ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12614000963628

Ethics application status

Approved

Date submitted

1/09/2014

Date registered

9/09/2014

Date last updated

10/07/2018

Type of registration

Prospectively registered

Titles & IDs

Public title

Detailed assessment of risks and benefits of inferior vena cava filters on patients with complicated injuries

Scientific title

Major trauma patients with inferior vena cava filters versus no prophylaxis in preventing venous thromboembolism

Secondary ID [1]

NIL

Universal Trial Number (UTN)

Trial acronym

The da Vinci Trial

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Multiple trauma

Venous thromboembolism

Condition category

Condition code

Surgery

Surgical techniques

Blood

Clotting disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

The filter should be inserted within 72 hours of admission to the study center

Intervention code [1]

Treatment: Devices

Intervention code [2]

Prevention

Comparator / control treatment

No early venous thromboembolism prophylaxis

Control group

Active

Outcomes

Primary outcome [1]

Symptomatic pulmonary embolism confirmed by CT pulmonary angiography

Timepoint [1]

Day 90 post randomisation

Primary outcome [2]

Death -all causes

Timepoint [2]

Day 90 post randomisation

Secondary outcome [1]

Lower limb deep vein thrombosis confirmed by lower limb ultrasonography

Timepoint [1]

Day 90 post randomisation

Secondary outcome [2]

Acute symptomatic pulmonary embolism within 7 days of randomisation confirmed by post-mortem examination or CT pulmonary angiography

Timepoint [2]

Within 7 days of randomisation

Secondary outcome [3]

Fatal pulmonary embolism

Timepoint [3]

Day 90 post randomisation

Secondary outcome [4]

Cost-effectiveness
Economic outcome analysis plan
This will comprise (a) the net resource cost of IVC compared to the status quo without IVC (cost analysis) and (b) comparison of net resource use with net health benefits (cost-effectiveness).

a) Cost analysis
The total cost of treatment using an IVC filter includes the device itself, the consumables required for insertion and removable, the costs of personnel required for the procedure and costs of complications. Cost components for both arms of the trial which require analysis include length of index hospital stay including number of days in ICU, readmission days including ICU, pharmaceuticals required to treat PE, DVT prophylaxis, associated investigations including all X-rays, CT pulmonary angiography, ultrasonography and any other associated procedures. Follow-up will extend to 90 days post procedure in the first instance; furthermore, long-term outcomes including survival and venous thromboembolic complications & the cost-effectiveness in preventing these complications beyond day-90 will be assessed through use of linked health data as a sub-study. Costs will be drawn from hospital finance data where possible, but all resources will be collected in standard units and otherwise quantified using standard Australian resource data such as the MBS for medical procedures and the PBS for pharmaceuticals. Costs will be standardized to 2015 Australian dollars. The cost analysis will take the perspective of the Australian Health system.

Current cost data estimates:
It is estimated that the total cost of the procedure using IVF filters is approximately $6,000, comprising: $3000 - IVF filter, $3000 - consumables for insertion + labour costs for insertion and removal. Given the significant number needed to treat (estimated to be 10), net savings are unlikely to accrue unless additional individual benefits are evident such as survival and venous insufficiency after VTE. Given estimates of 20% expected DVT and 9-10% expected PE in the study cohort, the device will only be cost saving if PE costs on average, more than A$60,000.
However, if there is a difference in life saved after the use of IVC filters – that is a reduction in fatal PE as suggested by existing observational studies – this will contribute enormously to cost-effectiveness (as distinct from cost savings).

b) Cost-effectiveness
Costs of the procedure will be compared to health outcomes as determined from the trial.
The cost analysis as described above will indicate whether IVC filters provide a net saving to the health care system. A net saving in costs combined with a net health benefit suggests a dominant health intervention strategy. In the event that the IVC filters demonstrate health benefits at some cost, formal cost-effectiveness analysis can provide information around the relative health benefits for a given cost, compared to alternative resource demands, such as comparable procedures.

Using mortality outcomes, both at 90 days after admission and long-term after hospital discharge obtained by linked health data, cost per LYG (life year gained) can be estimated. Long-term outcomes will be analysed as a sub-study through data-linkage. If funding for this sub-study is not available, long-term outcome will be estimated using Markov decision analysis based on probabilities from the literature. Sensitivity analysis will be undertaken to test robustness of the parameters, to identify cost drivers and to estimate conditions under which the procedure is cost-effective. Cost-effectiveness ratios can be compared with similar procedures to estimate potential acceptability for wider policy.

