The Clinical Utility of Thrombelastography in Guiding Prophylaxis of Venous Thromboembolism Following Trauma (VTEPX)

• ClinicalTrials.gov Identifier: NCT01050153
• Recruitment Status: Completed
• First Posted: January 15, 2010
• Results First Posted: April 25, 2014
• Last Update Posted: January 8, 2019
• Sponsor: Denver Health and Hospital Authority
• Collaborator: Eisai Inc.
• Information provided by (Responsible Party): Ernest E. Moore, MD, Denver Health and Hospital Authority

Tracking Information

• First Submitted Date: January 13, 2010
• First Posted Date: January 15, 2010
• Results First Submitted Date: August 14, 2013
• Results First Posted Date: April 25, 2014
• Last Update Posted Date: January 8, 2019
• Study Start Date: March 2010
• Actual Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 25, 2014)

• Hypercoagulability [ Time Frame: Study day five. ]
  To determine the incidence of, and to characterize, hypercoagulability in a sample of trauma patients admitted to the SICU at DHMC using TEG and conventional clinical coagulation testing (APTT, INR), antithrombin III levels and protein C activity. Hypercoagulability is defined as TEG parameter G (clot strength) >10.9.
• Incidence of VTE [ Time Frame: Day 28 or discharge, whichever comes first. ]
  The incidence and nature of hypercoagulability and the incidence of deep vein thrombosis and pulmonary embolism in each randomized group and in the subgroup receiving anti-platelet therapy in addition to Fragmin (descriptive analysis only)

• Original Primary Outcome Measures (submitted: January 14, 2010): The utility of a TEG-guided algorithm for monitoring prophylactic LMWH (Fragmin) therapy and for identifying the need for and guiding anti-platelet therapy for optimal prevention of venous thromboembolism. [ Time Frame: Until patient fully ambulatory ]

Current Secondary Outcome Measures (submitted: November 28, 2014)

• TEG Parameters [ Time Frame: Study day five. ]
  R is a reaction time. The time from the start of a sample run until the first significant levels of detectable clot formation (amplitude = 2 mm in the TEG tracing). Rf is a difference in reaction time between Fragmin-active and Fragmin-neutralized samples. Achievement of a certain clot strength K is a measure of the time from R until a fixed level of clot strength is reached (amplitude = 20 mm). Angle or α measures the rapidity of fibrin build-up and cross-linking (clot strengthening). This most represents fibrinogen level. Angle relates to K, since both are a function of the rate of clot formation. MA, or Maximum Amplitude, is a direct function of the maximum clot strength. In tests where platelets are part of the clot, this parameter most reflects platelet function/aggregation. Clot strength is the result of two components - the modest contribution of fibrin and the much more significant contribution of the platelets.
• International Normalized Ratio (INR) [ Time Frame: Study day five. ]
  Plasma based conventional coagulation testing parameters
• Platelet Count [ Time Frame: Study day five. ]
  Platelet count measured by CBC test
• TEG Parameters [ Time Frame: Study day five. ]
  Shear elastic modulus strength (SEMS). The MA parameter can be transformed into the actual measure of clot strength (G) using the formula below, and is measured in dyn/cm2 divided by 1000 (displayed in the software as Kd/sc). The absolute SEMS of the sample can be calculated from MA as follows: G = (5000MA/(100-MA))/1000 An amplitude of 50 mm corresponds to a SEMS of 5000 dyn/cm2. An increase in MA from 50 mm to 67 mm is equivalent to a two-fold increase in the SEMS. The G parameter not only provides a measurement of clot firmness in force units, but also is more indicative of small changes in the clot strength or clot breakdown than is the amplitude in mm because it is an exponential reflection of MA.
• Conventional Coagulation Testing Parameters [ Time Frame: Study day five. ]
  Plasma based conventional coagulation testing parameters - Anti Xa
• Conventional Coagulation Testing Parameters [ Time Frame: Study day five. ]
  Plasma based conventional coagulation testing parameters - Fibrinogen
• Conventional Coagulation Testing Parameters [ Time Frame: Study day five. ]
  Plasma based conventional coagulation testing parameters - Anti-thrombin III
• Conventional Coagulation Testing Parameters [ Time Frame: Study day five. ]
  Plasma based conventional coagulation testing parameters - Protein C

