A PILOT STUDY ON THE RANDOMIZATION OF INFERIOR VENA...
Transcript of A PILOT STUDY ON THE RANDOMIZATION OF INFERIOR VENA...
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A PILOT STUDY ON THE RANDOMIZATION OF INFERIOR VENA CAVA FILTER PLACEMENT FOR VENOUS THROMBOEMBOLISM PROPHYLAXIS IN HIGH-RISK
TRAUMA PATIENTS
By
ANITA RAJASEKHAR
A THESIS PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF
MASTER OF SCIENCE
UNIVERSITY OF FLORIDA
2012
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© 2012 Anita Rajasekhar
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To Raya, Anjali, and Tyson
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ACKNOWLEDGMENTS
This work supported in part by the NIH/NCATS Clinical and Translational
Science Award to the University of Florida UL1TR000064. This study was supported by
a Cook medical education grant in the form of 50 donated inferior vena cava filters. We
thank Huazhi Liu for performing the statistical analysis for this study. We thank Tera
Thigpin and Jennifer Lanz, the research coordinators for this study. We thank the
University of Florida, Department of Surgery, Division of Acute Care Surgery faculty for
recruiting patients for this study.
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TABLE OF CONTENTS page
ACKNOWLEDGMENTS .................................................................................................. 4
LIST OF TABLES ............................................................................................................ 6
LIST OF FIGURES .......................................................................................................... 7
ABSTRACT ..................................................................................................................... 8
CHAPTER
1 INTRODUCTION .................................................................................................... 10
Venous Thromboembolism in Trauma Patients ...................................................... 10 Pilot Feasibility Study .............................................................................................. 14
Study Objectives ..................................................................................................... 15
2 METHODS .............................................................................................................. 16
Patient Population ................................................................................................... 16 Study Design .......................................................................................................... 17 Screening and Follow-up ........................................................................................ 18
Study Outcomes ..................................................................................................... 19 Statistical Analysis .................................................................................................. 19
3 RESULTS ............................................................................................................... 21
Primary Outcomes .................................................................................................. 21 Secondary Outcomes ............................................................................................. 22
4 DISCUSSION ......................................................................................................... 26
LIST OF REFERENCES ............................................................................................... 32
BIOGRAPHICAL SKETCH ............................................................................................ 36
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LIST OF TABLES
Table page 3-1 Sociodemographic and clinical variables according to treatment group ............. 23
3-2 Primary outcomes of feasibility ........................................................................... 23
3-3 Secondary clinical outcomes .............................................................................. 24
3-4 Pharmacologic prophylaxis ................................................................................. 24
3-5 Follow-up compliance ......................................................................................... 24
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LIST OF FIGURES
Figure page 3-1 CONSORT flow diagram .................................................................................... 25
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Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science
A PILOT STUDY ON THE RANDOMIZATION OF INFERIOR VENA CAVA FILTER
PLACEMENT FOR VENOUS THROMBOEMBOLISM PROPHYLAXIS IN HIGH-RISK TRAUMA PATIENTS
By
Anita Rajasekhar
December 2012 Chair: Marian Limacher Major: Medical Sciences – Clinical and Translational Science
Prophylactic inferior vena cava filters (pIVCFs) for the prevention of pulmonary
embolism (PE) in high-risk trauma patients (HRTPs) are frequently inserted despite the
lack of supportive data demonstrating efficacy. This report details the two-year interim
analysis of the Filters in Trauma (FIT) Pilot Study, a single institution, prospective
randomized pilot feasibility study in a Level 1 trauma center. HRTPs were identified for
pIVCF placement by the Eastern Association for the Surgery of Trauma (EAST)
guidelines. From November 2008 to November 2010, 38 HRTPs were enrolled and
randomized to either pIVCF versus none. All patients received pharmacologic venous
thromboembolism (VTE) prophylaxis when safe. Primary outcomes included a priori
defined feasibility objectives and secondary outcomes were incidence of PE, deep vein
thrombosis (DVT), and death.
Thirty of 38 enrolled patients were eligible for analysis. The baseline socio-
demographic characteristics were balanced between both groups. Primary feasibility
results included: time from admission to enrollment (mean 45.7 ± 21.5hrs), time from
enrollment to randomization (mean 4.4 ± 8.5hrs), time from randomization to IVCF
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placement (mean 17.2 ± 9.1hrs), adherence to weekly compression ultrasound within
first month (IVCF group = 46.7%, non-IVCF group = 66.7%), and one month follow-up
(IVCF group=80%, non-IVCF group=100%). At 6-month follow-up one PE occurred in
the non-filter group. DVT was not diagnosed in either group. One non-VTE related
death occurred in the filter group. Barriers to enrollment included inability to obtain
informed consent due to patient refusal and no next of kin identified. Our pilot study
demonstrates for the first time that a randomized controlled trial evaluating the efficacy
of pIVCFs in trauma patients is feasible.
