Health Policy Advisory Committee on Technology Technology Brief

Health Policy Advisory Committee on Technology Technology Brief Inferior vena cava filters in the management of patients considered to be at high-risk of acute venous thromboembolism November 2013

State of Queensland (Queensland Health) 2013 This work is licensed under a Creative Commons Attribution Non-Commercial No Derivatives 3.0 Australia licence. In essence, you are free to copy and communicate the work in its current form for non-commercial purposes, as long as you attribute the authors and abide by the licence terms. You may not alter or adapt the work in any way. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/3.0/au/deed.en. For further information, contact the HealthPACT Secretariat at: HealthPACT Secretariat c/o Clinical Access and Redesign Unit, Health Service and Clinical Innovation Division Department of Health, Queensland Level 13, Block 7 Royal Brisbane and Women s Hospital HERSTON QLD 4029 Postal Address: GPO Box 48, Brisbane QLD 4001 Email: HealthPACT@health.qld.gov.au Telephone: +61 7 3646 9100 For permissions beyond the scope of this licence contact: Intellectual Property Officer, Department of Health, GPO Box 48, Brisbane QLD 4001, email ip_officer@health.qld.gov.au, phone (07) 3328 9824. Electronic copies can be obtained from: http://www.health.qld.gov.au/healthpact DISCLAIMER: This Brief is published with the intention of providing information of interest. It is based on information available at the time of research and cannot be expected to cover any developments arising from subsequent improvements to health technologies. This Brief is based on a limited literature search and is not a definitive statement on the safety, effectiveness or costeffectiveness of the health technology covered. The State of Queensland acting through Queensland Health ( Queensland Health ) does not guarantee the accuracy, currency or completeness of the information in this Brief. Information may contain or summarise the views of others, and not necessarily reflect the views of Queensland Health. This Brief is not intended to be used as medical advice and it is not intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for a health professional's advice. It must not be relied upon without verification from authoritative sources. Queensland Health does not accept any liability, including for any injury, loss or damage, incurred by use of or reliance on the information. This Brief was commissioned by Queensland Health, in its role as the Secretariat of the Health Policy Advisory Committee on Technology (HealthPACT). The production of this Brief was overseen by HealthPACT. HealthPACT comprises representatives from health departments in all States and Territories, the Australian and New Zealand governments and MSAC. It is a sub-committee of the Australian Health Ministers Advisory Council (AHMAC), reporting to AHMAC s Hospitals Principal Committee (HPC). AHMAC supports HealthPACT through funding. This Brief was prepared by Linda Mundy from the HealthPACT Secretariat

Technology, Company and Licensing Register ID Technology name Patient indication WP144 Inferior vena cava filters For the management of patients considered to be at highrisk of acute venous thromboembolism Description of the technology The first form of vena cava interruption for the prevention of pulmonary embolism (PE) was surgical vena caval ligation using sutures or external clips, first developed in the late 1800s. Up until the 1960s this procedure was associated with a high risk of mortality (14%) and PE still occurred at a high rate (6%), often with fatal results. Anticoagulation became a mainstay of treatment from the 1950s onwards, however this therapy is not suitable for all patients. 1 Vena cava filters were developed by Greenfield in the 1970s after initial attempts to address the problem of PE with the use of a catheter cup. Greenfield, in conjunction with a petroleum engineer, designed the original stainless steel device able to mechanically trap clots whilst not obstructing caval flow, using a system of hooks to secure the filter in the vein. 2 The original Greenfield filter, regarded to be a permanent device, required surgical implantation and was associated with problems including the development of deep vein thrombosis (DVT) at the insertion site, migration or tilting of the device, thrombosis and obstruction below the filter and recurrent PE despite the placement of the filter. 3 The original inferior vena cava (IVC) filter has undergone numerous iterations, however most modern devices are smaller than the original and have an umbrella-like structure (see Figure 1 for examples). 1 IVC filters do not prevent or treat venous thrombosis -their only function is to prevent PE by trapping venous emboli. Figure 1 Optional vena cava filters: (A) Günther Tulip, (B) OptEase, (C) G2, (D) Cook Celect, (E) SafeFlo, (F) Option 4 New iterations of IVC filters are made from metal alloys with thermal memory or low ferromagnetism, which allows patients to undergo magnetic resonance imaging if required. IVC filters are usually inserted percutaneously via the femoral vein by an interventional radiologist or a vascular surgeon using fluoroscopic guidance (see Figure 2). 3 Inferior vena cava filters in the management of acute VTE in high-risk patients: November 2013 1

Figure 2 Positioning of a vena cava filter 5 Some patients may experience a transient period where anticoagulant prophylaxis is contraindicated or they may only temporarily be considered at an elevated risk of developing venous thromboembolism (VTE). Therefore the placement of an IVC filter may only be a temporary means of protection, before conventional anticoagulant therapy can be resumed. 6 There are several types of IVC filters: permanent and non-permanent filters. Nonpermanent filters can then be divided into two types: temporary or optional filters. Optional filters may be used for a short period of time and then retrieved, or they may remain in situ permanently. Permanent and retrievable filters attach to the wall of the vena cava by means of hooks, barbs or radial pressure, however, temporary filters are usually held in place by tethers or catheters that are usually externalised or buried subcutaneously at a venous access site and traverse long segments of the central venous system. These temporary filters should be removed using an image-guided procedure within 2-6 weeks from implantation before either the filter or the tether becomes adhered to the venous wall. If permanent filtration is required the temporary filter must first be removed followed by the implantation of a different, permanent device. 7 Filter retrieval is usually successful but may fail due to device tilt or endothelialisation. Patients identified as good candidates for IVC filter removal are placed under general anaesthesia or sedation and imaging identifies the positioning of the filter and the absence of luminal thrombi. Once removed the filter should be inspected for fragmentation. 4 Inferior vena cava filters in the management of acute VTE in high-risk patients: November 2013 2

