New agents for orthopaedic thromboprophylaxis: caution essential, but time will tell

ans_5099 773.780 Orthopaedic surgery has been traditionally regarded as high risk for the development of post-operative venous thromboembolic disease. Accordingly, patients undergoing procedures such as total hip replacement or total knee replacement are uniformly placed on a thromboprophylactic agent, most usually the low-molecular-weight heparin enoxaparin. Occasionally, agents such as warfarin or unfractionated heparin are used if deemed more appropriate in the clinical context. The disadvantages of both warfarin and enoxaparin are well documented; warfarin has numerous interactions with diet and other medications, requires complex individualized dosing and has a delayed onset of action, making it problematic and inconvenient for clinicians and patients alike. Similarly, enoxaparin, which requires parenteral administration and poses a risk of haemorrhage, is less than ideal for thromboprophylactic use. The significant drawbacks of the current generation of thromboprophylactic agents have prompted research into novel drugs that are active orally, have sound safety profiles and that do not require routine monitoring. This research has focused largely on using specific molecules to directly inhibit clotting factors within the clotting pathway, such as thrombin or activated factor X (Xa). The Therapeutic Good Administration recently approved two such drugs for use in Australia. These agents include dabigatran etexilate, the prodrug of the direct thrombin inhibitor dabigatran, as well as the direct factor Xa inhibitor rivaroxaban. Both these medications have been approved for the use in venous thromboembolic prophylaxis in adults undergoing elective total hip or knee replacement. Dabigatran and rivaroxaban have both undergone large, prospective, double-blind, double-dummy, randomized international phase III trials. The results of these trials have been recently published in Lancet and New England Journal of Medicine, and both of these drugs are now available for use in Australia. However, despite the robust clinical trials and sound results obtained by both dabigatran and rivaroxaban in studies thus far, there are some important caveats with these drugs that merit consideration. These caveats relate, in particular, to the safety, efficacy and cost-effectiveness of these agents compared with warfarin and enoxaparin, and they comprise a valid indication as to why caution is essential when employing these largely unproven drugs. In terms of safety, there are a number of aspects of dabigatran and rivaroxaban usage that are of concern. One very important safety consideration applies to the risk of bleeding with the use of rivaroxaban. In the phase III RECORD clinical trials of rivaroxaban, the drug was found to have no significant difference in incidence of major bleeding compared with enoxaparin. However, it is pertinent to note that the definition of ‘major bleeding’ excluded surgical site bleeding, which is arguably of the most consequence to surgeons. This exclusion may have significantly skewed the safety data presented for rivaroxaban during its clinical studies and certainly warrants consideration when using this drug. Another concerning feature with these new drugs is the lack of a specific antidote for either dabigatran or rivaroxaban in the instance of an overdose. Warfarin, which can be slowly reversed with vitamin K or more rapidly reversed with fresh frozen plasma, has wellknown and efficacious antidotes. The same applies to heparins, which can be reversed with protamine sulphate. Although dabigatran is dialyzable, rivaroxaban is not, and the lack of a specific antidote for either of these drugs is troubling, especially if these medications are used in an outpatient setting where the risk of overdosing may be higher. It is salient to note for both dabigatran and rivaroxaban their limited application in patients with severe renal disease (creatinine clearance <30 mL/minute). Both warfarin and enoxaparin (dose adjusted) can be used in patients with severe renal disease. Rivaroxaban, however, is contraindicated in such patients. Dabigatran can be used at a reduced dosage in patients with moderate renal impairment (creatinine clearance 30–50 mL/minute) but is also contraindicated in patients with severe renal failure. A final safety issue with the use of dabigatran relates to its potential to cause hepatic dysfunction. Throughout the phase III studies of these drugs, it was noted that neither dabigatran nor rivaroxaban caused incidences of hepatic dysfunction that were statistically significant compared with enoxaparin. However, one must bear in mind that dabigatran follows in the footsteps of another thrombin inhibitor, ximelagatran, which was submitted for marketing approval but subsequently abandoned in 2006, after some 6% of patients taking the drug had abnormal liver functions. Given the ximelagatran experience, a concern remains that hepatic dysfunction may be a class effect with thrombin inhibitors, and this will require vigilant monitoring as dabigatran becomes more widely used. In terms of efficacy, one important issue is that dabigatran has only been shown to be non-inferior to enoxaparin in clinical studies thus far, and not clearly superior. In two trials, RE-NOVATE and RE-MODEL, dabigatran demonstrated comparable results to enoxaparin in preventing venous thromboembolic disease and all causes of mortality in post-operative orthopaedic patients; however, these trial were designed to only demonstrate non-inferiority. The trials Declaration: The author has not received any research funding or scholarship for this study. This paper is not based on any previous communication to a society or meeting. The author has not received any commission or honorarium for writing this paper or performing any research related to this paper. The author has no conflict of interest to declare. PERSPECTIVES