Timepoint [4]

1-year post randomisation

Eligibility

Key inclusion criteria

Patients will be eligible for the trial (1) if they are considered to have contraindications to pharmacologic thromboprophylaxis within 72 hours of hospital admission by their attending trauma or neurosurgeons AND (2) Injury Severity Score >15.

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. Severe head or systemic injury where death within 48 to 72 hours is expected.
2. Attending clinicians judge that patients are at low-risk of bleeding and can receive pharmacologic thromboprophylaxis within 3 days after major trauma.
3. Patients who have CT evidence of pulmonary embolism on admission to the hospital after trauma.
4. Patients who have been treated with full systemic anticoagulation by warfarin, UFH or LMWH for a pre-existing medical disease (e.g. patients with chronic atrial fibrillation requiring systemic anticoagulation) until admission due to trauma.
5. Pregnant patients.

Specific contraindications to heparin or other form of pharmacologic thromboprophylaxis are listed below.
1. Intracerebral haematoma or contusions
2. Active bleeding on admission requiring more than 6 units of blood transfusion within the first 24 hours of admission after the injury
3. Spinal cord injury resulting in neurological deficits or spinal cord haematoma is demonstrated in the MRI scan of the spine
4. Complex pelvic fractures resulting in significant retroperitoneal haematoma
5. Complex visceral organ injuries (e.g. splenic and liver lacerations) resulting in high risk of intraperitoneal bleeding
6. Others, please specify

Study design

Purpose of the study

Prevention

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Web-based randomisation and allocation of treatment involving contacting the holder of the allocation schedule who is “off-site” or at central administration site

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Web-based random number generator created by computer software (i.e. computerised sequence generation), stratified by study sites.

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Phase

Phase 2 / Phase 3

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

Although IVC filters are increasingly used for thromboprophylaxis in many trauma patients, their clinical effectiveness has never been well documented. They are invasive, expensive and have significant complications some of which are life-threatening. It is important to demonstrate clinical superiority before they are widely used in patients who are already at risk of mortality and, hence, a superiority trial rather than a non-inferiority trial is preferred. We are planning a study of independent intervention (IVC filters) and active controls with 1 control per intervention subject. The incidence of asymptomatic PE between 3 and 7 days after moderate to major trauma is extremely high (24%) despite LMWH or UFH prophylaxis. Prior data indicate that the PE rate among patients who are at high-risk of VTE without thromboprophylaxis (similar to our control patients) is >0.09 (or 9%). The relatively high incidence of PE is expected because (a) we use a proactive approach to detect mildly symptomatic PE, and (b) we have chosen the group of trauma patients who are at extreme risk of VTE and, at the same time, cannot receive pharmacologic thromboprophylaxis and lower limb compression. The TESS score of these patients is expected to be >10. Evidence suggested that IVC filters are highly effective in reducing PE. If the PE rate of the intervention group is close to 0.5%, we will need to study 97 intervention subjects and 97 active control subjects to be able to reject the null hypothesis that the failure rates for intervention and active control subjects are equal with probability (power) 0.8 (or 0.9 if the baseline risk of PE is 10%). We assume there will be a small proportion of patients who will have study intervention crossed over between the two groups. Therefore the total sample size of this study is 240 (120 per group) allowing up to 20% of the study subject crossed over between the active control and intervention groups without affecting the power of the study. If an IVC is associated with an increased risk of lower limb DVT, this sample size will also have >80% power to detect an increased risk of DVT due to the IVC filter from 10% to 25%.

Chi-square statistics for categorical outcomes.

Cox proportional hazard regression for time to primary outcome after adjusting for important baseline covariates

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

2/06/2015

Actual

5/06/2015

Date of last participant enrolment

Anticipated

Actual

24/12/2017

Date of last data collection

Anticipated

Actual

25/03/2018

Sample size

Target

240

Accrual to date

Final

240

Recruitment in Australia

Recruitment state(s)

Recruitment hospital [1]

Royal Perth Hospital - Perth

Recruitment hospital [2]

Sir Charles Gairdner Hospital - Nedlands

Recruitment hospital [3]

Royal Brisbane & Womens Hospital - Herston

Recruitment hospital [4]

Fiona Stanley Hospital - Murdoch

Recruitment postcode(s) [1]