In 2010, the United States Food and Drug Administration (FDA) identified a number of adverse events associated with the use of IVC filters, in particular retrievable filters intended for short-term placement that had remained in place for long periods of time, beyond the time when the patient s risk of PE had diminished. Although reasonably rare, complications associated with IVC filters include device migration, embolisation of device components, perforation of the inferior vena cava and filter fracture. An increased rate of lower limb DVT after long-term insertion of IVC filters has also been reported. The FDA recommends that all retrievable IVC filters be removed as soon as protection from PE is no longer required. 8 There are many international published guidelines describing best practice for the implantation and removal of IVC filters. However the National Health and Medical Research Council s (NHMRC) 2009 clinical practice guidelines for the prevention of VTE do not give guidance on the appropriate use of IVC filters but state that there is a significant gap in the evidence for several thrombo-prophylactic agents including the appropriateness of vena caval filters in trauma patients. These guidelines describe the use of pharmacological and mechanical thrombo-prophylaxis for surgical patients by procedure, during anaesthesia, medical patients by condition, cancer patients, during pregnancy and childbirth and for heparin-induced thrombocytopenia patients. 9 Similarly the guidelines produced by the Australian and New Zealand Working Party for the Management and Prevention of Venous Thromboembolism outlines strategies for pharmacological or mechanical thromboprophylaxis in high- and low-risk surgical patients, medical patients and in pregnant women. However, in respect to the use of IVC filters, these guidelines state.there are some that advocate insertion of a prophylactic inferior vena cava filter for trauma patients considered to be at very high risk for VTE or bleeding. However, their routine use is not advised due to lack of evidence of efficacy or cost-effectiveness. When discussing the diagnosis and treatment of VTE the guidelines state that Thrombolysis, thrombectomy, or insertion of an IVC filter may be required in selected patients without defining which patient groups this might be referring to. 10 Although the NHMRC guidelines make no recommendation on the use of IVC filters, most jurisdictions and hospitals have operational directives in place for patient selection, implantation and subsequent retrieval of IVC filters. Most conform to international guidelines stating that IVC filters may be used in patients at high-risk of VTE or high-risk patients where anticoagulation is contraindicated. Directives, such as that from the Western Australian Department of Health, discuss the use of retrievable IVC filters, which may be placed as a permanent or temporary measure. It is recommended that temporary devices be retrieved once the indication for insertion has subsided and the risk of pulmonary embolism is considered acceptably low. In addition, the directive states that data pertaining to the implantation and retrieval of IVC filters should be submitted to the Office of the Chief Medical Officer annually. This data should include the number of permanent and retrievable Inferior vena cava filters in the management of acute VTE in high-risk patients: November 2013 3

devices implanted, the indications for implantation and importantly the number of retrievable devices removed. 11 The United Kingdom s NICE 1 has published two clinical guidelines: one for patients with an identified VTE 12 and one for patients considered to be at risk of VTE 13. Temporary IVC filters should be offered to patients with proximal deep vein thrombosis (DVT) or PE, when anticoagulation is temporarily contraindicated. However the filter should be removed once the patient becomes eligible for anticoagulation therapy. IVC filters should also be considered for patients with recurrent proximal DVT despite adequate anticoagulation therapy only after considering switching treatment to low-molecule weight heparin or increasing the target international normalised ratio to 3-4 with long-term high-intensity oral anticoagulant therapy. The guideline states that a strategy for the removal of the IVC filter should be documented and put in place at the time of filter implantation and be reviewed regularly. 12 The NICE guidelines for reducing the risk of VTE state that IVC filters should only be offered to those patients considered to be at high-risk of VTE, such as those with an active malignancy or a previous VTE event, and who are contraindicated for mechanical (compression stockings or pneumatic compression devices) and pharmacological VTE prophylaxis. 13 In addition, the guidelines produced by the British Committee for Standards in Haematology state that retrievable IVC filters may be considered in pregnant women who are contraindicated for anticoagulation or who develop extensive VTE shortly before delivery (within 2 weeks). A retrievable IVC filter should be considered in patients about to undergo surgery who have experienced a VTE within one month and in whom anticoagulation must be interrupted. A free-floating thrombus or thrombolysis is not an indication for filter insertion. Importantly, no filter is considered to be superior to others. 14 The guidelines produced by the American Society of Interventional Radiology essentially reiterate the guidance above with indications divided into three categories: absolute, relative and prophylactic. As above, patients with recurrent VTE despite anticoagulation therapy or those who are contraindicated or cannot maintain adequate therapeutic coagulation should be implanted with an IVC filter. In patients considered to have a transient contraindication to anticoagulation therapy an optional IVC filter should be considered. The relative indications include poor compliance with or difficulty establishing anticoagulation therapy, a free-floating proximal DVT, iliocaval DVT and chronic PE. Of interest are those patients deemed to have prophylactic indications that do not have VTE but are considered at high-risk for the development of clinically significant PE, including patients with severe trauma and those about to undergo complex surgery. These patients typically cannot undergo anticoagulation due to a high-risk of bleeding or are unable to be 1 National Institute for Health and Clinical Excellence Inferior vena cava filters in the management of acute VTE in high-risk patients: November 2013 4