• Original Secondary Outcome Measures (submitted: January 14, 2010): The incidence and nature of hypercoagulability and the incidence of deep vein thrombosis and pulmonary embolism in each randomized group and in the subgroup receiving anti-platelet therapy in addition to Fragmin (descriptive analysis only) [ Time Frame: Until fully ambulatory ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: The Clinical Utility of Thrombelastography in Guiding Prophylaxis of Venous Thromboembolism Following Trauma
• Official Title: An Evaluation of the Clinical Utility of Thrombelastography (TEG) in Guiding Low Molecular Weight Heparin (LMWH) and Antiplatelet Prophylaxis of Venous Thromboembolism (VTE) Following Trauma

Brief Summary

This study plans to learn more about how to prevent blood clots in the veins of your extremities. You are at risk of forming these clots after a major injury and when you have had surgery and are hospitalized on bed rest.

Usually, patients in the SICU at Denver Health who are at risk for blood clots receive preventative treatment with a FDA-approved medicine called Fragmin. Fragmin is intended to prevent blood clots from forming but, with the way it is generally used, some patients may still develop blood clots. All patients treated with Fragmin to prevent blood clots at Denver Health, currently receive the same Fragmin dose. This treatment is called the "standard of care".

So far, in the US, there has not been a commonly available test that can tell us:

• if the standard dose of Fragmin is enough to prevent blood clots for everyone, or
• if different patients need different doses, or
• if other blood clot preventing medicines, that work in a different way, should be used in addition to Fragmin.

The ability of your blood to clot and the strength of the clot formed can be described by a FDA-approved blood test called thrombelastography, referred to as TEG. TEG may provide us with answers to each of the questions above. Our preliminary data indicate that it is helpful in assessing both clotting and bleeding tendencies and may prove useful in guiding treatment for the prevention of blood clots.

The aim of this study is to determine if a treatment plan using Fragmin, and, if indicated, one or two additional FDA-approved medicines called anti-platelet drugs, guided by the results of TEG testing, may be better at preventing blood clots than our current standard of care.

Detailed Description

This preliminary/pilot study involves a prospective, randomized, open-label, parallel group comparison of Denver Health's current standard of care for prevention of venous thromboembolism (VTE), commonly known as blood clots, using LMWH (Fragmin) 5000IU subcutaneously daily, with a thrombelastography (TEG)-guided, algorithm-based, individualized regimen of LMWH (Fragmin) plus/minus anti-platelet therapy (aspirin) guided by platelet mapping, in patients admitted to the SICU following trauma.

Approximately 50 trauma patients for whom prevention of VTE with LMWH is indicated, will be enrolled over a six month period.

The specific aims of this study are as follows:

1. To determine the incidence of, and to characterize, hypercoagulability using TEG and conventional clinical coagulation testing (APTT, INR), Antithrombin III levels and Protein C activity.

2. In the group of patients receiving LMWH (Fragmin) therapy alone for prevention of VTE:

   1. to assess the anticoagulant effect of standard LMWH (Fragmin) dosing (5000IU subcutaneously once daily) using TEG and Anti-Factor Xa level measurement, and
   2. to determine the extent of correlation of relevant TEG parameters with measured Anti-Factor Xa levels (U/ml).
3. To assess whether TEG is a useful clinical tool for monitoring and optimizing prophylactic LMWH (Fragmin) therapy and for identifying the need for anti-platelet therapy to minimize the risk of VTE in these patients.
4. To evaluate the clinical utility of platelet mapping for guiding anti-platelet therapy in those patients for whom it is indicated by TEG results.
5. To determine the incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in each randomized group and in the subgroup receiving anti-platelet therapy in addition to LMWH (Fragmin) for prevention of VTE.