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CHAPTER 1 INTRODUCTION
Venous Thromboembolism in Trauma Patients
Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and
pulmonary embolism (PE), is an important health care problem resulting in significant
morbidity, mortality, and health care expenditures. Clinicians attribute VTE to the
abnormalities described as Virchow’s triad: venous stasis, intimal injury, and a
hypercoagulable state. All three conditions commonly occur in trauma patients.
Hospitalized patients recovering from major trauma are among those at highest risk of
developing VTE. In fact, PE is the third most frequent cause of in-hospital death in
trauma patients who survive more than 24 hours after injury.1 The reported incidence of
VTE in trauma patients varies between studies, presumably as a result of heterogeneity
in the risk profile such as the nature of their injuries, the method of diagnosis, and
whether routine surveillance was performed. If VTE prophylaxis is not used, the
incidence of DVT may exceed 50%, with half of patients demonstrating no symptoms.2
PE may occur in as many as 25%, with 2% of patients symptomatic. Among trauma
patients with PE, mortality can be as high as 20 to 50%.2-3 Furthermore, post-thrombotic
syndrome, a chronic condition associated with chronic leg pain, intractable edema, and
leg ulcers, is a burdensome and potentially devastating complication of DVT. Also,
patients with a first episode of VTE are at increased risk for recurrent VTE. Therefore,
VTE results in significant morbidity and mortality, increasing length of hospital stay and
thus cost of care.
To date, Geerts et al. have performed the most comprehensive study on the
incidence of VTE in trauma patients.2 In this study, serial impedance plethysmography
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and lower-extremity contrast venography were performed to detect DVT in a cohort of
716 high-risk patients admitted to a regional trauma unit. Patients did not receive
mechanical or pharmacologic VTE prophylaxis. Lower extremity DVT was found in 58%
of patients. DVT was proximal in 18% of patients. Fewer than 2% of patients diagnosed
with DVT had symptoms. Two percent of the study population developed PE, 20% of
which were fatal despite clinical and venography surveillance. In a subgroup analysis,
DVT was diagnosed in 50% of patients with major injuries to the face, chest, and
abdomen, 62% with spinal injuries, 54% with head injuries, and 69% with lower
extremity injuries.2
Effective prophylaxis is essential as the clinical diagnosis of VTE is often difficult
and treatment is frequently delayed or inadequate. Several studies have attempted to
identify risk factors that place the trauma patient at high-risk for VTE. The largest study
to date was reported by Knudson et al.3 Using the American College of Surgeons
National Trauma Data Bank, 1,602 patients with VTE were evaluated. Nine risk factors
were found to be significantly associated with VTE: age, spinal cord injury (SCI), head
injury, days on ventilator, venous injury, shock on admission, major surgical procedure,
and pelvic and lower extremity fracture.3 Geerts reported five independent risk factors
for DVT on multivariate analysis including age, blood transfusion, surgery, spinal cord
injury, and fracture of femur or tibia.2
While VTE risk can be decreased with pharmacologic prophylaxis2, a subset of
trauma patients do not qualify for anticoagulation as a result of their injury and are
therefore at great risk for VTE. To address this issue, mechanical methods to prevent
VTE in trauma patients have been explored. An inferior vena cava filter (IVCF) is an
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endovascular device placed to prevent PE. Accepted indications for insertion of IVCFs
are: 1) known VTE when anticoagulation is contraindicated, 2) recurrent pulmonary
embolism (PE) despite adequate anticoagulation, 3) known complications to
anticoagulant therapy.1 Despite the paucity of reliable data on efficacy and safety,
indications for IVCFs have liberalized. The PREPIC (Prévention du Risque d'Embolie
Pulmonaire par Interruption Cave) study enrolled 400 non-trauma patients with proximal
DVT with or without PE who were randomly assigned to receive an IVCF or no filter. All
patients received therapeutic anticoagulation for known VTE. Early findings revealed
that IVCFs reduced the occurrence of symptomatic and asymptomatic PE (IVCF group
1.1% vs. no filter group 4.8%; p = 0.03). However, after eight years this initial benefit
was counterbalanced by a significant increase in DVT (IVCF group 36% vs. no filter
group 28%; p = .042) with no effect on long-term mortality.4,5 These data indicate that
filters, when used in conjunction with anticoagulation, offer a short-term reduction in the
total number of PEs at the cost of a long-term increase in recurrent DVT with no
reduction in mortality. Unfortunately, because 94% of patients received anticoagulation
for at least 3 months, these data offer no insight into the outcome of the typical patient
who has had a vena caval filter due to a contraindication to anticoagulant therapy.