adequately monitored for VTE. 7 Figure 3 describes the decision tree for the placement of IVC filters. Figure 3 The decision tree for the placement of IVC filters: PE = pulmonary embolism; AC = anticoagulation; O = optional IVC filter; P = permanent IVC filter 7 Company or developer Several companies manufacture and distribute vena cava filters in Australia: B Braun Australia Pty Ltd, Bard Australia Pty Ltd, Inovanz Pty Ltd, Johnson & Johnson Medical Pty Ltd, Medtel Pty Ltd and William A Cook Australia Pty Ltd. Reason for assessment Implantation of vena cava filters have become a common part of clinical practice despite a paucity of good quality evidence supporting their use, especially in patients deemed to be at high-risk of developing a pulmonary embolism. In addition, although it is recommended in numerous guidelines that vena cava filters are retrieved, in practice this does not occur routinely. The lack of evidence warrants a further assessment of this practice. Inferior vena cava filters in the management of acute VTE in high-risk patients: November 2013 5

Stage of development in Australia Yet to emerge Experimental Investigational Nearly established Established Established but changed indication or modification of technique Should be taken out of use Australian Therapeutic Goods Administration approval Yes ARTG number (s) No Not applicable Licensing, reimbursement and other approval Numerous vena cava filters are approved for use in Australia TGA in addition to several filter retrieval systems (not listed here): Tempofilter Vena Cava Filter (B Braun Australia Pty Ltd) ARTG 135820 This device is indicated to provide protection against pulmonary embolism for a period ranging from a few days to 12 weeks in patients in whom the thromboembolic risk is judged to be temporary. VenaTech LP Vena Cava Filter (B Braun Australia Pty Ltd) ARTG 135805 Designed for patients in whom the risk of thromboembolism is believed to be permanent or of very long duration. G2 X Vena Cava Filter System Femoral (Bard Australia Pty Ltd) ARTG 163303 G2 X Vena Cava Filter System - Jugular/Subclavian ARTG 163302 For use in prevention of recurrent pulmonary embolism via permanent placement in the vena cava. Denali Vena Cava Filter System Femoral (Bard Australia Pty Ltd) ARTG 198865 Denali Vena Cava Filter System Jugular/Subclavian ARTG198866 For use in the prevention of recurrent pulmonary embolism via permanent placement in the vena cava. Optional Vena Cava Filter FB.010500 (Inovanz Pty Ltd) ARTG 184698 Optional Vena Cava Filter FB.HOOK ARTG 184697 Optional Vena Cava Filter FF.010995 ARTG 184699 Optional Vena Cava Filter FF.HOOK ARTG 184700 Optional Vena Cava Filter FJ.120096 ARTG 184695 Optional Vena Cava Filter FJ.HOOK ARTG 184696 Inferior vena cava filters in the management of acute VTE in high-risk patients: November 2013 6

For use in the prevention of pulmonary embolism during high thromboembolic risk surgical procedures in patients with recent history of deep vein thrombosis or pulmonary embolism. OptEase Retrievable Vena Cava Filter (Johnson & Johnson Medical Pty Ltd) ARTG 186230 and ARTG 165592 Indicated for the prevention of pulmonary embolism (PE) via percutaneous placement in the IVC in patients considered at high risk of PE. Aegisy Vena Cava Filter and delivery system (Medtel Pty Ltd) ARTG208061 For filtrating thrombus after percutaneous placement in the inferior vena cava in the following situations: pulmonary embolism, when anticoagulants are contraindicated; failure of anticoagulant therapy in thrombo-embolic diseases; emergency treatment following massive pulmonary embolism when anticipated benefits of conventional therapy are reduced and in chronic, recurrent pulmonary embolism when anticoagulant therapy has failed or is contraindicated. Gunther Tulip Vena Cava Filter Femoral & Jugular Approach (William A Cook Australia Pty Ltd) ARTG 169954 Cook Celect Filter (William A Cook Australia Pty Ltd) ARTG 146226 Cook Celect Vena Cava Filter Femoral & Jugular Approach ARTG 170111 Indicated for the prevention of recurrent pulmonary embolism. Technology type Technology use Device Therapeutic and Preventative Patient Indication and Setting Disease description and associated mortality and morbidity Blood clots or deep vein thromboses that form in the lower extremities may break up and travel through the venous system (usually the vena cava) to the lungs, causing a PE. Most VTEs occur in hospitalised or recently hospitalised patients and may result from prolonged immobility, recent surgery, trauma, pregnancy, oestrogen therapy, or in patients with 1, 15 cancer or an inherited hypercoaguable tendency. In Australia, VTE is estimated to complicate 2-3 per 1,000 hospital admissions, however post-mortem studies indicate that approximately 10 per cent of all hospital deaths can be attributed to PE, making it the most common preventable cause of hospital death. Approximately 50-70% of symptomatic thromboembolic events and 70 per cent of fatal PEs occur in non-surgical patients. 15 It has been estimated that trauma patients recovering from severe injuries have a 58 and 18 per cent risk of developing a distal or proximal DVT, respectively. If left untreated, half of Inferior vena cava filters in the management of acute VTE in high-risk patients: November 2013 7

