin. The dosage used will be 5000 units once daily (administered as a subcutaneous injection). This is an established prophylactic dose used to prevent the incidence of VTE after surgery.; Other Names: Fragmin
Placebo Comparator: Placebo; After undergoing lung resection these patients will research standard post-op TE prophylaxis and upon discharge will be administered a placebo injection of subcutaneous saline for 30 days duration.	Other: Placebo; Upon hospital discharge, half of the patients will be assigned to receive saline placebo injections for up to 35 days after surgery. These injections will have no effect.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite primary outcome: To determine the feasibility of a full scale trial by determining the recruitment rates and loss to follow up rates	Measuring accrual rates, patient compliance, adherence to protocol, any-cause loss to follow up, tolerability of the intervention (safety), adverse events, and coordination of participating centre infrastructure	1-1.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical outcome:Comparison of Incidence of DVT and PE at 30 days after surgery between control and interventional arms (Outcome will be measured by a Chest Computed Tomography (CT) scan with PE contrast protocol and a full leg doppler ultrasound)	As a pilot study, there is an insufficient number of patients to definitively calculate incidence and compare treatment arms. However, this is a key outcome and the study will seek to determine this outcome. Outcome will be measured by a Chest Computed Tomography (CT) scan with PE contrast protocol and a full leg doppler ultrasound at approximately 30 days after surgery to seek the occurrence of clots	30 days, +/- 5 days
Occurrence of major and minor bleeding at 30 days post-surgery, +/- 5 days	Bleeding is a potential adverse event of Fragmin use. Major bleeding is defined as: Fatal bleeding OR Critical bleeding in a symptomatic area (intracranial, intraspinal, retroperitoneal, pericardial, or intramuscular with compartment syndrome) OR Bleeding causing a fall in hemoglobin level of 2g/dL or more as measured by a blood test at 30 days follow up, OR Bleeding requiring a blood transfusion of at least 2 units of packed red blood cells (excluding transfusions administered intra-operatively or 6-hrs post-operatively since these could not be impacted by post-surgical prophylaxis). Minor bleeding is defined as any bleeding episode not classified as major.	30 days after surgery
Comparison of mortality within 90 days of surgery between control and interventional arms	Both procedure-specific and all-cause mortality rates will be calculated	90 days
Number of cases of heparin administration related HIT (Heparin Induced Thrombocytopenia) within 90 days of surgery		90 days
Number of participants with study-related adverse events within 90 days of surgery		90 days
Comparison of non-DVT-associated PE events (those occurring without an antecedent DVT) between control and interventional arms		90 days

Collaborators and Investigators

• Sponsor: McMaster University
• Investigators: Principal Investigator: Yaron Shargall, MD, FRCSC, FCCP, McMaster University

Publications and helpful links

General Publications

• Fahim C, Hylton D, Simunovic M, Agzarian J, Finley C, Hanna WC, Shargall Y. Development of the IRIS-AR strategy: an intervention to improve rates of accrual and retention for the VTE-PRO randomized controlled trial. Trials. 2019 Jul 19;20(1):447. doi: 10.1186/s13063-019-3536-8.

Study record dates

Study Major Dates

• Study Start: September 1, 2015
• Primary Completion (Actual): September 1, 2018
• Study Completion (Actual): September 1, 2018

Study Registration Dates

• First Submitted: December 18, 2014
• First Submitted That Met QC Criteria: January 7, 2015
• First Posted (Estimate): January 8, 2015

Study Record Updates

• Last Update Posted (Actual): September 18, 2018
• Last Update Submitted That Met QC Criteria: September 17, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: lung resection; deep vein thrombosis; pulmonary embolism; low molecular weight heparin; venous thromboembolism prophylaxis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Embolism and Thrombosis; Lung Neoplasms; Embolism; Thromboembolism; Venous Thromboembolism; Pulmonary Embolism; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin
• Other Study ID Numbers: SJHH_VTEpro001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED