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1 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
2 2012 Anita Rajasekhar
3 To Raya, Anjali, and Tyson
4 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 perform ing 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.
5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 6 LIST OF FIGURE S ................................ ................................ ................................ .......... 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 Stud y Outcomes ................................ ................................ ................................ ..... 19 Statistical Analysis ................................ ................................ ................................ .. 19 3 RESULTS ................................ ................................ ................................ ............... 21 Primary Outcomes ................................ ................................ ................................ .. 21 Secondary Outcomes ................................ ................................ ............................. 22 4 DISCUSSI ON ................................ ................................ ................................ ......... 26 LIST OF REFERENCES ................................ ................................ ............................... 3 2 BIOGRAPHICAL SKETCH ................................ ................................ ............................ 36
6 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
7 LIST OF FIGURES Figure page 3 1 CONSORT flow diagram ................................ ................................ .................... 25
8 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 ca va filters (pIVCFs) for the prevention of pulmonary embolism (PE) in high risk trauma patients (HRTPs) are frequently inserted despite the lack of supportive data demons trating efficacy. This report details the two year interim analysis of the Filters in Trauma (FIT) P ilot S tudy, a single institution prospective randomized pilot feasibility study in a Level 1 trauma center. HRTPs were identi fied for pIVCF placement by the Easter n Association for the Surgery of Trauma (EAST) guidelines. From No v ember 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 se condary outcomes were incidence of PE, deep vein thrombosis (D VT ) 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 ad mission to enrollment (mean 4 5.7 2 1 5 hrs ), time from enrol lment to randomization (mean 4.4 8.5 hrs ), time from randomization to IVCF
9 placement (mean 17.2 9. 1 hrs ), adherence to weekly compression ultrasound w ithin first month ( IVCF group = 4 6.7 %, non IVCF group = 6 6.7 % ), 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 c onsent 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 traum a patients is feasible.
10 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 morbidi ty, mortality, and health care expenditures. Clinicians attribute VTE to the abnormalities described as hypercoagulable state. All three conditions commonly occur in trauma patients. Hospitalized patien ts 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 pa tients 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 m ay 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 re sults 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 plethysm ography
11 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 DV T 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, D VT 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 o f 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 sur gical procedure, and pelv ic 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 W hile VTE risk can be decreased with pharmacologic prophylaxis 2 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 filt er (I VCF ) is an
12 endovascular device placed t o prevent PE. Accepted indications for insertion of IVCFs are: 1) known VTE when anticoagulation is contraindicated 2) re current pulmonary embolism (PE) despite adequate anticoagulation 3) known complications t o anticoagulant therapy. 1 Despite the paucity of reliable data on efficacy and safety, indications for IVCFs have liberalized The PREPIC ( Prvention du Risque d'Embolie Pulmonaire par Interruption Cave ) study enrolled 400 non trauma patients with proxima l DVT with or without PE who were random ly 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 pati ents 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 T ulip V ena C ava F ilter 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 r etrievable IVCFs is to offer mechanical protection against PE during the limited high risk period when anticoagulation may be
13 contraindicated. The largest proportional increase in the us e of r etrievable 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 de cade 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 rec eived 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. 1 1 The considerable variation in use of IVCFs cannot be explained by patient or center characteristics. 1 2 Acute complications of filter placement include improper positioning, tilting, and insertion site thrombosis. Long term complications are DVT, inferior ven a 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 th an half of IVCFs are placed for temporary prophylaxis and therefore should be removed. 1 3 1 6 However retrospective studies report that the rate of removal of these retrievable filters is only approximately 20%. 1 7 20 The overall retrieval rate is a product of the clinical and procedural rate. 2 1 If attempted, ~ 90% of IVCF retrievals are successful. 2 1 Procedural factors associated with retrieval failure include prolonged dwelling time, advanced age, filter head position, and filter design. 2 2 2 4 The true time frame for successful retrieval of IVCFs remains undefined, but proceduralists have reported retrieval as long as 494 days after insertion. 2 5 Clinical factors that influence whether or not IVCF retrieval is