The overall aim is to utilize the above data to evaluate a) the adequacy of our standard Fragmin dosing regimen (5000IU subcutaneously once daily) alone for prevention of VTE in our trauma/SICU patients, b) the need for anti-platelet agents in addition to LMWH (Fragmin) for prevention of VTE in our population, and c) to validate/further develop the TEG-guided algorithm for optimal prophylaxis of VTE using LMWH (Fragmin) plus/minus anti-platelet therapy guided by platelet mapping.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Prevention
• Condition: Venous Thromboembolism

Intervention

• Drug: Dalteparin sodium
  Dalteparin sodium injection 5000IU subcutaneously daily until fully ambulatory
  Other Name: Dalteparin sodium (Fragmin)
• Drug: Dalteparin sodium/aspirin
  Dalteparin sodium (2500-10,000IU sc daily), aspirin (81-325mg daily) po.
  Other Name: dalteparin sodium (Fragmin)

Study Arms

• Active Comparator: Control (standard of care)
  Dalteparin sodium 5000IU subcutaneously daily
  Intervention: Drug: Dalteparin sodium
• Experimental: TEG-guided thromboprophylaxis
  Dalteparin sodium plus/minus anti-platelet medication (aspirin) per a TEG-guided algorithm
  Intervention: Drug: Dalteparin sodium/aspirin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 14, 2010): 50
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: December 2011
• Actual Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• age at least 18 years,
• blunt or penetrating trauma requiring admission to the SICU
• requirement for LMWH (Fragmin) therapy for prophylaxis of VTE as standard of care, and
• informed consent by patient, legally authorized representative or proxy decision maker (if patient incompetent to provide) obtained and documented.

Exclusion Criteria:

Presence of any of the following absolute contraindications to LMWH (Fragmin) therapy:

• known hypersensitivity to dalteparin sodium,
• known hypersensitivity to heparin or pork products,
• thrombocytopenia associated with positive tests for antiplatelet antibody in the presence of Fragmin,
• history of heparin-induced thrombocytopenia (HIT),
• chronic liver disease (bilirubin >2 mg/dl) or kidney insufficiency (CrCl <30mL/min),
• intravascular thrombolytic therapy within 24 hours,
• resuscitation that required massive transfusion (>10 units RBC within 6 hours),
• ongoing resuscitation for hemorrhagic shock,
• known bleeding disorder or coagulopathy (INR >2 not on warfarin),
• thrombocytopenia (platelets <20K/uL),
• subdural or epidural hematoma.

Or

Presence of any of the following relative contraindications to LMWH (Fragmin) therapy:

• new intracranial lesions, neoplasms or monitoring devices,
• extravascular thrombolytic therapy,
• severe uncontrolled hypertension,
• arterial dissection
• recent (within 12 hours) intraocular surgery (prior or planned),
• recent (within 72 hours) intracranial or spine surgery (prior or planned),
• conditions associated with increased risk of hemorrhage, e.g. active gastrointestinal ulceration, angiodysplastic disease, gastrointestinal bleeding within the past six months, bacterial endocarditis, history of hemorrhagic stroke, diabetic retinopathy.

Or

Presence, or removal within the last 12 hours, of an indwelling epidural or spinal catheter, OR recent (within the last 12 hours) or planned neuraxial (spinal/epidural) anesthesia or spinal puncture.

Or

Per history taken from patient or family, concomitant or known use within one week prior to hospitalization, of drugs affecting hemostasis such as NSAIDS, platelet inhibitors or other anticoagulants, except as specified in this protocol.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01050153
• Other Study ID Numbers: COMIRB # 09-0753
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Ernest E. Moore, MD, Denver Health and Hospital Authority
• Original Responsible Party: Ernest E. Moore, Jr M.D., Chief, Department of Surgery and Trauma Services Rocky Mountain Regional Trauma Center, Denver Health Medical Center
• Current Study Sponsor: Denver Health and Hospital Authority
• Original Study Sponsor: Same as current
• Collaborators: Eisai Inc.

Investigators

• Principal Investigator: Ernest E. Moore Jr, M.D.; Chief, Department of Surgery and Trauma Services , Denver Health Medical Center

• PRS Account: Denver Health and Hospital Authority
• Verification Date: December 2018