Dabigatran - A New Oral Agent for Prevention of Venous Thromboembolism After Hip and Knee Arthroplasty

Fathi Abuzgaya, M.D., FRCSC
Orthopaedic surgery, Rouge Valley Health System
Toronto, ON

Venous thromboembolic events (VTEs) are highly prevalent following knee and hip replacement, up to 72% and 40-50%, respectively1. Of orthopaedic surgery patients developing VTE without prophylaxis, pulmonary embolisms occur in as many as 28% of hip replacement patients and 10% of knee replacement patients2. These events can be significantly reduced with antithrombotic prophylaxis345 which has therefore become standard practice in many institutions and recommended by evidence-based management guidelines6.

Balancing efficacy without increasing bleeding rates is the challenge of anticoagulation. This becomes even more difficult after hospital discharge. Vitamin K antagonists such as warfarin have a narrow therapeutic window and an extensive interaction profile; they require close monitoring to maintain levels that balance adequate protection from VTE without elevated risks of bleeding7. These challenges may discourage physicians from using such agents after hospital discharge, despite their demonstrated effectiveness. Low-molecular-weight heparin and newer agents such as fondaparinux are parenteral, and it is difficult to ensure compliance in the outpatient setting.

Dabigatran
Recently, the first oral direct thrombin inhibitor became available for the prevention of VTE in patients undergoing elective total hip or knee replacement surgery. Dabigatran etexilate (PradaxTM) is a prodrug of dabigatran, a highly specific inhibitor of both clot-bound and free thrombin that can be used in both the hospital and outpatient setting. It offers greater ease of use, fast and predictable onset and offset: reaching peak plasma concentrations with anticoagulant effect 0.5-2 hours after administration, a linear dose-effect relationship, and it does not require coagulation or platelet monitoring8. It is not metabolized by the cytochrome P450 enzyme system, nor does it induce it, thereby offering a low potential for drug interactions9.

Phase IIb and III trials of dabigatran etexilate have demonstrated that this agent offers protection equivalent to enoxaparin against VTE following both total knee and total hip replacement surgery. BISTRO II was a phase IIb study that evaluated four doses of oral dabigatran ranging from 100-450 mg/day starting one to four hours postoperatively versus enoxaparin 40 mg/d subcutaneously starting 12 hours preoperatively10. Both VTE and bleeding rates were dose-dependent, and suggested that the optimal dosing for dabigatran was in the range of 100 to 300 mg/d.

Efficacy
The phase III clinical trial programme includes three orthopaedic surgery trials. RE-MODEL and RE-NOVATE were non-inferiority trials conducted in Europe, Australia and South Africa11,12. They evaluated two doses of dabigatran (150 and 220 mg once daily) started one to four hours postoperatively versus enoxaparin (40 mg once daily) started the evening prior to surgery in patients undergoing total knee (RE-MODEL) or hip (RE-NOVATE) replacement surgery, dosed for 6-10 and 28-35 days, respectively. Both trials met their primary efficacy endpoint, demonstrating that dabigatran was as effective as enoxaparin in preventing VTE events and all-cause mortality during the treatment period.

RE-MOBILIZE, a North American study, compared the same doses of dabigatran, though administered later (6-12 hours postoperatively), to a higher dose of enoxaparin (30 mg twice daily) administered 12-24 hours postoperatively in patients undergoing knee arthroplasty surgery13. In this study, neither dose of dabigatran achieved non-inferiority to enoxapafrin in the primary efficacy endpoint of DVT or all-cause mortality. Several factors may have contributed to this result. Enoxaparin was dosed at a 50% higher daily dose, compared to the 40 mg, once daily regimen used in the European RE-MODEL study. In a post-hoc analysis, the DVT rate in patients who received dabigatran within two hours of surgery was 14.1%, compared with 22.4% and 24.0% in patients receiving a first dose two to four hours and >4 hours after surgery, respectively (p=0.0005)10, supporting the possibility that the delayed initiation of dabigatran played a role. 

Safety
There were no statistically significant differences between dabigatran and enoxaparin for the primary safety endpoint of bleeding events in any of the three trials.

The incidence of bleeding at the surgical site was numerically lower in the dabigatran arms (0.2 and 0.4%, compared with 1.3% for enoxaparin) in RE-MOBILIZE, although this was not statistically significant. The other two trials did not report agent-specific rates for surgical site bleeding.

Conclusions
Dabigatran is a well-tolerated alternative to enoxaparin for the prevention of VTE following hip and knee arthroplasty. Initiation of dabigatran one to four hours after surgery offers the balance of efficacy with safety. Dabigatran's reported rates for surgical site bleeding, information relevant to many orthopaedic surgeons are low.

Thromboprophylaxis achieved with once daily oral dosing promotes adherence to the therapeutic regimen beyond the hospital stay. Since coagulation monitoring is not required, dabigatran offers significant benefits in terms of health care utilization and patient satisfaction. As the first oral direct thrombin inhibitor, dabigatran addresses a substantial unmet medical need in the prophylaxis of VTE in patients requiring major orthopaedic surgery.

References

  1. Lubin M.F., Smith R.B., Dodson T.F., Spell N.O., Walker H.K. Medical Management of the Surgical Patient: A Textbook of Perioperative Medicine. Cambridge University Press: 2006.
  2. Geerts W.H., Bergquist D., Pineo G.F., Heit J.A., et al. Prevention of venous thromboembolism. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). CHEST 2008; 133(6) Supplement:381S-453S.
  3. Agnelli G. Prevention of venous thromboembolism in surgical patients. Circulation 2004;110 (Suppl 1):IV4-12.
  4. Bauer K.A., Eriksson B.I., Lassen M.R., Turpie A.G. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001;345:1305-10.
  5. Bergqvist D., Benoni G., Bjorgell O., Fredin H., et al. Low-molecular-weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. N Engl J Med 1996;335:696-700.
  6. Hirsch J., Guyatt G., Albers G.W., et al. Executive summary: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:71S-109.
  7. Eriksson B.I., Dahl O.E. Prevention of venous thromboembolism following orthopaedic surgery: clinical potential of direct thrombin inhibitors. Drugs 2004;64:577-94.
  8. Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008;47:285-95.
  9. Blech S., Ebner T., Ludwig-Schewellinger E., et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008;36:386-99.
  10. Eriksson B.I., Dahl O.E., Buller H.R., et al. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost 2005;3:103-11.
  11. Eriksson B.I., Dahl O.E., Rosencher N., et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomized, double-blind, non-inferiority trial. Lancet 2007;370:949-56.
  12. Eriksson B.I., Dahl O.E., Rosencher N., et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007;5:2178-85.
  13. The RE-MOBILIZE Writing Committee. The oral thrombin inhibitor dabigatran etexilate vs the North American enoxaparin regimen for the prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2008 Apr 11 [Epub ahead of print].

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