those presenting with a proximal DVT will develop a clinically significant PE, and of these patients, 2-3 per cent will die. 16 Number of patients It is difficult to estimate the true number of DVT or PE events in any given population. A Western Australian study reported the results of a 13-month population based study conducted in 2003 that surveyed 151,923 residents of Perth. A total of 137 patients experienced 140 VTE events (87 DVT and 53 PE). This translated to a crude annual incidence rate of 0.83 [95% CI 0.69, 0.97] per 1,000 residents for VTE, 0.52 [95% CI 0.41, 0.63] for DVT and 0.31 [95% CI 0.22, 0.4] for PE. 17 Based on Australian Institute of Health and Welfare hospital separation data triangulated against other Australian and international data, it was estimated that in 2008 there were 14,716 cases of VTE in Australia, with more cases occurring in females (9,250 or 62.9%). Of these cases, it was estimated that 8,253 (56%) were PEs and 6,462 were DVTs. This represents an overall rate of 70 separations for VTE per 100,000 Australians, a rate that is increasing by two per year due to the ageing population. A large proportion of these cases (6,335 or 43%) occurred in relatively young people (15-64 years). 18 In Australia during the period 2009-10, there were a total of 9,339 public hospital admissions for a PE (ARDG E61A and E61B). However, the number of patients deemed to be at risk from a thromboembolism, and therefore likely to be implanted with a vena cava filter, is difficult to estimate. In addition, a large number of patients may experience a VTE event whilst admitted for a different indication. Usage of the Medicare Benefits Schedule item number 35330 indicates that 541 vena cava filter insertion procedures were performed during the period July 2012 to June 2013 in the private hospital system. For the equivalent period, there were, however, only 225 vena cava filter retrieval procedures (41.6% of the number inserted) using MBS item number 35331. The number of insertions and retrievals is likely to be much higher in the public system. Speciality Technology setting Cardiovascular disease and vascular surgery Specialist hospital/general Hospital Impact Alternative and/or complementary technology Vena cava filters have been an established technology since the 1970s. Current technology There are currently seven vena cava filters listed on the Commonwealth Prostheses List with a private health insurance reimbursement benefit of $2,348. 19 Inferior vena cava filters in the management of acute VTE in high-risk patients: November 2013 8

Diffusion of technology in Australia The use of vena cava filters is widespread in Australia and New Zealand, and is a common clinical practice used to reduce the risk of pulmonary embolism in patients contraindicated for anticoagulants. To give an indication of the increase in use of this technology, in the United States the number of patients implanted with an IVC filter has increased from 2,000 in 1979 to 49,000 in 1999, and there has been a threefold increase from 2001 to 2006. 20 International utilisation Country Level of Use Trials underway or completed Limited use Widely diffused Worldwide Cost infrastructure and economic consequences The 2008 Access Economics report on the burden of VTE in Australia estimated the total financial cost to be $1.72 billion, which represented 0.15 per cent of gross domestic product. The majority of this cost was due to loss of productivity ($1.38 billion or 80%) primarily due to the premature death of patients. In addition it was estimated that the value of the lost wellbeing (disability and premature death) was a further $19.99 billion, with a range of estimates after a sensitivity analysis of $11.97 to 27.31 billion reflecting the uncertainty in the model. In per capita terms, this amounts to a financial cost of $116,970 per person with VTE in2008 and when the value of lost wellbeing is included, this figure approaches $1.5 million per person. Figure 4 summarises the total costs of VTE by type and by who bears the cost. The majority of financial costs are borne by the individual (54%). The Commonwealth government bears approximately one third of these costs (31%) through forgone taxation revenue. 18 Figure 4 Financial costs of VTE (%total) by a) type of cost and b) the bearer DWL = deadweight loss Inferior vena cava filters in the management of acute VTE in high-risk patients: November 2013 9

There are two MBS item numbers associated with vena cava filters: 35330 for the insertion of an inferior vena cava filter, percutaneous or by open exposure, excluding associated radiological services or preparation, and excluding aftercare (Fee: $515.35 Benefit: 75% = $386.55, 85% = $440.85); and 35331 for the retrieval of an inferior vena cava filter, percutaneous or by open exposure, not including associated radiological services or preparation, and not including aftercare (Fee: $592.45 Benefit: 75% = $444.35). Although usage of these MBS item numbers are relatively low in the private hospital system (541 insertions and 225 retrievals in the last financial year), usage, and therefore cost, in the public hospital system is likely to be much higher. To give an indication of usage in Australia, hospital IVC filter procurement data from the Queensland Department of Health was obtained. For the 12-month period ending 28 February 2013, a total of 302 IVC filters were purchased, details of which are summarised in Table 1. Table 1 12-month IVC filter procurement data from Queensland Department of Health Company and filter type Number Price Bard G2X femoral delivery system 104 $2,348 Bard G2X Jugular/Subclavian delivery system 73 $2,348 Cook CELECT Uni set 115 $1,818 CordisOptease Retrieve 55cm vena cava filter 10 $1,200 It should be noted that: purchase quantity does not necessarily equate to quantities inserted; although the use of SOA 2 is mandatory, there could be additional purchase of non- SOA products; and some devices may have been supplied free of charge due to a special "cost saving" initiative associated with stent usage. Ethical, cultural or religious considerations There is little evidence to support the routine use of vena cava filters in patients to be considered at high-risk of developing a PE. Therefore the insertion and subsequent retrieval of a vena cava filter represents an unnecessary procedure being performed on patients who 2 SOA = standing offer arrangements Inferior vena cava filters in the management of acute VTE in high-risk patients: November 2013 10