Since the FDA approval of the Gunther Tulip™ Vena Cava Filter for retrieval in
2003, six new retrievable filters have been approved for use in the United States and
filter use has increased dramatically.6 In 2003, the FDA approved changes to three
existing permanent filters to allow percutaneous retrieval, but did not specify retrieval
indications.7 The rationale for using retrievable IVCFs is to offer mechanical protection
against PE during the limited high-risk period when anticoagulation may be
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contraindicated. The largest proportional increase in the use of retrievable IVCFs in the
United States has been in patients at risk for PE but who have neither PE nor DVT (i.e.
prophylactic IVCFs).2 Overall, IVCF insertion has increased significantly during the past
10 years in trauma patients.8,9 Over the last decade IVCF placement increased by
111% in the Medicare population.10 Data from the National Hospital Discharge Survey
indicate that 49,000 hospitalized patients received an IVCF in 1999.6 Based on the most
recent data from this registry, 92,000 patients received IVCFs in 2006, representing an
almost 200% increase.6 In 2012, vena cava filter sales are expected to exceed 250,000
units of which 80% (200,000) are expected to be retrievable filters.11 The considerable
variation in use of IVCFs cannot be explained by patient or center characteristics.12
Acute complications of filter placement include improper positioning, tilting, and
insertion site thrombosis. Long term complications are DVT, inferior vena cava (IVC)
obstruction, filter migration, strut fracture, filter erosion through the IVC, and proximal
PE. Timely removal may prevent most of these complications, which provides the
rationale for the increasing popularity for retrievable filters. More than half of IVCFs are
placed for temporary prophylaxis and therefore should be removed.13-16 However,
retrospective studies report that the rate of removal of these retrievable filters is only
approximately 20%.17-20 The overall retrieval rate is a product of the clinical and
procedural rate.21 If attempted, ~ 90% of IVCF retrievals are successful.21 Procedural
factors associated with retrieval failure include prolonged dwelling time, advanced age,
filter head position, and filter design.22-24 The true time frame for successful retrieval of
IVCFs remains undefined, but proceduralists have reported retrieval as long as 494
days after insertion.25 Clinical factors that influence whether or not IVCF retrieval is
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attempted include comorbidities, concurrent anticoagulation, primary indication for
placement, and documented plans for removal at the time of insertion or when the
patient is discharged.19,26 On August 8, 2010 the FDA issued a safety alert encouraging
timely removal of IVCFs in order to avoid long-term complications.27 Therefore,
improving the rate of IVCF retrieval is an important objective and strategies to increase
retrieval rates are needed.
Pilot Feasibility Study
Despite conflicting data on their efficacy, pIVCFs have become part of the
treatment algorithm at many trauma centers for prevention of VTE in trauma patients at
highest risk. However, the use of pIVCF in any patient population remains controversial.
No randomized controlled trials have addressed the efficacy of pIVCFs in trauma
patients. Practice management guidelines have been published for trauma patients. In
2002, the Eastern Association for the Surgery of Trauma (EAST) cited Class III
evidence (retrospective data, expert opinion, or case report) in support of the use of
pIVCFs in high-risk trauma patients (HRTPs)28. However, the 2012 American College of
Chest Physicians (ACCP) guidelines recommended against the use of pIVCFs as
primary prophylaxis in trauma patients based on nearly the same body of evidence
(GRADE 2C-weak recommendation based on low strength of evidence).29 This
dichotomy in clinical recommendations may reflect differences in practice patterns
across trauma centers in North America. Therefore we designed this pilot study to
determine the feasibility of performing a prospective randomized controlled trial of
pIVCF use among high-risk trauma patients.
The goal of a pilot feasibility study is to identify issues related to study
conceptualization, design, sample size and patient selection, data collection
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procedures, and approaches for data analysis.30 This type of clinical investigation is
essential for maximizing the success of a future prospective trial. Pilot studies with
explicit feasibility objectives and a priori success criteria are important foundation steps
to prepare for a large trial, ensuring a rigorous trial design that is implemented efficiently
and safely.31
The Filters in Trauma (FIT) Pilot Study was designed to optimally prepare for a
larger multicenter randomized controlled trial evaluating the efficacy and safety of
pIVCFs in trauma patients. Herein the outcomes of this pilot feasibility study are
represented. In addition, the logistics of the trial design and implementation barriers that
were identified over the first two years that the study was open for enrollment are
delineated.
