Venous Thromboembolism Prevention in Lower Leg Injury Requiring Immobilisation: a Feasibility

Protocol

Venous thromboembolism prevention in lower leg injury requiring immobilisation: a feasibility study and open-label trial of Jet Impulse Technology (JIT) within-cast (JIT in-cast study)

Investigators:

Irene Braithwaite Senior Medical Research Fellow, MRINZ

Grant Kiddle Orthopaedic surgeon

Nigel Willis Orthopaedic surgeon

Tony Mallon Clinical Trials Coordinator, MRINZ

Allie Eathorne Research Assistant, MRINZ

Mark Weatherall Biostatistician, University of Otago

Richard Beasley Director, MRINZ

Contact: Dr Irene Braithwaite Medical Research Institute of New Zealand Private Bag 7902, Wellington, New Zealand Telephone: +64 4 805 045 Facsimile: +64 4 389 5707 Email: [email protected]

Protocol: JIT in-cast feasibility. Version 1.1: 20/Jan 2015 Background

Prolonged cast immobilisation of the lower limb after injury is associated with an increased risk of venous thromboembolism (VTE)1-7. A 2008 Cochrane review of low molecular weight heparin (LMWH) for prevention of VTE in patients with lower limb immobilisation found a wide range in the incidence of VTE in patients in the control arms of these studies, between 4.3% to 40%1. In the review 80% of deep venous thromboses (DVT) were distal which in general are associated with a good prognosis, however 10% of distal DVT propagate proximally and, of these, 10% result in massive pulmonary embolism (PE) and death1.

The preferred method to reduce the risk of VTE during lower limb immobilisation is uncertain with many conflicting opinions and little robust evidence. The recent American College of Chest Physicians Evidence-based Clinical Practice Guidelines on Prevention of Thrombosis (2012)8 suggests no prophylaxis for cast immobilisation in isolated lower leg injuries distal to the knee.

There is limited evidence to support the prophylactic use of LMWH1, but concerns about bleeding risk, the fact that it is not funded for this indication in NZ, and practical difficulties with daily or twice daily administration form the basis of the proposed full study (MAIN RCT) to consider other evidence-based preventive treatments.

There is evidence to support the use of low dose oral aspirin prophylaxis for VTE in a variety of medical and surgical patient groups9-10. A single large randomised placebo-controlled trial of low dose aspirin in hip fracture and elective arthroplasty found a relative risk of 0.66 for VTE with only a small increase in post-operative bleeding11. There are no trials of low dose aspirin in lower limb immobilisation.

The clinical effectiveness of intermittent pneumatic compression (IPC) systems in the prevention of DVT was established in the 1980s12 and is a non-pharmacological alternative for VTE prevention without the risk of bleeding8. However there are no randomised trials of IPC devices in the situation of prolonged lower-leg cast immobilisation.

New oral anticoagulants include rivaroxaban (a direct factor Xa inhibitor) and dabigatran (a direct thrombin inhibitor). These agents reduce the risk of VTE in total hip and knee arthroplasty with a favourable efficacy / risk profile compared with LMWH13,14. Rivaroxaban

Protocol: JIT in-cast feasibility. Version 1.1: 20/Jan 2015 is widely used in orthopaedic surgery in New Zealand. It is relatively straight-forward to use as it is given by mouth, does not require monitoring, and studies to date do not indicate a major bleeding risk.

We intend to undertake a full study (MAIN RCT) consisting of a three-arm parallel groups randomised-controlled trial of low dose aspirin, an intermittent pneumatic compression device commercially known as Jet Impulse Technology (JIT) plus low dose aspirin, or rivaroxaban alone to prevent venous thromboembolism (VTE) secondary to cast immobility for a ruptured Achilles tendon or ankle fracture.

For the proposed MAIN RCT to be viable, we need to establish the capacity to recruit, tolerability of JIT placement under a lower limb cast for a protracted period of time (up to 8 weeks), and adherence to the proposed JIT in-cast regime. This feasibility trial has been designed to establish the proportion of subjects likely to enrol in the MAIN RCT, the ease of application and acceptability of the JIT system under a cast, possible adverse events with the JIT system, and the proportion of symptomatic VTE events in the population enrolled in the trial.

Objective

To determine the following 1. The proportion of eligible subjects likely to enrol in the MAIN RCT 2. Likely adherence to JIT system utilisation during the MAIN RCT 3. Ease of application and most appropriate materials to aid patient comfort during application of the JIT system under the lower limb cast 4. Possible adverse events associated with utilising the JIT system under a lower limb cast for two to three weeks duration at a time between reviews 5. Proportion of participants in the trial with asymptomatic DVT at 2 weeks, 4 weeks and 8 weeks post their index event. 6. Proportion of participants in the trial with symptomatic DVT and or PE

Primary Outcome Variable

The proportion of eligible participants recruited into the open-label trial of the JIT system .