may or may not be fully informed about the risks or benefits of such a procedure. However, as guidelines currently suggest that patients considered to be at high-risk of developing a PE should have an IVC implanted, then informed consent would be required for clinicians not to implant, with an explanation that there may be evidence of harm without evidence of benefit. 21 Evidence and Policy Safety and effectiveness The majority of evidence on the placement of IVC filters is of a low quality, being case series evidence, which can only inform on the safety and not the effectiveness of a technology or intervention. To adequately assess the effectiveness of an intervention or technology, comparative studies are required. There is a paucity of comparative studies describing the use of permanent IVC filters, with only one published randomised controlled trial (RCT) the PREPIC trial first published in 1998 22, with 8-year follow-up results published in 2005. 23 The follow-up PREPIC2 trial has recently been completed with publication of results expected soon (NCT00457158). This large RCT (n=399) compared 3- and 6-month outcomes (recurrent or fatal PE and filter complications including thrombosis and failure to retrieve) in patients who received an ALN filter (ALN, France) to patients who received no intervention. However, the inclusion criteria comprised patients with acute PE or deep or superficial vein thrombosis, in addition to having at least one other risk factor. To date, no RCTs have been conducted to evaluate the short- or long-term safety and effectiveness of retrievable IVC filters. 24 The Cochrane systematic review on the use of IVC filters for the prevention of pulmonary embolism conducted by Young et al. (2010) stated that only comparative, controlled trials would be included for assessment (level I intervention evidence). That is, potential included studies would compare: filters to no filters in patients contraindicated for anticoagulation (AC) therapy; filters plus AC therapy compared to AC therapy alone; filters plus AC therapy compared to filters with no AC therapy; permanent versus temporary filters; or a direct comparison of different filters. Only two studies were identified for inclusion: the original 1998 PREPIC study, with followup 8-year results, and the quasi-randomised trial by Fullen et al. (1973) in patients with a traumatic hip fracture. 25 Two ongoing RCTs were identified: the PREPIC2 study as described above and a RCT in cancer patients, which has since been terminated due to poor accrual. Three controlled studies were excluded due to major methodological issues including non- Inferior vena cava filters in the management of acute VTE in high-risk patients: November 2013 11

comparable intervention and control groups (prospective intervention group compared to historical controls). 1 The PREPIC study enrolled 400 adult patients who had acute proximal DVT, with or without PE, who were considered to be at high-risk of either developing a PE or experiencing a recurrent PE (average age 73 years, 64% male). Of note is that patients who were contraindicated for anticoagulation therapy were excluded. Patients were randomised to receive a permanent IVC filter plus anticoagulation therapy 3 (intervention arm, n=200) or anticoagulation therapy alone (control arm, n=200).there was no difference in mortality between the two groups at two years, however there was a 10 per cent (95% CI [11.6%, 20.8%]) higher rate of DVT in those patients who received an IVC filter. Although there was a reduced number of symptomatic PEs in the intervention group compared to controls, this difference was not significant (p=0.16).at eight year follow-up, there was a significant reduction in the number of patients experiencing a PE in the intervention group compared to the control arm (6.2% vs 15.2%, hazard ratio (HR) = 0.37, 95% CI [0.17, 0.79], p value not stated).it should be noted, however, that PE in these patients was not independently documented. It is also unclear whether these patients were experiencing a de-novo or recurrent PE. At the 2-year time point, there was a significantly higher rate of DVT in the filter group compared to the control group (35.7% vs27.5%, HR 1.52, 95% CI [1.02, 2.27], 1, 21 p=0.04). There was no difference in mortality between the two groups. In the study by Fullen et al. (1973), patients with a proximal hip fracture were randomised to receive either a permanent filter or no treatment. Neither group received anticoagulation therapy. Mortality was lower in the intervention group compared to the control group (4/41 (9.8%) vs 14/59 (23.7%), RR 4 = 0.41, 95% CI [0.15, 1.16]). However, six patients in the control group had fractures that could not be repaired by internal fixation, which may enable faster healing, compared to only one patient in the intervention group. Therefore the difference in mortality may be due to differences in the severity of injury. 1 From these two studies, no conclusions regarding the use of permanent IVC filters could be made and the authors recommended further RCTs, especially comparing the use of permanent versus temporary IVC filters. 1 A systematic review on the use of retrievable IVC filters identified no RCTs and included case series (level IV intervention evidence). Of the 37 identified studies, 11 were prospective with the remaining retrospective. None of the included 37 studies directly compared anticoagulation therapy to filters, or compared different devices, therefore no conclusions in respect to the effectiveness of retrievable IVC filters can be made. A total of 6,834 filters were inserted, of which 3,667 (58%) were prophylactic. Retrieval rates in the included studies ranged from 12-45 per cent (mean 34%), with an average time to retrieval of 72 days 3 Anticoagulation therapy with either low molecular weight heparin or unfractionated heparin 4 RR = relative risk Inferior vena cava filters in the management of acute VTE in high-risk patients: November 2013 12

