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Trial registered on ANZCTR


Registration number
ACTRN12609000762257
Ethics application status
Approved
Date submitted
26/08/2009
Date registered
2/09/2009
Date last updated
21/04/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Assessment of microbleeding after prophylaxis with enoxaparin or rivaroxaban against venous thromboembolic disease following hip and knee surgery
Scientific title
Assessment of micro-bleeding after prophylaxis with enoxaparin or rivaroxaban against venous thromboembolic disease following hip and knee arthroplasty
Secondary ID [1] 251941 0
PREVENT trial
Universal Trial Number (UTN)
Trial acronym
PREVENT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Prevention and treatment of venous thromboembolism (VTE); comprising deep vein thrombosis (DVT) and pulmonary embolism (PE) after hip and knee arthroplasty. 237373 0
Condition category
Condition code
Blood 239696 239696 0 0
Haematological diseases
Cardiovascular 239892 239892 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Assess thoroughly post-operative micro-bleeding in patients undergoing knee and hip surgery after treatment with the standard prophylaxis with low molecular weight heparin compared to the new oral anti-Xa rivaroxaban for prevention of the post operative development of thrombosis.
For the new oral anti-Xa rivaroxaban intervention a) the dose will be once daily 10 mg tablet; b) the duration of administration will be 35 days for hip replacement surgery and 14 days for knee replacement surgery (first dose at 124 hours after wound closure); and c) the mode of administration is oral tablet. In the first 24 hours after surgery we commence an intermittent pneumatic compression (IPC) device for prevention of DVT for all patients and at the same time to avoid unnecessary bleeding.
Intervention code [1] 237023 0
Treatment: Drugs
Intervention code [2] 241194 0
Prevention
Comparator / control treatment
low molecular weight heparin (enoxaparin). For this comparator treatment the dose will be a) once daily 40 mg dose; b) the duration of administration,will be 35 days for hip replacement surgery and 14 days for knee replacement surgery (first dose at 24 hours after wound closure); and c) the mode of administration is subcutaneous injection.
In the first 24 hours after surgery we commence an intermittent pneumatic compression (IPC) device for prevention of DVT for all patients and at the same time to avoid unnecessary bleeding.
Control group
Active

Outcomes
Primary outcome [1] 240466 0
1. Primary Outcome based upon intent to treat: Composite outcome of assessment of micro-bleeding post surgery.

Post-operative: Postoperative bleeding will be assessed via a) wound drainage volumes if there is a drainage b) number of dressings c) weight of dressings d) knee circumference in case of Total Knee Replacement (TKR) performed during follow up process daily in the treatment period.
Assessment of miro-bleeding/wound bleeding post operatively with the methods described above up to 14 days post surgery or until patient-discharge from hospital will be considered as primary endpoint of the trial. Other types of bleeding will be also assessed during whole period of administration of study drugs i.e. 14 days for TKR and 35 days for Total Hip Replacement (THR).
Timepoint [1] 240466 0
Time Frame: 14 days for knee surgery post operatively and 35 days for hip surgery
Primary outcome [2] 240688 0
2. Assessment of other types of bleeding postoperatively
Assessment of non major bleeding i.e. miro-bleeding/wound bleeding post operatively with until discharge. Other types of bleeding will be also assessed during whole period of administration of study drugs i.e. 14 days for TKR and 35 days for THR.

Major bleeding defined as:
1. Fatal bleeding;
2. Non-fatal bleeding at critical site;
3. Re-operation due to bleeding; and
4. Overt bleeding with bleeding index (BI)>or=2. Bleeding Index=number of blood units transfused plus pre-bleeding minus post-bleeding haemoglobin (g/dL) values.
Timepoint [2] 240688 0
Time Frame: 14 days for knee surgery post operatively and 35 days for hip surgery
Secondary outcome [1] 245002 0
1. Patient compliance with post-operative anticoagulation medications schedule.


This will be assessed via interview and returning back the unutilised medications.
Symptomatic VTE will be assessed via regular monthly check up post operatively for the first 6 months after surgery.
Timepoint [1] 245002 0
Time Frame: 6 months for knee and hip surgery post operatively.
Secondary outcome [2] 257327 0
2. Complications with development of VTE
Timepoint [2] 257327 0
via ultrasound doppler of both lower limbs at day 21

Eligibility
Key inclusion criteria
1. Arthroplasty for knee or hip disease.
2. Over 18 years of age.
3.Normal baseline platelet count, prothrombin and partial thromboplastin times.
4.The patient or legally authorized representative must sign a written informed consent, prior to the procedure according to the Ethics code of conduct. .
5.The potentially eligible patient is at high (post-orthopedic surgery) risk of VTE and the treatment plan will include anticoagulation.
6.Women of childbearing potential must be using adequate measures of contraception (as determined by the Investigator) to avoid pregnancy and should be highly unlikely to conceive during the study period.
7.Women of childbearing potential must have a negative pregnancy test at screen
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1.Surgery for acute fracture (< 4 weeks), septic joint, or extraction arthroplasty.
2.Patients with personal history of thromboembolic disease or documented hypercoagulation disease.
3.Increased risk of haemorrhage for example gastro-intestinal bleeding, as from active gastric ulcer, or bleeding diathesis; or persistent intestinal or urinary tract bleed.
4.Haemorrhagic stroke; brain, spinal, or ophthalmologic surgery in previous 12 months.
5.Requires chronic anticoagulation with warfarin.
6.Requires chronic platelet function suppressive therapy for coronary or peripheral artery stents.
7.Prior adverse reaction to any of the study drugs.
8.Pregnant and/or lactating women and women of child bearing potential not using acceptable means of contraception.
9.Participation in any other clinical trials involving investigational or marketed products within 30 days prior to entry in the study