Protocol: JIT in-cast feasibility. Version 1.1: 20/Jan 2015 Secondary Outcome Variables

1. The number of patients eligible for recruitment in the MAIN RCT from the Wellington Hospital fracture clinic for one year. 2. The proportion of participants adhering to use of the JIT system for ≥60% of each 24 hour period averaged over the days between review 3. Proportion of participants in the open-label trial who have complications specific to use of the JIT system, and the consequent proportion that withdrew due to JIT- related adverse events 4. Proportion of all participants with asymptomatic DVT detected by ultrasound of the popliteal to femoral vein (accessible above the cast) at weeks 2 and 4 5. Proportion of all participants with asymptomatic DVT detected by ultrasound of the entire index limb after removal of the lower limb immobilisation (between 6 and 8 weeks in most cases). 6. Proportion of all participants with symptomatic DVT and / or PE

Study design

A feasibility study with an open-label trial of the JIT system in-cast.

Study subjects Volunteers Aged between 18 and 70 years with  ruptured Achilles tendon or  stable ankle fracture requiring a non-weight bearing cast, or  ankle fracture with operative fixation and then cast immobilisation, or  elective operation of the lower limb subsequently requiring cast immobilisation

Inclusion criteria  Aged between 18 to 70 years  Able to provide informed consent

Exclusion criteria  History of previous or current DVT or PE  Pregnancy  Current active cancer, other than basal cell carcinoma of the skin.  Known thrombophilic state Protocol: JIT in-cast feasibility. Version 1.1: 20/Jan 2015  Already using anticoagulation  Use of low molecular weight heparin or immobility greater than two days prior to enrolment.  Any other criteria which at the discretion of the investigator will affect the safety of the participant or the participants ability to comply with the requirements of the study

Protocol: JIT in-cast feasibility. Version 1.1: 20/Jan 2015 Study Procedures

The study will run for approximately nine months. Six months will be used for recruiting participants for the open-label trial of the JIT system with a further three months to both confirm the annual number of potential participants and to provide three month follow-up for all participants in the randomised study.

During working hours, investigators – in conjunction with nursing staff at the fracture clinic will identify potentially eligible participants. Subjects will be informed about the open-label trial and asked if they would participate. Those who decline to participate will be asked if this is because the treatment is a device rather than a medication. A log will be kept of potential participants who were treated and discharged outside of working hours and of all potential participants approached during the working day. This will be used to identify the proportion of eligible participants likely to be recruited into the proposed MAIN RCT.

Participants who agree to be enrolled into the open-label trial of the JIT system will have the JIT placed under their lower limb cast and the usual care of Aspirin EC 100mg daily will be prescribed. They will be reviewed fortnightly at fracture clinic for up to eight weeks. We plan in-cast pad changes at weeks two and four and possibly six depending on adherence of participants to the device (the exact schedule will be defined by planned orthopaedic follow- up). The JIT system is supposed to be used during non-weight bearing so those using the device will be asked to use it while they are seated or immobile during the day and while in bed at night. Information about device usage will be collected at each visit to determine the use of JIT (60%, or 14.4 hours per day average is defined as good adherence). Participants who withdraw from the study will be asked if the reason for this was related to discomfort or adverse events from using the device. At clinic visits, nursing staff will be asked to complete a semi-structured record regarding the practicalities of device placement and related issues such as skin condition.

All participants will be asked to attend offices of Pacific Radiology in a location most convenient to them for ultrasound examination of the popliteal to femoral vein of the affected limb (accessible above the leg cast) at 2 and 4 weeks, and again for ultrasound of the entire limb after removal of the cast / moonboot at the end of their orthopaedic treatment period (expected to be 6 to 8 weeks). At any time between clinic visits and during the ensuing six week follow up period, if participants experience signs or symptoms of DVT or PE, they will

Protocol: JIT in-cast feasibility. Version 1.1: 20/Jan 2015 undergo ultrasound or CTPA respectively, and be treated according to Wellington Hospital protocols.

As in the proposed MAIN RCT, all participants will be given advice about the symptoms of DVT and PE and advised to seek medical review should these happen. They will be given a card indicating that they are participating in the open-label trial of the JIT system which will include contact details for the investigators. Also, as in the MAIN RCT the final follow up phone call or visit will be six weeks after completion of cast-immobilisation treatment.

Serious Adverse Events (SAEs) For the purposes of this study the following events will be considered to be SAEs if they have been associated with the study intervention:

 Death  Life-threatening event  Permanently disabling or incapacitating event  Hospitalisation  Any event considered serious by the study investigator

Serious adverse events will be reported to the Medical Research Institute of New Zealand in accordance with standing HDEC reporting procedures, and will be reviewed on a case by case basis by an independent Data Monitoring Committee (DMC). The DMC will undertake a formal review of all adverse and serious adverse events at the point that the 35th participant is recruited. All other adverse events will be reviewed by an internal safety data monitoring committee on a case by case basis.