and a mean length of follow-up of 9.9 months (range 2-25 months). Only 30/37 studies reported on PE as an outcome, with a total of 44 PEs reported in 3,485 patients (1.3%). Although many studies have reported an increase in the rate of DVT with the use of IVC filters, this outcome was only reported by 13/30 (43%) of these studies. A total of 69 DVTs were reported in 1,277 patients (5.4%). 24 In addition, this review examined the FDA MAUDE database for adverse events associated with the use of retrievable IVC filters. A total of 842 adverse events were reported, however, rates cannot be calculated due to an unknown denominator. The database contained 192 reports of filter migration and embolisation (10% within 30 days), 174 perforations of the vena cava, 188 filter fractures, 111 reports of complications that occurred during removal of the filter and 228 reports of complications during deployment of the filter. 24 A retrospective audit of the use of IVC filters in an Australian tertiary referral and level I trauma centre was conducted at Westmead Hospital between 2003 and 2007 (level IV intervention evidence). A total of 66 patients had an IVC filter inserted, 17 of which were permanent, two temporary and 47 were considered optional. Five filters were implanted for prophylaxis (1 permanent and 4 optional filters), however the majority of patients were implanted (n=49) with filters due to a contraindication to anticoagulation therapy (11 permanent, 1 temporary and 37 optional filters). 26 Of the total 49 patients implanted with a temporary or optional filter, only 22 patients (45.8%) had their filters removed. Two patients had clinical reasons for leaving the filter in place and a clinical decision was made to leave five others in place. However the remaining 20 patients were candidates for filter removal, highlighting the need for institutional protocols to be put in place and for adequate follow-up to ensure that protocols are adhered to. The authors noted that although filter insertion numbers could be considered modest in this retrospective review, they have observed a growing trend towards the insertion of IVC filters in trauma patients. Of particular concern is that trauma patients are likely to be younger and therefore more likely to be lost from follow-up. The need for institutional protocols for the removal of retrievable IVC filters is reiterated by a retrospective review of IVC filter procedures conducted in a large US hospital s trauma centre (level IV intervention evidence). Retrieval rates in trauma patients who underwent temporary IVC filter implantation before the commencement of an institutional retrieval protocol (3-year period between 2004-2007) were compared to those patients implanted after the implementation of the protocol (data collected prospectively for 1-year between 2007-2008). 27 In the before group, 94 consecutive patients from a total of 12,172 trauma admissions (0.8%) had a temporary IVC filter inserted (mean age 44.5 ± 18.9 years, 66% male). Of these 64 (68.1%) were considered prophylactic due to being considered high-risk and 30 were Inferior vena cava filters in the management of acute VTE in high-risk patients: November 2013 13

therapeutic (30.9%). In the after group, 61 patients from a total of 4,858 trauma admissions (1.3%) had a temporary IVC filter inserted (mean age 46.9 ± 17.3 years, 72% male). As reported by Tiwari et al. above, these figures indicate an increase in the rate of filter insertion over time. Rates of filter retrieval are summarised in Table 2.In addition, in the before group, of the 54/64 patients who received a prophylactic IVC filter, only 23 (43%) had the filter removed. Of the 26/41 patients in the after group who were implanted with a prophylactic filter who were eligible for filter removal, 22 (85%) underwent a successful retrieval. The leading reason for failure to retrieve all eligible filters was the failure by clinicians to arrange the removal (81%) followed by patient non-compliance (10%). These results highlight the need for an institutional protocol to increase the rate of filter removal. Table 2 Filter retrieval rates 27 Group Before (n=94) After (n=61) p value Number eligible for retrieval 76/94 (80.9%) 37/61 (60.7%) <0.01 Retrieval attempts amongst eligible patients 32/76 (42.1%) 35/37 (94.6%) Retrieval rate amongst eligible patients 28/76 (36.8%) 31/37 (83.8%) Overall filter retrieval rate 28/94 (30%) 31/61 (51%) Average filter dwell time (days) 24.0 ± 30.0 range 6-166 days 20.0 ± 14.6 range 7-79 days <0.001 RR 2.25, 95% CI [1.67, 3.03] <0.001 RR 2.27, 95%CI [1.61, 3.21] <0.05 RR 1.71, 95% CI [1.15, 2.54] NS NS = not significant The recent Australian study by Batty et al (2012) reported the results of the Alfred Hospital s Trauma Registry, which retrospectively collected data on all trauma patients admitted over a 7-year period (level IV intervention evidence). The Alfred Hospital is a Level 1 Trauma Centre in Victoria, admitting approximately 5,000 trauma cases per year, with 1,200 of these considered to be major trauma cases. Over the 7-year period a total of 6,344 major trauma patients were treated, the majority being male (73.2%) with a mean age of 44.2 years. The majority of injuries were caused by a blunt mechanism (90.2%), with motor vehicle accident being the predominate cause (n=2,291, 34.5%). IVC filters were inserted as a prophylactic measure in 511 (8.1%) of these patients either due to being considered at an increased risk of PE or contraindicated to pharmacological prophylaxis. Filters were implanted at a mean of 3.6 days after injury. Of the 511 patients implanted with an IVC, four experienced a PE, two of whom had a confirmed thrombosis superior to the ICV filter. One patient experienced a non-fatal PE after an attempt to retrieve the IVC filter was aborted after a thrombus was noted within the filter. In the remaining trauma patients not implanted with a prophylactic IVC, 45 developed Inferior vena cava filters in the management of acute VTE in high-risk patients: November 2013 14