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)
Patients who undergoing elective joint replacement (hip or knee) are approached by the research assistant while attending a preadmission clinic at Launceston General Hospital or Cavalry Hospital. The trial be then explained to the subjects and inclusion criteria will be examined. When the patient is eligible and willing to participate in the trial and sign a consent form then randomisation process through the Pharmacy Dept will follow.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation occurs by using a specific computer programme in the Pharmacy Department with 10-20 blocks of patients that allow random allocation of subjects.
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 3 / Phase 4
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/10/2009
Actual
1/01/2010
Date of last participant enrolment
Anticipated
31/12/2012
Actual
14/12/2012
Date of last data collection
Anticipated
Actual
Sample size
Target
1060
Accrual to date
Final
746
Recruitment in Australia
Recruitment state(s)
TAS
Recruitment hospital [1] 5659 0
The Northern Hospital - Epping

Funding & Sponsors
Funding source category [1] 237409 0
Self funded/Unfunded
Name [1] 237409 0
Country [1] 237409 0
Funding source category [2] 237552 0
Hospital
Name [2] 237552 0
Launceston General Hospital
Country [2] 237552 0
Australia
Primary sponsor type
Hospital
Name
Launceston General Hospital
Address
Launceston General Hospital
Charles Street
Launceston
TAS 7250
Country
Australia
Secondary sponsor category [1] 236906 0
Hospital
Name [1] 236906 0
St Leukes Hospital, Launceston, Tasmania
Address [1] 236906 0
24 Lyttelton Street, Tsamania, 7250, Australia
Country [1] 236906 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 239537 0
Health and Medical Office of Research Services
Ethics committee address [1] 239537 0
University of Tasmania
Private Bag 01
HOBART TAS 7001
Ethics committee country [1] 239537 0
Australia
Date submitted for ethics approval [1] 239537 0
Approval date [1] 239537 0
18/08/2009
Ethics approval number [1] 239537 0
H0010635

Summary
Brief summary
Anticoagulants are recommended for prevention and treatment of venous thromboembolism (VTE); comprising deep vein thrombosis (DVT) and pulmonary embolism (PE).

Without prophylaxis, DVT occurs in 10–40% of general surgical or medical patients. Patients undergoing major orthopaedic surgery are at a higher risk; without prophylaxis, 40–60% of these patients may develop VTE.

Guidelines for VTE prevention recommend the routine use of thromboprophylaxis with low molecular weight heparins (LMWHs) or vitamin K antagonists (VKAs) for patients undergoing major orthopaedic surgery; however, the oral VKAs are rarely used for this indication. The American College of Chest Physicians (ACCP) guidelines currently recommend that thromboprophylaxis be continued for at least 14 days after total knee replacement (TKR), and up to 35 days after total hip replacement (THR). LMWHs are effective; however, their long-term use is limited by their parenteral route of administration.

VKAs are the only licensed oral anticoagulants and, although they are effective, they have unpredictable pharmacokinetics (PK) and pharmacodynamics (PD), which are affected by drug and food interactions. As a result, VKAs require frequent monitoring and dose adjustment to ensure that their anticoagulant effects remain within the therapeutic range.

Advances in the understanding of the coagulation pathway have enabled the development of novel anticoagulants targeting specific enzymes within the coagulation cascade, including Factor Xa (FXa) and Factor IIa. FXa has been identified as a particularly attractive target for effective anticoagulation: by catalysing the conversion of prothrombin to thrombin through the prothrombinase complex, one molecule of FXa results in the generation of more than 1000 thrombin molecules.

Therefore, inhibition of FXa activity may block the amplification of thrombin generation, limiting thrombinmediated activation of coagulation and platelets, without affecting existing thrombin levels.

Several FXa inhibitors, such as rivaroxaban, apixaban, betrixaban and edoxaban, are currently at advanced stages of development. Rivaroxaban (Bayer Healthcare AG, Wuppertal, Germany) is a novel, oral, direct FXa inhibitor in advanced development for the prevention and treatment of thromboembolic disorders.

Rivaroxaban 10 mg orally once-daily (od) has recently received approval by the Therapeutic Goods Administration (TGA). Australia for the prevention of VTE in patients undergoing elective total hip or knee replacement (THR or TKR) surgery.

Recent reports showed high efficacy of rivaroxaban compared to different regimen of LMWH in the prevention of VTE in patients undergoing elective total hip or knee replacement (THR or TKR) surgery. A once-daily, 10-mg oral dose of rivaroxaban was significantly more effective for extended thromboprophylaxis than a once-daily, 40-mg subcutaneous dose of enoxaparin in patients undergoing elective total hip arthroplasty. The two drugs had similar safety profiles.

However further studies are warranted to establish the safety profile and to assess the effect of different anticoagulants on the post operative microvascular bleeding.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 29974 0
Prof Alhossain Khalafallah
Address 29974 0
Charles Street, Launceston General Hospital, Tasmania
Country 29974 0
Australia
Phone 29974 0
+61367776777
Fax 29974 0
+61363353388
Email 29974 0
[email protected]
Contact person for public queries
Name 13221 0
Alhossain Khalafallah
Address 13221 0
Department of Pathology
Charles Street
Launceston General Hospital
Launceston
TAS 7250
Country 13221 0
Australia
Phone 13221 0
+61363487111
Fax 13221 0
+61363487695
Email 13221 0
[email protected]
Contact person for scientific queries
Name 4149 0
Alhossain Khalafallah
Address 4149 0
Department of Pathology
Chareles Street
Launceston General Hospital
Launceston
TAS 7250
Country 4149 0
Australia
Phone 4149 0
+61363487111
Fax 4149 0
Email 4149 0
[email protected]

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