DVT Prophylaxis for Total Joint Arthroplasty
New Oral Agents

Richard W. McCalden, M.D., MPhil(Edin), FRCSC
Associate Professor, University Western Ontario
Department of Surgery
London Health Science Centre
London, ON

There is a general agreement that some form of DVT prophylaxis is required for patients undergoing a total joint arthroplasty. However, many questions remain concerning the best method of prophylaxis and the appropriate duration of treatment.

The ideal drug for the prophylaxis of DVT following total joint surgery should rapidly inhibit thrombus formation, could be given by oral means, require no therapeutic monitoring, have little or no side effects, have little or no risk of bleeding complications and have minimal or no drug interactions. While both Warfarin and more recently, low-molecular-weight Heparin (LMWH), have been shown to be efficacious in preventing DVT postoperatively, neither represents the ideal anticoagulant based on the aforementioned prerequisites.

In response to these concerns, a number of new drugs have been developed for use in both the treatment and prophylaxis of a DVT. These drugs can be given orally and do not require any monitoring and therefore represent a potentially significant advantage over current drug treatments. There are two types of drugs being developed. The first of these drugs are so-called direct thrombin inhibitors (DTI), which act by directly inhibiting thrombin without requiring an intermediate such as anti-thrombin, as in the case of Heparin and LMWH. Of interest, the first known DTI was Hirudin, which was isolated from leech protein in the 1800's, but has not been used clinically until recently. From a number of injectible DTI agents, two main oral agents have been developed. The first of these is Ximelagatran, which is the pro drug of the active thrombin inhibitor Melagatran. This drug can be taken orally and has a very rapid peak concentration that occurs at two hours. It has a fairly short half-life and therefore requires fixed dosing every 12 hours. This drug has been through Phase III trials and shown to be efficacious in the prevention of DVT following total joint surgery1,2,3. However, it has not been approved for use by the FDA because of some concerns over hepatic toxicity. In fact, it was released in Europe and has been subsequently withdrawn from the global market because a patient developed hepatic insufficiency following the use of this drug. More recently, a second DTI drug, Dabigatran Etexilate, has been developed and involved in several clinical trials4,5. It has a similar mechanism of action to Ximelagatran, although it has a longer half-life suggesting the possibility of a once daily dosing. To date, there are no known liver toxicity issues. Table 1 provides a summary of these DTI drugs10.

The second main class of oral agents are those drugs that directly inhibit factor Xa. Rivaroxaban and Apixaban are the two main drugs that have undergone clinical trials and testing. These drugs are very similar to each other with respect to their pharmokinetics with the exception of Apixaban having a longer half-life and therefore the potential for once daily administration. The comparison of these drugs is found in Table 210,11. There are other oral factor Xa inhibitors which have undergone Phase II testing6.

To be complete, there are also oral Heparin drugs being developed although far less is known about their efficacy and safety in the prevention of a DVT compared to the other oral agents7,8.

Table 1: Comparison of the features of direct thrombin inhibitors.

Features

Dabigatran etexilate

Ximelagatran

Molecular weight

628

474

Target

Thrombin

Thrombin

Double prodrug

Yes

Yes

Bioavailability (%)

4

20

Formulation

Capsule

Tablet

CYP450 metabolism

No

No

Time to peak drug level (h)

2

2

Half-life (h)

14 - 17

4 - 5

Renal excretion (%)

80

80

Liver toxicity

Unknown

Yes

As noted, several studies have been published examining the efficacy of these new oral agents (DTI and factor Xa inhibitors) compared to conventional treatment such as Warfarin or LMWH1-6,9. The overall consensus of these studies would appear to show equal efficacy with these new drugs compared to LMWH and perhaps slightly better results compared to traditional Warfarin treatment. Very recently, several Phase III studies were reported in July 2007 at the Congress of the International Society on Thrombosis and Hemostasis in Geneva, Switzerland. These studies demonstrated either superiority or equivalence of Rivaroxaban and Dabigatran compared to Enoxaparin (LMWH) in total hip or knee replacement patients12-14.

Table 2. Comparison of the features of factor Xa inhibitors.