14 attempted include comorbidities, concurrent antico agulation, primary indication for placement, and documented plans for removal at the time of insertion or when the patient is discharged. 1 9 ,2 6 On August 8, 2010 the FDA issued a s afety a lert encouraging timely removal of IVCFs in order to avoid long term complications. 2 7 Therefore improv ing 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 rand omized 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 C lass III evidence ( retrospective data, expert opinion, or case report) in support of the use of pIVCFs in hig h risk trauma patients (HRTPs) 2 8 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 recommendati on based on low strength of evidence ) 2 9 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
15 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 rigor ous trial design that is implemented efficiently and safely. 3 1 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 a re 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 Objec t ives 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 pha rmacologic prophylaxis prescription of sequential compression devices (SCDs), compliance with follow up, and removal rates of filters were examined
16 CHAPTER 2 METHODS Patient Population This was a single ins titution 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 Sh ands Hospital a t 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 proph ylaxis 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 base d on the EAST guidelines for high risk trauma patients. 2 8 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 th e 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/m 2 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
17 placement, or were deemed to be ineligible for pharmacologic prophylaxis throughout their entire hospital stay Additi onal exclusion criteria included inability to obtain informed co nsent 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 inve stigate 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 popu lation 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 point s of contact to introduce the study to eligible patients. After immediate stabil ization and initial surg ical procedures, the principal investigator or study coordinator who were not affiliated with the direct care of the patient obtain ed 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 surg eon 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 Cook TM Celect TM retrievable IVCF donated by Cook Medical (Bloomington, Indiana, USA) Filters were i nserted at the bedside using
18 intravascular ultrasound guidance via the femoral route and advanced to an i nfrarenal 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 ., suspicio n 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 al location. Patients in both treatment groups receive d 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 f or 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, a n 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 wa s defined as a PE Patients who developed a venous thromboembolism (PE or DVT) were treated with therapeutic anticoagulation, if not
19 All patients were followed prospectiv ely 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 P atients 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 thi s appointment. Upon return to vascular clinic patients under went duplex ultrasound for IVCF retrieval planning and clinical evaluation to determine ambulatory status and ongoing VTE risks The decision to offer removal depend ed on whether the VTE risk ha d 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 fe asibility 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) compli ance 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
20 powered to determ ine the relative benefit of pIVCF versus no pIVCF on the development of PE. A sample size of convenience was chose n based on hospital record review, which indicated that approximately 200 patients per year received a pIVCF prior to initiation of the FIT Pi lot 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 conductio n 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 t Whitney test for nonparametric data). Logistic regression was performed to compare binary outcomes of presence or absenc e of thrombotic events. As patients were randomized to treatment groups, we did not perform multivariate regression.
21 CHAPTER 3 RESULTS Between Novem ber 2008 and November 2010, 3 8 patients were enrolled and 30 of 38 were eligible for analysis (Figure 3 1). Differences between s ocio demographic and clinical characteristics in the IVCF group and non IVCF group were not significant ly different (Table 3 1). The DSMB met every 4 months and all DSMB reports were conveyed to the IRB. There were no acute compli cations 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 (me an 4 5.7 2 1 5 hrs), time from enrollment to randomization (mean 4.4 8.5 hrs), time from randomization to placement of IVCF (mean 1 7.2 9. 1 hrs), and adherence to weekly CUS within first month (IVCF group = 4 6.7 %, non IVCF group = 6 6.7 % p=0.28 ). Examining eligible patients that were ultimately not enrolled in the study elucidated b arriers 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=2 3 ), 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 notif ication 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 w as obtained.
22 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 patie nts in the non IVCF group (p=0.29 ). In the IVCF g roup, we were able to reach 80 % of patients for 1 month follow up compared with 10 0% 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 p atients who received an IVCF, 13 patients were eligible for 3 month follow up with the vascula r 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 n ot have their filter removed, 20% were lost to follow up and 20 % were deemed to be at continued risk for VTE.