Study Objectives
The primary outcome measures of this pilot study were the following feasibility
objectives: 1) timely enrollment of high-risk trauma patients, 2) acceptable time to
randomization, 3) timely receipt of allocated treatment, 4) adherence to weekly lower-
extremity surveillance compression ultrasounds (CUS). Secondary objectives were to
obtain preliminary data on VTE event rates at hospital discharge, 1 month, and 6
months post-discharge. Additionally, barriers to recruitment and randomization, use of
pharmacologic prophylaxis, prescription of sequential compression devices (SCDs),
compliance with follow-up, and removal rates of filters were examined.
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CHAPTER 2 METHODS
Patient Population
This was a single institution prospective randomized pilot study to evaluate the
feasibility of investigating the use of pIVCFs in HRTPs at the University of Florida in
Gainesville, Florida. The study opened for enrollment in November 2008. All patients
were recruited from Shands Hospital at the University of Florida, a Level 1 trauma
center serving 13 counties in North Central Florida with a population base of 1.1 million
citizens. Prior to this study the standard of practice at the University of Florida for VTE
primary prophylaxis included placement of pIVCF in any trauma patient deemed high-
risk for VTE. In addition, immediate pharmacologic prophylaxis was used when deemed
safe by the primary service, usually within 24 hours.
The inclusion criteria for this study were based on the EAST guidelines for high-
risk trauma patients.28 Patients considered high-risk for VTE and therefore included in
the study were those over the age 18 admitted to the trauma service within 96 hours
before the enrollment, and with at least one of the following injury patterns: 1) spinal
cord injury with paralysis; 2) multiple complex pelvic fractures; 3) bilateral lower-
extremity (LE) long bone fractures, excluding fibula; 4) pelvic fracture plus one or more
LE long bone fracture(s) excluding fibula; 5) expected non-weight bearing bilaterally > 7
days; 6) body mass index (BMI) > 35kg/m2. All patients were required to have expected
hospitalization for > 1 week to ensure at least two CUS of the LE were performed prior
to hospital discharge. In addition, to be eligible, patients must have had a negative
baseline lower-extremity CUS. Patients were excluded if they had indications for
therapeutic anticoagulation, had a previous IVCF or contraindications for IVCF
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placement, or were deemed to be ineligible for pharmacologic prophylaxis throughout
their entire hospital stay. Additional exclusion criteria included inability to obtain
informed consent from the patient or proxy; pregnant, institutionalized, or terminally ill
patients; or anticipated survival < 24hours.
The University of Florida Institutional Review Board (IRB) approved this study.
An independent data safety monitoring board (DSMB) comprising a hematologist, a
cardiologist, and a vascular surgeon at our institution was convened every four months
to investigate potential adverse events and safety issues. Pre-specified stopping rules
included a 10% absolute difference of fatal PEs or deaths between the two treatment
groups. This absolute difference was chosen based on heterogeneous population
studies in which a total event rate of fatal PEs or death were reported to be less than
10%.
Study Design
Physicians on the admitting trauma service were the first points of contact to
introduce the study to eligible patients. After immediate stabilization and initial surgical
procedures, the principal investigator or study coordinator, who were not affiliated with
the direct care of the patient, obtained written informed consent from the patient or
legally authorized representative. Once enrolled in the study, patients underwent
computer-generated simple randomization to receive pIVCF placement or no pIVCF.
For patients allocated to pIVCF the vascular surgeon or trauma surgeon associated with
the study was notified and performed placement of the IVCF. All patients in the pIVCF
arm received a market-approved CookTM CelectTM retrievable IVCF donated by Cook
Medical (Bloomington, Indiana, USA). Filters were inserted at the bedside using
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intravascular ultrasound guidance via the femoral route and advanced to an infrarenal
position.
When considered safe by the primary service, all patients received
pharmacologic VTE prophylaxis in the form of either enoxaparin (Sanofi-Aventis, Paris,
France) 30mg subcutaneous (SQ) twice daily, unfractionated heparin (UFH) 5000 units
SQ three times daily (for spinal cord injury), or fondaparinux (GlaxoSmithKline, London,
UK) 2.5mg SQ daily (if clinically indicated, e.g., suspicion of heparin induced
thrombocytopenia) at the discretion of the primary clinical service. Given the nature of
device placement, the patient, treating physician and nurses, ultrasound technologists,
and research personnel were not masked to the treatment allocation. Patients in both
treatment groups received all other standards of care for their injuries. Sequential
compression devices were employed when the site of injury did not preclude them.
