- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00767559
Prophylaxis Against DVTs After Primary Hip and Knee Replacement Surgery (DVT)
Prophylaxis Against Thromboembolic Disease Following Orthopaedic Surgeries on Extremities
The purpose of this research is to find a better way to prevent the post operative development of clots in the deep veins of the legs (also called Deep Vein Thrombosis or DVT). DVT causes redness, swelling, and pain in the involved leg(s). Long-term complications may include permanent swelling and pain of the leg(s), and even skin ulcers around the ankle. If clots form in a leg after surgery, and break off, they can move to the lungs and block the pulmonary artery (also called Pulmonary Emboli or PE). With PE there can be chest pain, chest tightness, shortness of breath, coughing up blood, heart failure, and occasionally death.
Doctors have studied ways to reduce these complications. These studies led to the development of drugs which interfere with your body's clotting processes. However, it is still unclear which drug and which drug schedule is best. This study will evaluate two of the standard FDA approved drugs using different dosing schedules.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Inclusion Criteria:
- Planned for elective primary arthroplasty for knee and hip disease at New England Baptist Hospital.
- Over 20 years of age.
- Normal baseline platelet count, prothrombin and partial thromboplastin times.
- Signed consent.
Exclusion Criteria:
- Surgery for acute fracture (< 4 weeks), septic joint, or extraction arthroplasty.
- Patients with personal history of TED, or documented hypercoagulation disease.
- Increased risk of hemorrhage, as from active gastric ulcer, or bleeding diathesis; or persistent intestinal or urinary tract bleed within the last year.
SPECIFIC AIMS:
This prospective, randomized study seeks to determine if there is an advantage for fixed, low dose of warfarin Thromboembolic Disease (TED) prophylaxis among patients undergoing elective lower extremity joint arthroplasty, as compared to variable dose warfarin and a low molecular weight heparin (LMWH). If confirmed as effective fixed, low dose warfarin would be an almost ideal prophylaxis against Deep Vein Thrombosis (DVT) and Pulmonary Embolus (PE): inexpensive, easy to administer, with minimal hemorrhagic potential, needing minimal laboratory support .
BACKGROUND AND SIGNIFICANCE:
A progression of studies has been performed to examine the efficacy of low dose warfarin. These studies demonstrated that low dose warfarin has antithrombotic activity, with little anticoagulant effect. Critical to this approach that the warfarin therapy be initiated prior to surgery. A summary of other studies offering supportive or conflicting data is available. (1-9)
- Low dose warfarin (2mg) dampens activated coagulation. (1-3)
- Two-step low dose warfarin begun 10-14 days pre-op is effective prophylaxis. (4)
- Low dose warfarin (1mg) prevents DVT's surrounding central venous catheters when started 3 days before catheter insertion among patients at very high risk for subclavian DVT. (5,6)
- Low dose warfarin (1mg) started 7 days prior to surgery is equal to variable dose warfarin for TED prophylaxis following hip arthroplasty. (7)
- Low dose warfarin (1mg) started 7 days prior to surgery is effective TED prophylaxis for patients having hip replacement arthroplasties in retrospective study of 1003 patients. (8)
The sentinel study used a fixed low dose warfarin regimen given to patients at extreme risk for DVT. Patients requiring central venous catheters for chemotherapy for metastatic cancer participated in a randomized study of 0.0 mg vs.1.0 mg daily warfarin starting 3 days prior to catheter placement. Subclavian vein venograms were performed at the time of symptoms of subclavian vein DVT or after 90 days. When using this low dose warfarin schedule there was a reduction in the incidence of thrombosis from 37.5% to 9.5%. (p<0.05) Four patients acquired vitamin K-responsive prolongation of the PT due to concomitant advanced liver disease and/or malnutrition. Concentrations of factors II, VII, IX, X, and protein C showed no difference between treated and untreated patients. (5)
Two orthopedic surgery studies from NEBH on this question have been published. (7,8) The first was a pilot study of 100 patients demonstrated no difference between the effectiveness of low fixed dose and variable dose warfarin in a population of patients at high risk for TED (7) Patients studied were planning total hip replacement arthroplasty were randomized between the standard regimens using warfarin of 5 mg the night prior to surgery followed by variable dose (target PT 1.3 - 1.5 times normal) for 30-45 days, or the experimental regimen using 1 mg beginning 7 days prior to surgery and continued until follow up at 30-45 days. Ultrasounds of the deep veins of the legs were performed at baseline, at discharge following surgery, and at 30-45 day follow-up. There was no difference between the groups for incidence of venous thrombosis. The second study was a retrospective study of patients undergoing primary (833) or revision (170) hip replacement arthroplasty receiving 1 mg warfarin for 7 days before surgery, variable dose while in hospital, (INR target 1.5 - 2.0) followed by 1 mg daily until follow-up at 30-45 days. (8) Each patient used pneumatic followed by elastic compression stockings. Of these 1003 patients, with 9 lost to follow-up. Three patients had TED, including 1 PE and 2 DVT.
Study Type
Enrollment (Anticipated)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
Massachusetts
-
Boston, Massachusetts, United States, 02120
- New England Baptist Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Planned for elective arthroplasty for knee and hip disease.
- Over 20 years of age.
- Normal baseline platelet count, prothrombin and partial thromboplastin times.
- Signed consent.
Exclusion Criteria:
- Surgery for acute fracture (< 4 weeks), septic joint, or extraction arthroplasty.
- Patients with personal history of TED, or documented hypercoagulation disease.
- Increased risk of hemorrhage, as from active gastric ulcer, or bleeding diathesis; or persistent intestinal or urinary tract bleed within the last year.