23 Table 3 1. Sociodemographic and clinical variables according to treatment group Variable IVCF (n = 15 ) Non IVCF (n = 15 ) Total p value Male 1 1 10 0.7 Female 4 5 0. 7 Age (y ea rs) 39.3 16. 2 5 4.2 2 5.2 46. 5 22.0 0.1 2 GCS 1 4.3 1.0 13. 5 3.7 13. 9 2.7 0. 37 ISS 2 4.2 15. 4 24. 9 12.1 2 4.6 13. 5 0. 84 Insurance status Yes 9 11 0. 45 No 6 4 0. 45 Mechanism of injury Penetrating 0 1 0.3 2 Blunt 1 5 1 4 0.3 2 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) 4 6.9 19.9 4 4.4 23. 6 4 5.7 2 1.5 0.6 5 Time from enrollment to randomization (h) 2 .8 6.6 6.4 10.4 4. 4 8.5 0.0 6 Time from randomization to IVCF placement (h) 1 7.2 9. 1 NA 1 7.2 9. 1 Adherence to weekly CUS within 1 st month b y service (%) Trauma ( n=14) 66.7 100 0. 16 Neurosurgery (n=7) 50 6 0 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
24 Table 3 3. Secondary clinical outcomes Outcome IVCF (n = 15 ) Non IVCF (n = 1 5 ) 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 v alue Average time to initiation (h) 20.0 13 2 23.5 20.3 0.79 Pharmacologic prophylaxis at enrollment (%) 93.3 8 6.7 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 8 0.0 100 .0 0. 07 6 month 4 0 .0 60.0 0. 28
25 Figure 3 1. CONSORT f low d iagram
26 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 a nd 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 hou rs of randomization. Although adherence to weekly surveillance CUS was suboptimal, patients who were not transferred off the trauma service throughout their hospitalization did ha ve better compliance with CUS. Conversely patients transferred to other surg ical services during their hospitalization often did not c ontinue to receive weekly CUS. L ack 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 thei s tudy opened, as was the case with the trauma service. 3 2 33 Fifty three eligible patient s 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. 3 4 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
27 staff of eligibility status by the primary trauma service. To enhance this collaboration, we advertised the FIT s tudy with posters on the trauma units, as well as laminated pocket cards detailing inclusion/exclusi on 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 diff iculty 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 dedicate d study coordinator all eligible patients who were admitted to the trauma service over a weekend were not enrolled E xclusion and inclusion criteria may have contributed to our low recruitment rates. We excluded patients if they were ineligible for pharm acologic prophylaxis during their entire hospitalization. The clinical question that w as 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 conside red 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 i n HRTPs at the University of Florida was determined by the attending physician and therefore highly variable and
28 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. Pl acement 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 tre ating trauma surgeon introduced t he study and obtain ed 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 researc h coordinator for the FIT study who then perform ed 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 addit ion, 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 informa tion of patient and next of kin. In addition, the informed conse nt 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 disch arge because of inaccurate contact information in the hospital records. We therefore introduced a contact information sheet as part of the informed consent process 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, 2 0 % were lost to follow up with the vascular surgery service. This is consistent with prior reports in the literature of retrieval rates of 20%. 3 5 Reasons for lack of follow up to remove filters and metho ds 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 s afety a lert recommending that clinicians responsible for the ongoing care of patients with r etrievable IVCFs consider removing the filter as soon as protecti on 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 Desp ite recent reports of filter complications 24, 36 37 placement of p IVC Fs 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 associate d 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 r isk trauma. Our results will help inform the d esign 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 multic enter R C CT 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), s horter acceptable time frame s 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 wel l as timely notification of a potential candidate by the primary trauma service. A future trial can maximize r ecruitment 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 pat ients. 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 serve d a critical function in identifying conce ptual and methodological issues and was an essential foundation step in preparing for a larger trial investigating the role of IVCFs in trauma patients.
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36 BIO GRAPHICAL 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 / on cology 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. Raj asekhar graduated with a Master of Science in Cli nical and Translational Science from th e University of Florida in 2012 primary academic interests include diagno sis 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).