Screening and Follow-up
Standard of clinical practice included weekly lower extremity surveillance
compression ultrasound (CUS) to monitor for asymptomatic DVT.32,33 CUS of the lower
extremities were also performed for evaluation of clinically suspected DVT For
symptoms or signs suggestive of PE, a spiral computed tomography of the chest using
a standard PE protocol was performed. On CUS, an inability to compress the vein or
actual visualization of a thrombus was characterized as a DVT. On computed
tomography of the chest, a filling defect noted in a main, segmental, or subsegmental
pulmonary artery was defined as a PE. Patients who developed a venous
thromboembolism (PE or DVT) were treated with therapeutic anticoagulation, if not
contraindicated, based on practitioner’s choice.
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All patients were followed prospectively until death or hospital discharge and then
as an outpatient in 1 month (in follow-up clinic or via phone call if no trauma clinic
appointment was needed per standard of practice) and at 6 months (via phone call)
post-discharge. Following discharge IVCF removal was attempted as per the following
current vascular surgery practices. Patients were scheduled for a vascular surgery
clinic appointment 3 months after filter placement. A letter was sent from the vascular
surgery office to remind patients of this appointment. Upon return to vascular clinic
patients underwent duplex ultrasound for IVCF retrieval planning and clinical evaluation
to determine ambulatory status and ongoing VTE risks. The decision to offer removal
depended on whether the VTE risk had returned to baseline. At 6 months post-
discharge patients were asked about complications of the filter, diagnosis of any new
VTE, continued pharmacologic prophylaxis, and whether the filter had been removed.
Study Outcomes
The primary outcomes were the feasibility objectives described above. A priori
we specified the following criteria to define success of this pilot feasibility study: 1)
timely enrollment within 96 hours of admission, 2) randomization within 24 hours of
enrollment, 3) treatment allocation within 48 hours of randomization, and 4) adherence
with weekly surveillance CUS during hospitalized. Secondary outcome measures
included: 1) event rates of PE, DVT, and death; 2) investigation of barriers to
recruitment and randomization; 3) pharmacologic prophylaxis initiation; 4) compliance
with follow-up; 5) filter retrieval rates.
Statistical Analysis
The goal of this feasibility study was to inform the planning of a large multicenter
randomized controlled clinical trial (RCCT). By design, the FIT Pilot Study was not
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powered to determine the relative benefit of pIVCF versus no pIVCF on the
development of PE. A sample size of convenience was chosen based on hospital
record review, which indicated that approximately 200 patients per year received a
pIVCF prior to initiation of the FIT Pilot Study. A sample size of 100 patients was
targeted over a 12-month enrollment phase. It was felt that this sample size would be
sufficient to address issues related to the consent process, to refine the protocol as
needed, identify barriers to conduction of the study, and perform an interim analysis.
Statistical analysis was performed with SAS (version 9.2; SAS Inc., Cary, NC).
Descriptive statistical analysis was performed to compare characteristics of patients in
the two treatment groups (chi square test or Fischer’s exact test for bivariate categorical
data, Student’s t test for continuous variables with normal distribution and Mann-
Whitney test for nonparametric data). Logistic regression was performed to compare
binary outcomes of presence or absence of thrombotic events. As patients were
randomized to treatment groups, we did not perform multivariate regression.
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CHAPTER 3 RESULTS
Between November 2008 and November 2010, 38 patients were enrolled and 30
of 38 were eligible for analysis (Figure 3-1). Differences between socio-demographic
and clinical characteristics in the IVCF group and non-IVCF group were not significantly
different (Table 3-1). The DSMB met every 4 months and all DSMB reports were
conveyed to the IRB. There were no acute complications related to the device
placement and no serious adverse events that required stopping the study by the
oversight of the DSMB.
Primary Outcomes
Results of the primary feasibility objectives (Table 3-2) included: time from
admission to enrollment (mean 45.7 ± 21.5hrs), time from enrollment to randomization
(mean 4.4 ± 8.5hrs), time from randomization to placement of IVCF (mean 17.2 ±
9.1hrs), and adherence to weekly CUS within first month (IVCF group = 46.7%, non-
IVCF group = 66.7%, p=0.28). Examining eligible patients that were ultimately not
enrolled in the study elucidated barriers to recruitment. One hundred four patients were
screened for participation in the study. Fifty-three patients who were considered eligible
for the study were not enrolled for the following reasons (Figure 3-1): patient or proxy
refusal of consent (n=23), inability to obtain informed consent and no next of kin
identified (n=12), research staff or translator unavailable to obtain informed consent
(n=6), delayed notification by primary service of eligible patient (n=2), patient received
pIVCF prior to notification of eligibility (n=5), site unable to place IVCF (n=4), patient
unavailable for consent (n=1). There were no barriers to randomization once informed
consent was obtained.