a PE in a mean time of 12-days post injury, two of which were fatal. Five of these patients developed a PE after being discharged home. Of the 45 patients, 24 were implanted with a therapeutic IVC filter. The overall rate of PE was 0.71 per cent, which was considered lower than previous reports. A univariate analysis was conducted to identify factors that may be associated with the occurrence of PE after major trauma, and these are summarised in Table 3. A multivariate analysis revealed that the presence of lower limb injuries and central venous catheterisation were factors that were independently associated with an increased risk of PE in major trauma patients, whereas the presence of an IVC filter was associated with a decreased risk (Table 4). Although these results appear to support the use of IVC filters in major trauma patients, registry data can only provide concerning the safety rather than the effectiveness of a device. Data on rates of IVC filter retrieval were not provided, nor the loss to follow-up of patients, the majority of whom were young males, or the rate of DVTs. In addition, PE was not actively screened for, so some asymptomatic patients may have developed a PE and presented to an alternative hospital after discharge, and therefore not be registered in this study. 28 Table 3 Factors associated with pulmonary embolism after major trauma 28 Factor Odds ratio [95% CI], p-value Age >40 years 2.28 [1.21, 4.28], 0.01 Injury severity score >20 2.37 [1.23, 4.59], 0.01 Number of injuries to lower extremities 1.25 [1.13, 1.38], <0.001 (AIS) Maximum injury severity lower extremity 1.31 [1.08, 1.59], 0.005 (AIS) Number of pelvis fractures 1.73 [105, 2.86], 0.03 Number of lower limb long bone fractures 1.42 [1.16, 1.73], <0.001 Pelvis fracture with lower limb fractures 2.76 [1.23, 6.22], 0.01 Number of major operations (>2 hours) 1.11 [1.04, 1.19], 0.003 Central venous catheterisation 3.30 [1.84, 5.93], <0.001 Blood transfusion 2.79 [1.54, 5.05], <0.001 Intensive care stay (days) 1.03 [1.01, 1.05], <0.001 Number of mechanical ventilation days 1.03 [1.01, 1.06], 0.01 Hospital length of stay (days) 1.02 [1.01, 1.03], <0.001 AIS = abbreviated injury scale, CI = confidence interval Table 4 Independent risk and protective factors for pulmonary embolism 28 Factor Odds ratio [95% CI], p-value Vena cava filter 0.28 [0.088, 0.890], 0.031 Number of injuries to lower extremities 1.31 [1.174, 1.469], <0.001 (AIS) Central venous catheterisation 3.41 [1.879, 6.172], <0.001 AIS = abbreviated injury scale, CI = confidence interval Of interest is the voluntary web-based registry that was initiated by the British Society of Interventional Radiology, which has been in operation since October 2007, where data on Inferior vena cava filters in the management of acute VTE in high-risk patients: November 2013 15

IVC filter insertions and retrievals in the United Kingdom is collated (level IV intervention evidence). 29 In the three and a half years since its inception, the registry has recorded a total of 1,434 IVC placements at 68 UK centres. Although this registry may not capture all filter implantations, the number of events recorded has grown from 10 patients per month in 2007, to 70 per month in 2011, indicating that a registry is a feasible option. Reasons for filter implantation included prophylaxis in high-risk patients (21%), contraindication to anticoagulation (24%) and pre-operatively for DVT or PE (31%). The majority of filters were retrievable (89.5%), however many were implanted with the intention of being permanent, as summarised in Figure 5. In young patients (20-29 years) 91 per cent of filter insertions were intended to be temporary, compared to only 19 per cent in patients aged 80-89 years. Failure to deploy occurred in only 3.3 per cent of cases, usually due to filter tilting or an unexpected anatomical variation. Interestingly there was a difference by device in the success of deployment, with two of the less frequently implanted devices being the most successfully placed. There was no retrieval information on 207 of the 721 (28.7%) filters implanted with the intention of removal. Of the remaining 514, retrieval was attempted in 415 and was successful in 344 cases, or 83 per cent of attempts. On an intention to treat basis, however, successful removal was achieved in 344/721 (47.7%). PE was reported in 16 cases and was cited as a cause of death in six cases, although this was not independently verified. New lower limb DVT was reported in a total of 88 cases, and was associated with increasing age as well as the permanent placement of filters (OR 5 1.22, 95% CI [1.001, 1.411], p=0.013). A total of 35 deaths occurred within 30 days, five of which were patients implanted with permanent filters (3.33%), which was similar to those implanted with temporary filters (30/1283, 2.34%). However, when analysed by whether filters were intended to be permanent or temporary, there was a much higher mortality rate in those inserted with the intention of being permanent (12.3% vs 4.3%). This may possible be due to differences in the severity of the patient s underlying condition. Although registries such as these do not inform on the effectiveness of the use of IVC filters, it is an excellent resource that can be used to identify safety issues that may be associated with a particular device, or issues associated with a particular patient group. 5 OR = odds ratio Inferior vena cava filters in the management of acute VTE in high-risk patients: November 2013 16

Figure 5 Placement intention (temporary versus permanent) over time Since the completion of this brief, a systematic review reporting on the effectiveness of the placement of prophylactic IVC filters in trauma patients has been published. 30 Only comparative studies were included for assessment. A total of 58 studies were identified that described the use of prophylactic IVC filters in trauma patients, however the majority were case series (n=48). Of the remaining eight comparative studies, one was a small RCT (n=34), two were prospective cohort studies with concurrent controls, four were prospective cohort studies with historical controls and the remaining study was a retrospective cohort (level III- 3 intervention evidence). The majority of studies were quite old being published between 1995 and 1997, with only two published recently in 2009 and 2011. All of the studies bar one were assessed as having a high risk of bias, including the small RCT due to issues around the blinding of assessors. In all of these studies, the number of patients in the IVC filter group was small (mean 59 ± 26.4, range 15 to 108), compared to larger numbers in the control group (mean 592 ± 641, range 58 to 2,525). The majority of patients in all studies were male (58-96%) with a mean age ranging from 31.4 to 58.4 years. Six studies reported on the incidence of PE in the two groups. Overall, there were fewer PEs in the IVC filter group compared to the control group, with no evidence of statistical heterogeneity between the studies (I 2 = 0%) (Table 5). The small RCT reported no difference in the incidence of PE between the two groups (RR= 0.32, 95% CI [0.01, 6.91]). When a baseline risk of 1.15 per cent is assumed for PE in trauma patients, the number needed to treat to prevent one additional PE with an IVC filter is estimated to be 109 (95% CI [93, 190]). However, if the lowest reported baseline risk obtained from the American College of Surgeons National trauma Data Bank is used, the NNT is 962 (95% CI [819, 2,565]). Inferior vena cava filters in the management of acute VTE in high-risk patients: November 2013 17