Statistical Methods

70 participants in the open-label trial of the JIT system will give 80% power, alpha 5%, to rule out a complication rate of at most 33% if the anticipated rate is 10%; and to rule out adherence of less than 60% if the adherence rate is 75%.

This sample size also has over 95% power to rule out a recruitment rate of less than 50%. If the recruitment rate is 75% from an estimated annual pool of 250 patients from Wellington Regional Hospital, then the open-label trial of the JIT system should run for six to seven

Protocol: JIT in-cast feasibility. Version 1.1: 20/Jan 2015 months, however as the accuracy of diagnostic coding is uncertain we plan to run the trial for nine months.

The main analyses will be calculation of 95% confidence intervals for a proportion.

Data Management Data gathered during this study, including any personal information relating to the participants will be securely stored for 15 years by the MRINZ to meet our ethical and Good Clinical Practice responsibilities. After this period of time, the records will be destroyed to maintain confidentiality and privacy of all participants. It is possible we may use some of the data from this study to contribute to future studies. If we do so, the data will be used in such a way that participants will not be personally identified.

During the informed consent process, participants will have the opportunity to tell us if they would like a copy of the final results of the study. We should be able to provide these within approximately 6 months of study completion. The MRINZ aims to have all studies written up and published in reputable peer-reviewed journals, and to present our findings in medical and scientific forums. Participants will not be able to be personally identified in any of these publications or presentations.

Protocol: JIT in-cast feasibility. Version 1.1: 20/Jan 2015 References

1. Testroote M, Stigter W, de Visser DC, Janzing H. Low molecular weight heparin for prevention of venous thromboembolism in patients with lower-leg immobilization. Cochrane Database Syst Rev. 2008(4):CD006681. 2. Ettema HB, Kollen BJ, Verheyen CC, Buller HR. Prevention of venous thromboembolism in patients with immobilization of the lower extremities: a meta- analysis of randomized controlled trials. J Thromb Haemost. 2008 Jul;6(7):1093-8. 3. Lassen MR, Borris LC, Nakov RL. Use of the low-molecular-weight heparin reviparin to prevent deep-vein thrombosis after leg injury requiring immobilization. N Engl J Med. 2002 Sep 5;347(10):726-30. 4. Lapidus LJ, Ponzer S, Elvin A, Levander C, Larfars G, Rosfors S, et al. Prolonged thromboprophylaxis with Dalteparin during immobilization after ankle fracture surgery: a randomized placebo-controlled, double-blind study. Acta Orthop. 2007 Aug;78(4):528-35. 5. Lapidus LJ, Rosfors S, Ponzer S, Levander C, Elvin A, Larfars G, et al. Prolonged thromboprophylaxis with dalteparin after surgical treatment of achilles tendon rupture: a randomized, placebo-controlled study. J Orthop Trauma. 2007 Jan;21(1):52-7. 6. Kock HJ, Schmit-Neuerburg KP, Hanke J, Rudofsky G, Hirche H. Thromboprophylaxis with low-molecular-weight heparin in outpatients with plaster- cast immobilisation of the leg. Lancet. 1995 Aug 19;346(8973):459-61. 7. Jorgensen PS, Warming T, Hansen K, Paltved C, Vibeke Berg H, Jensen R, et al. Low molecular weight heparin (Innohep) as thromboprophylaxis in outpatients with a plaster cast: a venografic controlled study. Thromb Res. 2002 Mar 15;105(6):477-80. 8. Falck-Ytter Y, Francis CW, Johanson NA, Curley C, Dahl OE, Schulman S, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence- Based Clinical Practice Guidelines. Chest. Feb;141(2 Suppl):e278S-325S. 9. Antiplatelet Trialists Collaboration. Collaborative overview of randomized trials of anti-platelet therapy-III: reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. BMJ. 1994;308:235-46. 10. Collins R, Baigent C, Sandercock P, Peto R. Antiplatelet therapy for thromboprophylaxis: the need for careful consideration of the evidence from randomised trials. Antiplatelet Trialists' Collaboration. BMJ. 1994 Nov 5;309(6963):1215-7. 11. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet. 2000 Apr 15;355(9212):1295- 302. 12. Niikura T, Lee SY, Oe K, Koh A, Koga T, Dogaki Y, et al. Incidence of venous thromboembolism in fractures around and below the knee with physical prophylaxis. Orthopedics. Oct;35(10):e1476-82. 13. Eriksson BI, Kakkar AK, Turpie AG, Gent M, Bandel TJ, Homering M, et al. Oral rivaroxaban for the prevention of symptomatic venous thromboembolism after elective hip and knee replacement. J Bone Joint Surg Br. 2009 May;91(5):636-44. 14. Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. 15. Wells PS, Anderson DR, Bormanis J, Guy F, Mitchell M, Gray L et al. Value fo assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet. 1997;350:1795-98

Protocol: JIT in-cast feasibility. Version 1.1: 20/Jan 2015