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Secondary Outcomes
At 6-month follow-up, one PE was diagnosed in the non-IVCF group, one death
unrelated to VTE in the IVCF group, and no DVT in either group (Table 3-3). The
average time to pharmacologic prophylaxis was less than 24 hours in each cohort. A
trend towards extended pharmacologic prophylaxis in the non-IVCF patients was noted
at hospital discharge. At 1 month more patients in the non-IVCF group (93.3% in non-
IVCF and 46.7% in IVCF, p=0.01) were still on pharmacologic prophylaxis (Table 3-4).
Physician ordering of SCDs was documented in 80% of patients receiving IVCF and
93.3% of patients in the non-IVCF group (p=0.29).
In the IVCF group, we were able to reach 80% of patients for 1-month follow-up
compared with 100% in the non-IVCF group (p=0.07). At 6 months post-discharge,
follow-up dropped off in each group (40% in IVCF and 60% in non-IVCF, p=0.28) (Table
3-5). Of the 15 patients who received an IVCF, 13 patients were eligible for 3-month
follow-up with the vascular clinic and 10 patients for 6-month follow-up. No patients had
their filter removed at 3 months. At 6 months 2 of the 10 patients (20%) had their filter
removed. Of the remaining patients who did not have their filter removed, 20% were lost
to follow-up and 20% were deemed to be at continued risk for VTE.
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Table 3-1. Sociodemographic and clinical variables according to treatment group
Variable IVCF (n = 15)
Non-IVCF (n = 15)
Total p-value
Male 11 10 0.7 Female 4 5 0.7 Age (years) 39.3± 16.2 54.2 ± 25.2 46.5 ± 22.0 0.12 GCS 14.3 ± 1.0 13.5 ± 3.7 13.9 ± 2.7 0.37 ISS 24.2 ± 15.4 24.9 ± 12.1 24.6 ± 13.5 0.84 Insurance status
Yes 9 11 0.45 No 6 4 0.45
Mechanism of injury Penetrating 0 1 0.32 Blunt 15 14 0.32
Qualifying injury pattern BLE fx 2 7 0.05 Complex pelvic fx 5 2 0.2 SCI BMI>35
2 3
4 4
0.37 0.67
NWB ≥7d 1 0 0.32 BLE fx+ SCI 0 1 0.32 Pelvic+ LE fx 2 1 0.32 NWB> 7d + BMI>35 1 0 0.32
GCS, Glasgow coma scale; ISS, injury severity score; BLE, bilateral lower extremity; fx, fracture; SCI, spinal cord injury; NWB, non-weight bearing; BMI, body mass index, LE, lower extremity; d, days Table 3-2. Primary outcomes of feasibility
Outcome IVCF (n = 15)
Non-IVCF (n = 15)
Total p-value
Time from admission to enrollment (h)
46.9 ±19.9 44.4 ± 23.6 45.7 ± 21.5 0.65
Time from enrollment to randomization (h)
2.8 ± 6.6 6.4 ± 10.4 4.4 ± 8.5 0.06
Time from randomization to IVCF placement (h)
17.2 ± 9.1 NA 17.2 ± 9.1
Adherence to weekly CUS within 1st month by service (%)
Trauma (n=14) 66.7 100 0.16 Neurosurgery (n=7) 50 60 0.82 Orthopedics (n=8) 0 50 0.13 Vascular (n=1) NA 0 Total (n=30) 46.7 66.7 0.28
h, hours; CUS, compression ultrasound
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Table 3-3. Secondary clinical outcomes
Outcome IVCF (n = 15)
Non-IVCF (n = 15)
DVT Inpatient 0 0 At 1-mo follow-up 0 0 At 6-mo follow-up 0 0
PE Inpatient 0 0 At 1-mo follow-up 0 0 At 6-mo follow-up 0 1
Death VTE related 0 0 Non-VTE related 1 0
DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism Table 3-4. Pharmacologic prophylaxis
Pharmacologic prophylaxis IVCF Non-IVCF p-value
Average time to initiation (h) 20.0 ± 13.2 23.5 ± 20.3 0.79 Pharmacologic prophylaxis at enrollment (%) 93.3 86.7 0.55 Pharmacologic prophylaxis at hospital discharge (%) 46.7 93.3 0.01 Pharmacologic prophylaxis at 1-month follow-up (%) 6.7 6.7 1.0
h, hours Table 3-5. Follow-up compliance
Follow-up IVCF (%) Non-IVCF (%) p-value
1 month 80.0 100.0 0.07 6 month 40.0 60.0 0.28
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Figure 3-1. CONSORT flow diagram
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CHAPTER 4 DISCUSSION
The results of this pilot study demonstrate that it is feasible to perform a
randomized study comparing pIVCF versus no IVCF for VTE prevention in high-risk
trauma patients. We designed the FIT Pilot Study to address four specific feasibility
objectives and several secondary outcomes. Our a priori defined feasibility objectives