- Hemorrhagic stroke; brain, spinal, or ophthalmologic surgery in previous 6 months.
- Liver enzymes or bilirubin greater than 2 x normal.
- Decreased renal function with GFR < 30ml/min. (24-27)
- Cancer in last 1 year, other than localized cancers of the skin.
- Requires chronic anticoagulation with warfarin or heparins.
- Requires chronic platelet function suppressive therapy for coronary or peripheral artery stents..
- Prior adverse reaction to any of the study drugs.
- Pregnancy
- Uncontrolled hypertension
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: 1
Variable dose warfarin: 5 mg beginning the night before surgery, followed by 5mg the PM of surgery*, and then variable daily dose,until day 30 follow-up. (target INR 2.0-2.5) |
5 mg beginning the night before surgery, followed by 5 mg the PM of surgery*, and then variable daily dose, until day 28 (+/-2 days) from day of surgery follow-up.
(target INR 2.0 -2.5)
Other Names:
Fixed Low Dose warfarin 1 mg daily beginning 7 days preoperative, and continued at 1 mg daily until follow-up 28 day (+/- 2 days) from day of surgery.
Other Names:
|
Active Comparator: 2
Fondaparinux: 2.5 mg daily starting more than 6 hours following surgery and no later than 6 AM the next day*,or 6-8 hours after epidural catheter removal, and continued until follow-up (28 days +/-2) from day of surgery. |
2.5 mg daily starting more than 6 hours following surgery and no later than 6 AM the next day*, or 6-8 hours after epidural catheter removal, and continued until follow up day 28 (+/-2 days) from day of surgery.
Other Names:
|
Active Comparator: 3
Fixed Low Dose warfarin 1 mg daily beginning 7 days preoperative, and continued at 1 mg daily follow-up at Day 28 (+/-2 days from surgery). |
5 mg beginning the night before surgery, followed by 5 mg the PM of surgery*, and then variable daily dose, until day 28 (+/-2 days) from day of surgery follow-up.
(target INR 2.0 -2.5)
Other Names:
Fixed Low Dose warfarin 1 mg daily beginning 7 days preoperative, and continued at 1 mg daily until follow-up 28 day (+/- 2 days) from day of surgery.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Primary Outcome based upon intent to treat: Composite outcome of
Time Frame: 28 days
|
28 days
|
Ultrasound or venogram confirmed deep vein thrombosis.
Time Frame: 28 days
|
28 days
|
Lung scan, pulmonary angiogram or CTA confirmed pulmonary embolus.
Time Frame: 28 days
|
28 days
|
Death due to TED
Time Frame: 28 days
|
28 days
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Patient compliance with preoperative and post-operative medication schedule. Not enough space to note all measures
Time Frame: 28 days
|
28 days
|
Distribution of proximal vs distal deep vein thrombosis of the leg
Time Frame: 28 days
|
28 days
|
Amount of intraoperative bleeding
Time Frame: follow until Dec. 31, 2010
|
follow until Dec. 31, 2010
|
Amount of postoperative bleeding A. transfusion requirement B. Hematomas requiring intervention, or other bleed clinically thought to be related to study drug. C. Other hemorrhagic events.
Time Frame: follow until Dec. 31, 2010
|
follow until Dec. 31, 2010
|
Number of ultrasounds and V/Q or CTA's required
Time Frame: follow until Dec. 31, 2010
|
follow until Dec. 31, 2010
|
Costs associated with each study arm, including that of drug, laboratory monitors, radiology procedures required, lengths of stay, and management of complications
Time Frame: follow until Dec. 31, 2010
|
follow until Dec. 31, 2010
|
Determine if negative D-D dimer can eliminate need for ultrasound analysis at follow-up visit.
Time Frame: follow until Dec. 31, 2010
|
follow until Dec. 31, 2010
|
Death due to any other cause than TED
Time Frame: follow until Dec. 31, 2010
|
follow until Dec. 31, 2010
|
Use of low molecular weight dextran
Time Frame: follow until Dec. 31, 2010
|
follow until Dec. 31, 2010
|
Use of nonsteroidal anti-inflammatory drugs
Time Frame: follow until Dec. 31, 2010
|
follow until Dec. 31, 2010
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Murray Bern, MD, New England Baptist Hospital
Publications and helpful links
General Publications
- Bern MM, Hazel D, Deeran E, Richmond JR, Ward DM, Spitz DJ, Mattingly DA, Bono JV, Berezin RH, Hou L, Miley GB, Bierbaum BE. Low dose compared to variable dose Warfarin and to Fondaparinux as prophylaxis for thromboembolism after elective hip or knee replacement surgery; a randomized, prospective study. Thromb J. 2015 Oct 7;13:32. doi: 10.1186/s12959-015-0062-0. eCollection 2015.
- Bern MM, Hazel D, Reilly DT, Adcock DM, Hou L. Effects of anticoagulation on markers of activation of clotting following major orthopedic surgery. Int J Lab Hematol. 2015 Oct;37(5):673-9. doi: 10.1111/ijlh.12384. Epub 2015 May 15.
Study record dates
Study Major Dates
Study Start
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Cardiovascular Diseases
- Vascular Diseases
- Respiratory Tract Diseases
- Lung Diseases
- Embolism and Thrombosis
- Embolism
- Pulmonary Embolism
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Fibrinolytic Agents
- Fibrin Modulating Agents
- Protease Inhibitors
- Factor Xa Inhibitors
- Antithrombins
- Serine Proteinase Inhibitors
- Anticoagulants
- Warfarin
- Fondaparinux
- PENTA
Other Study ID Numbers
- NEBH 2008-016
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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