Only four studies reported on the incidence of fatal PE, however one study had no fatal PE events in either arm. Of the three studies with fatal PEs, none occurred in patients with an IVC filter. Although there was an increased risk of developing a DVT in the IVC filter group, this was not significant (RR = 1.76, [0.50, 6.19], p = 0.38) and there was considerable heterogeneity between the studies (I 2 = 56.7%). Overall, the strength of the evidence was considered to be low and not of sufficient strength to support a reduction in mortality, or to support any increased or decreased probability of DVT, in trauma patients with IVC filters. The authors concluded that, from these results, it remained unclear as to which patients would benefit (reduced PE or mortality from PE) or which ones would experience harm (DVT) from the placement of an IVC filter. Retrieval of filters was not an outcome assessed. Table 5 Relative risk of PE and mortality from PE with IVC filters vs no filter 30 Outcome IVC filter Control no filter RR [95% CI] PE 2/334 (0.6%) 48/730 (6.6%) Fatal PE 0/163 (0%) 20/407 (4.9%) RR = 0.20, [0.06, 0.70] p= 0.01 RR = 0.09, [0.01, 0.81] p= 0.03 Economic evaluation Chiasson et al. (2009) conducted an economic evaluation of VTE prophylaxis strategies in critically ill trauma patients considered to be contraindicated for anticoagulant therapy due to a high-risk of bleeding complications, or unable to undergo mechanical prophylaxis due to injuries to lower limbs. This Canadian study initially identified a great deal of variation in the frequency of IVC filter insertion in trauma patients, with low-volume trauma centres inserting twice as many as high-volume trauma centres. The authors noted that the safety and effectiveness of this clinical practice was not guided by the results of a randomised controlled trial. 16 This complex analysis modelled a cohort of trauma patients 6 admitted to intensive care in a large trauma referral centre with severe injuries over a 30-year period 7, with patients considered to be contraindicated to anticoagulant therapy for 2-weeks due to a high-risk of major bleeding. Three prophylaxis strategies were modelled: pneumatic compression devices (PCD); serial Doppler ultrasound (US) screening and the insertion of an IVC filter. The base case analysis was conducted from the health care purchaser perspective, with costs in 6 Guidelines suggest that trauma patients considered for IVC filter implantation may have intracranial haemorrhage, ocular injury with associated haemorrhage, sold intra-abdominal injury (liver, spleen, kidney), or pelvic or retroperitoneal haematoma requiring transfusion. 7 As patients were an average age of 40 years, this was considered a lifetime horizon. Inferior vena cava filters in the management of acute VTE in high-risk patients: November 2013 18

2007 Canadian dollars. In addition to healthcare costs, the incidence of PE, DVT and death was estimated at 12-weeks for all strategies. A cohort study was undertaken to estimate mortality and direct healthcare costs based on data from trauma patients admitted over a 5-year period with severe trauma who were not treated with an IVC filter as a means of VTE prophylaxis. Estimates on the probability of DVT and PE were obtained from observational studies and RCTs. The model was populated with a cohort of 1,015 patients admitted for severe trauma, 76 per cent of whom were male with an average age of 39.3 years. A total of 242 patients (24%) died before discharge. Prophylaxis costs whilst an impatient included IVC insertion (C$2,310), IVC removal (C$1,300), bilateral US (C$386) and weekly heparin (C$308). Outcomes are summarised in Table 6. At 12-weeks, mortality was similar across all three strategies. The incidence of DVT at 12-weeks was higher in the IVC filter group (25.7%) compared to the other two strategies: PCD (14.9%) and US screening (15.0%). However, the incidence of PE was highest in the PCD group (2.9%), followed by the US screening group (15%) and was lowest in the IVC filter group (0.3%). Following the diagnosis of a DVT, 5.5 and 11.5 per cent of patients in the PCD and US screening group were implanted with an IVC filter. Of note is that one third of the US screening group (or 4.2% or the total US group) were false positives. Healthcare costs were similar for all three strategies at 12-weeks as were lifetime QALYs. A sensitivity analysis was conducted, however little variation in costs was noted in any of the strategies, apart from the additional $637 cost of IVC filter removal upon discharge. Table 6 Clinical outcomes and costs for PCD, US and IVC filter prophylactic strategies 16 Outcome at 12-weeks PCD US IVC filter DVT, % 14.9 15.0 25.7 PE, % 2.9 1.5 0.3 Mortality, % 24.5 24.4 24.5 IVC filter insertion, % 5.5 11.5 100 Cost of ICU, hospital and subsequent care, Can$ 55,831 55,334 57,377 Outcome over patient lifetime PCD US IVC filter Cost of ICU, hospital and subsequent care, Can$ 66,900 65,800 68,700 Expected QALYs 6.9 6.9 6.9 DVT = deep vein thrombosis, PE = pulmonary embolism, ICU = intensive care unit, PCD = pneumatic compression device, US = ultrasound, QALYs = quality adjusted life year The authors concluded that although the rates of PE varied between the three strategies, this appeared to have a minimal effect on mortality, and that mortality in patients with Inferior vena cava filters in the management of acute VTE in high-risk patients: November 2013 19