were met. Patients were enrolled within 96 hours of admission to the trauma service,
randomized within 24 hours of enrollment, and received an IVCF if allocated to one
within 24 hours of randomization. Although adherence to weekly surveillance CUS was
suboptimal, patients who were not transferred off the trauma service throughout their
hospitalization did have better compliance with CUS. Conversely, patients transferred to
other surgical services during their hospitalization often did not continue to receive
weekly CUS. Lack of adherence to protocol may be explained by unfamiliarity with the
FIT Study by the non-trauma services as well as the fact that weekly CUS were not part
of their service’s standard of practice even before the FIT study opened, as was the
case with the trauma service.32,33
Fifty-three eligible patients were not enrolled. Barriers to enrolling these patients
included mainly patient refusal to participate or no next of kin identified for informed
consent, a common dilemma in trauma studies.34 Other barriers to recruitment were
delayed notification by the primary service of an eligible patient and inability to obtain
timely informed consent due to logistics (research staff/translator unavailable, patient
unavailable due to multiple operating room visits, site unable to place IVCF). As the
study progressed over 2 years, trauma attendings, residents, and physician extenders
became more familiar with the FIT study, which led to timely notification of the research
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staff of eligibility status by the primary trauma service. To enhance this collaboration, we
advertised the FIT study with posters on the trauma units, as well as laminated pocket
cards detailing inclusion/exclusion criteria and research staff contact information. We
also regularly attended trauma service meetings to reintroduce the FIT study to new
residents rotating on the service. We faced several logistic barriers to enrolling patients.
For example, we had difficulty obtaining baseline CUS or informed consent within 96
hours of admission in patients with severe injuries who returned to the operating room
multiple times within the first few days of hospitalization. Also, since we did not initially
have a dedicated study coordinator, all eligible patients who were admitted to the
trauma service over a weekend were not enrolled.
Exclusion and inclusion criteria may have contributed to our low recruitment
rates. We excluded patients if they were ineligible for pharmacologic prophylaxis during
their entire hospitalization. The clinical question that was to be addressed was whether
IVCFs add any protection against venous thromboembolism beyond pharmacologic
prophylaxis delivered when deemed safe. In designing a multicenter randomized
controlled trial patients who are ineligible for pharmacologic prophylaxis should be
considered for inclusion. Finally, modifications to the inclusion criteria to reflect only the
highest-risk patients have contributed to the decreased recruitment rates. Revisions of
the inclusion criteria such as spinal cord injuries with paralysis, bilaterally long bone LE
fractures not including fibula fractures, non-weight bearing bilaterally, multiple complex
pelvic fractures may have narrowed the eligible patient population for the study. Prior to
the opening, the FIT study the criteria for pIVCF placement in HRTPs at the University
of Florida was determined by the attending physician and therefore highly variable and
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likely more inclusive. These less strict inclusion criteria prior to the opening of the FIT
Study likely contributed to our over-estimation of sample size calculation based on prior
experiences.
No obstacles to randomization were encountered once informed consent was
signed. Randomization occurred within 24 hours of enrollment. Similarly, we found no
barriers to timely placement of the IVCF. Placement of the IVCF occurred within 24
hours of randomization to this group.
