Official Title: “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 Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Active Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: September 2010

Inclusion Criteria:

1. Planned for elective arthroplasty for knee and hip disease.

2. Over 20 years of age.

3. Normal baseline platelet count, prothrombin and partial thromboplastin times.

4. Signed consent.

Exclusion Criteria:

1. Surgery for acute fracture (< 4 weeks), septic joint, or extraction arthroplasty.

2. Patients with personal history of TED, or documented hypercoagulation disease.

3. 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)

1. Low dose warfarin (2mg) dampens activated coagulation. (1-3)

2. Two-step low dose warfarin begun 10-14 days pre-op is effective prophylaxis. (4)

3. 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)

4. Low dose warfarin (1mg) started 7 days prior to surgery is equal to variable dose warfarin for TED prophylaxis following hip arthroplasty. (7)

5. 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.

Intervention(s) in this Clinical Trial

• Drug: warfarin
  • 5 mg beginning the night before surgery, followed by 5 mg the PM of surgery*, and then variable daily dose, until day 30 follow-up. (target INR 1.8-2.0)
• Drug: 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 30-day follow-up
• Drug: warfarin
  • Fixed Low Dose warfarin 1 mg daily beginning 7 days preoperative, and continued at 1 mg daily until day 30 follow-up.

Arms, Groups and Cohorts in this Clinical Trial

• 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 1.8-2.0)
• 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 day 30 follow-up.
• Active Comparator: 3
  • Fixed Low Dose warfarin 1 mg daily beginning 7 days preoperative, and continued at 1 mg daily until day 30 follow-up.

Primary Measures

• Primary Outcome based upon intent to treat: Composite outcome of
  • Time Frame: 28 days
    Safety Issue?: Yes
• Ultrasound or venogram confirmed deep vein thrombosis.
  • Time Frame: 28 days
    Safety Issue?: Yes
• Lung scan, pulmonary angiogram or CTA confirmed pulmonary embolus.
  • Time Frame: 28 days
    Safety Issue?: Yes
• Death due to TED
  • Time Frame: 28 days
    Safety Issue?: Yes

Secondary Measures

• Patient compliance with preoperative and post-operative medication schedule. Not enough space to note all measures
  • Time Frame: 28 days
    Safety Issue?: Yes
• Distribution of proximal vs distal deep vein thrombosis of the leg
  • Time Frame: 28 days
    Safety Issue?: Yes

Inclusion Criteria:

• 1. Planned for elective arthroplasty for knee and hip disease.
• 2. Over 20 years of age.
• 3. Normal baseline platelet count, prothrombin and partial thromboplastin times.
• 4. Signed consent.

Exclusion Criteria:

• 1. Surgery for acute fracture (< 4 weeks), septic joint, or extraction arthroplasty.
• 2. Patients with personal history of TED, or documented hypercoagulation disease.
• 3. Increased risk of hemorrhage, as from active gastric ulcer, or bleeding diathesis; or persistent intestinal or urinary tract bleed within the last year.
• 4. Hemorrhagic stroke; brain, spinal, or ophthalmologic surgery in previous 6 months.
• 5. Liver enzymes or bilirubin greater than 2 x normal.
• 6. Decreased renal function with GFR < 30ml/min. (24-27)
• 7. Cancer in last 1 year, other than localized cancers of the skin.
• 8. Requires chronic anticoagulation with warfarin or heparins.
• 9. Requires chronic platelet function suppressive therapy for coronary or peripheral artery stents..
• 10. Prior adverse reaction to any of the study drugs.
• 11. Pregnancy

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 20 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: The New England Baptist Hospital

Overall Clinical Trial Officials and Contacts

Murray Bern, MD Principal Investigator New England Baptist Hospital  

Overall Contact: Fae L Williams, B.S. 617-754-6664 flwillia@caregroup.harvard.edu

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00767559

Study ID Number: NEBH 2008-016

ClinicalTrials.gov Identifier: NCT00767559

Health Authority: United States: Food and Drug Administration