Features

Rivaroxaban

Apixaban

Molecular weight

436

460

Target

Factor Xa

Factor Xa

Prodrug

No

No

CYP450 metabolism

Minimal

Minimal

Time to peak drug level (h)

3

3

Half-life (h)

9

9 - 14

Biliary excretion (%)

35

75

Renal Excretion (%)

65

25

While all of these drugs appear to be efficacious in the prevention of DVT, there are several downsides to the use of these drugs. Firstly, as with all anticoagulation therapies, they are also associated with increased bleeding when compared to placebo treatment. Unique to these drugs, they have no known specific antidote. Therefore, cessation of treatment is the only way of normalizing anticoagulation status, which fortunately is fairly rapid as these drugs have a short half-life. In addition, monitoring of these new anticoagulants is problematic as these agents have a variable effect on the routine tests of coagulation and thus none of these tests provide a good estimate of drug level. Lastly, the cost of these new drugs is likely to have some impact on their overall use. In particular, with the cost of Warfarin being so low, even taking into account the need for monitoring, these new drugs may not be cost-effective.

In conclusion, these new oral drugs, which directly inhibit either factor Xa or thrombin, may represent a step forward in the treatment and prophylaxis of DVT. In many ways, they represent the ideal anticoagulant in that they rapidly inhibit thrombin formation, they can be given orally, and require no therapeutic monitoring. In addition, their bleeding, side effects, and drug interaction profile seem to be on par with the currently used drugs. The exact role of these drugs is yet to be determined and will be dependent on their relative cost and effectiveness compared to conventional DVT prophylaxis strategies.

References

  1. Colwell C.S. Jr., Berkowitz S.D., Davidson B.L. et al. Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip replacement: a randomized, double-blind study. J Thromb Haemost 2003;1:2119-30
  2. Francis C.W., Davidson B.L., Berkowitz S.D., et al. Ximelagatran versus Warfarin for the prevention of venous thromboembolism after total knee arthroplasty; a randomized, double-blind trial. Ann Intern Med 2002; 137:648-55
  3. Francis C.W., Berkowitz S.D., Comp P.C., et al. Comparison of ximelagatran with Warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 2003; 349:1703-12
  4. Eriksson B.I., Dahl O.E., Ahnfelt L., et al. Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I. J Thromb Haemost 2005; 2: 1573-80.
  5. Eriksson B.I., Dahl O.E., Buller H., 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.
  6. Agnelli G., Haas S.K., Kruegar K.A., et al. A phase II study of the safety and efficacy of a novel oral fXa inhibitor (LY517717) for the prevention of venous thromboemblolis following TKR and THR. Blood 2005; 106: 85a (Abstract #278).
  7. Berkowitz S.D., Marder V.J., Kosutic G., et al. Oral heparin administration with a novel drug delivery agent (SNAC) in healthy volunteers and patients undergoing elective total hip arthroplasty. J Thromb Haemost. 2003; 1:1914-1919.
  8. Hull R.D., Kakkar A.T., Marder V.J., et al. Oral SNAC-heparin versus enoxaparin for preventing venous thromboembolism [abstract]. J Thromb Haemost. 2003; suppl:P1889.
  9. Eriksson B.I., Agnelli G. Cohen A.T. et al. The direct thrombin inhibitor melagatran followed by oral ximelagatran compared with enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement: the EXPRESS study. J Thromb Haemost 2003;1:2490-6
  10. Weitz J.I., Emerging anticoagulants for the treatment of venous thromboembolism. Thromb Haemost 2006; 96: 274-84
  11. Di Nisio M., Middeldorp S., Bller H.R. Review Article: Direct Thrombin Inhibitors. N Engl J Med 2005; 353:1028-40
  12. Lassen M. et al. Rivaroxaban--an oral, direct factor Xa inhibitor--for the prevention of venous thromboembolism in total knee replacement surgery: Results of the RECORD 3 study. 2007 Congress of the International Society on Thrombosis and Hemostasis; July 7-13, 2007; Geneva, Switzerland.
  13. Eriksson B.I., Dahl O.E., Rosencher N., et al. Dabigatran etexilate is effective and safe for the extended prevention of venous thromboembolism following total hip replacement. 2007 Congress of the International Society on Thrombosis and Hemostasis; July 7-13, 2007; Geneva, Switzerland.
  14. Friedman R.J., Caprini J.A., Comp P.C., et al. Dabigatran etexilate versus enoxaparin in preventing venous thromboembolism following total knee arthroplasty. 2007 Congress of the International Society on Thrombosis and Hemostasis; July 7-13, 2007; Geneva, Switzerland.

Submit Community Content

If you have orthopedic information that you would like to share with the Orthogate Community, please register/login and submit your news, event, job, article, case or workshop from the Submit Content menu under the My Account area. Learn more!