Several changes to the informed consent process were made over the course of
2 years. Initially, when the study opened in November 2008, the treating trauma
surgeon introduced the study and obtained informed consent. However, given the direct
patient care that the primary surgeon delivered to the patient and the variation in the
informed consent process between each trauma surgeon we shifted the duty of
obtaining informed consent to the principal investigator. Unfortunately, due to logistical
issues such as manpower and time constraints, this led to the inability to consent all
eligible patients in a timely manner. Approximately 1 year into the study we secured a
dedicated research coordinator for the FIT study who then performed all informed
consents. This key step of obtaining informed consent by one person led to a 65%
increase in enrollment rates as well as improved patient/physician compliance with the
study protocol. In addition, we instituted an informed consent documentation form to
help streamline the informed consent process. This form served as a reminder checklist
to document: 1) eligibility requirements, 2) the opportunity given to the patient and
family to discuss the study and ask questions, 3) copies of informed consent placed in
medical records and given to the patient, and 4) primary and secondary contact
29
information of patient and next-of-kin. In addition, the informed consent documentation
form served as a standardized script to explain the study and answer questions most
commonly asked by the patient and family.
Follow-up at 1-month post-discharge was significantly better than follow-up after
6 months. If a patient was not scheduled for a clinic appointment as per standard of
practice for their injuries the research coordinator conducted follow-up over the phone.
The sole reason for lack of follow-up with patients was inability to contact patients after
discharge because of inaccurate contact information in the hospital records. We
therefore introduced a contact information sheet as part of the informed consent
process. This included the patient’s and legal representative’s contact phone number
and address. At 3 months no patients had their IVCF removed. At 6 months only 2 of
the 10 patients eligible for removal had successful retrieval. Of those that did not have
retrieval, only 20% were deemed to be at continued risk for VTE justifying non-retrieval
of IVCF. Of the remainder who did not have the IVCF removed, 20% were lost to follow-
up with the vascular surgery service. This is consistent with prior reports in the literature
of retrieval rates of 20%.35 Reasons for lack of follow-up to remove filters and methods
to improve retrieval rates needs to be addressed prospectively given the recent
attention to complications of IVCFs reported in the literature.24, 36-37 On August 8, 2010,
the FDA issued a safety alert recommending that clinicians responsible for the ongoing
care of patients with retrievable IVCFs consider removing the filter as soon as protection
from PE is no longer needed.27 Therefore, improved retrieval rates of IVCFs is
mandatory and methods for increasing retrieval rates should be explored.
30
Despite recent reports of filter complications24, 36-37, placement of pIVCFs may be
appropriate when anticoagulation may be contraindicated in the short-term. When
removed in a timely fashion, retrievable filters may avoid the long-term complications
associated with permanent IVCFs. However, the efficacy of pIVCFs beyond appropriate
pharmacologic prophylaxis remains to be elucidated.
We conducted this pilot study feasibility to determine the feasibility of conducting
a future large multicenter RCCT evaluating the efficacy of pIVCFs in high-risk trauma.
Our results will help inform the design of a future large trial. We conclude that by
addressing the multifaceted issues in recruitment, protocol adherence, and follow-up we
faced during this pilot study a multicenter RCCT is feasible. Several key considerations
emerge from the results of this study that should be addressed in the protocol of a
future large trial. First, since the quality endpoints for our feasibility objectives were met
(e.g., enrollment within 96 hours of admission), shorter acceptable time frames for
quality endpoints can likely be implemented to prevent exclusion of patients that
develop VTE during the first few days of hospitalization. During the first 2 years of this
study our institution did not have an electronic medical record system. For recruitment
we relied on manual screening of the daily trauma census as well as timely notification
of a potential candidate by the primary trauma service. A future trial can maximize
recruitment rates by utilizing a computerized alert system that automatically and
accurately identifies potential study subjects, thereby improving efficiency of enrollment.
This electronic tool is especially important in time sensitive trials in trauma patients. In
addition, this computerized method would effectively reduce the screening burden while
minimizing error associated with recruitment by research staff.
31
In summary, this comprehensive pilot study served a critical function in
identifying conceptual and methodological issues and was an essential foundation step
in preparing for a larger trial investigating the role of IVCFs in trauma patients.
32
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36
BIOGRAPHICAL SKETCH
Anita Rajasekhar, M.D., is an associate professor in the Department of Medicine
at the University of Florida College of Medicine. Dr. Rajasekhar received her M.D.
from the University of Florida in 2004. She then completed her internal medicine
residency in 2007 and hematology/oncology fellowship in 2010 at the University of
Florida. Dr. Rajasekhar is board certified in medical oncology and hematology. She
joined the University of Florida as an assistant professor in 2010. Dr. Rajasekhar
graduated with a Master of Science in Clinical and Translational Science from the
University of Florida in 2012. Dr. Rajasekhar’s primary academic interests include
diagnosis and treatment of benign hematologic conditions, particularly related to
thrombosis and hemostasis. Her academic focus is on the prevention and treatment
of venous thromboembolism. She is a member of the American Society of
Hematology (ASH).