4029 - Herston

Recruitment postcode(s) [2]

6150 - Murdoch

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

State Health Research Advisory Council, Department of Health, Western Australia

Address [1]

SHRAC, Level 2, C Block, Department of Health, 189 Royal Street, East Perth, Perth, WA 6004

Country [1]

Australia

Primary sponsor type

Charities/Societies/Foundations

Name

Medical Research Foundation, Royal Perth Hospital

Address

MRF Building, Perth, Royal Perth Hospital, PO Box 2323, East Perth, WA 6892

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Royal Perth Hospital

Ethics committee address [1]

Wellington Street, Royal Perth Hospital, WA 6000

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

01/10/2014

Approval date [1]

22/10/2014

Ethics approval number [1]

EC14-139

Ethics committee name [2]

WA Coroner's Ethics Committee

Ethics committee address [2]

WA Coroner's Office, 10th floor, Central Law Courts
501 Hay Strret, Perth, WA 6000

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

15/08/2014

Approval date [2]

20/08/2014

Ethics approval number [2]

EC03-14

Ethics committee name [3]

Sir Charles Giardner Hospital Ethics Committee

Ethics committee address [3]

Level 2  A Block, Hospital Avenue, Nedlands, WA 6009

Ethics committee country [3]

Australia

Date submitted for ethics approval [3]

Approval date [3]

17/04/2015

Ethics approval number [3]

2014-161

Summary

Brief summary

Venous thromboembolism (VTE) is a significant health problem especially in hospitalized patients, with a high associated morbidity and mortality. For most patients, the standard of care is to use prophylactic anticoagulation (heparin) and intermittent pneumatic compression to both lower limbs. There is a group of patients who are at very high risk of VTE but these VTE prophylactic measures cannot be used or considered adequate, either for physical reasons (lower limb fractures / open wounds ) or risk of bleeding from anticoagulants (such as severe brain injury). In these patients, the options are to use no intervention or to insert an Inferior Vena Cava filter (IVCF). Although IVCFs are widely used as a mechanical VTE prophylaxis in patients who have contraindications to conventional VTE prophylactic measures, their effectiveness in this regard has not been established. This phase II / III randomized controlled trial aims to assess the clinical effectiveness, benefits and harms, and also the cost- effectiveness of the early use of IVCFs (<72 hrs of admission after severe injury) for trauma patients who have contraindications to conventional VTE prophylactic measures (pharmacological thromboprophylaxis). This trial has the capacity to influence the management of trauma patients worldwide, and to establish the place of IVCFs in modern medical practice.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

A/Prof Kwok Ming Ho

Address

ICU, 4th Floor, North Block, Royal Perth Hospital, Wellington Street, Perth, WA 6000

Country

Australia

Phone

61-08-92241056

Fax

61-08-92243668

[email protected]

Contact person for public queries

Name

Kwok Ming Ho

Address

ICU, 4th Floor, North Block, Royal Perth Hospital, Wellington Street, Perth, WA 6000

Country

Australia

Phone

61-08-92241056

Fax

61-08-92243668

[email protected]

Contact person for scientific queries

Name

Kwok Ming Ho

Address

ICU, 4th Floor, North Block, Royal Perth Hospital, Wellington Street, Perth, WA 6000

Country

Australia

Phone

61-08-92241056

Fax

61-08-92243668

[email protected]

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Detailed assessment of benefits and risks of retrievable inferior vena cava filters on patients with complicated injuries: The da Vinci multicentre randomised controlled trial study protocol.	2017	https://dx.doi.org/10.1136/bmjopen-2017-016747
Embase	Benefits and harms of early prophylactic inferior vena cava filter in major trauma patients: A multicenter randomizedcontrolled-trial (RCT).	2018	https://dx.doi.org/10.1097/SHK.0000000000001158
Embase	A multicenter trial of vena cava filters in severely injured patients.	2019	https://dx.doi.org/10.1056/NEJMoa1806515
Embase	Cost-effectiveness of early placement of vena cava filters to prevent symptomatic pulmonary embolism in patients with contraindications to prophylactic anticoagulant.	2021	https://dx.doi.org/10.1177/1358863X211023559
Embase	Incremental cost of venous thromboembolism in trauma patients with contraindications to prophylactic anticoagulation: a prospective economic study.	2022	https://dx.doi.org/10.1007/s11239-021-02618-w

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically