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FDA Approves rivaroxaban (Xarelto) for DVT/PE prevention with knee and hip replacement surgery, but cynics remain
James Groce, Pharm.D.
December, 2011
Reduce the deficit---balance the budget. The current debate in Washington is not dissimilar to that we face regarding prevention of DVT/PE in the setting of total joint replacement surgery. Reduce the VTE rate—balance the bleeding concerns. Indeed, there are parties of opposite persuasion with competing interests—and indeed there are financial interests as well. Finally, it is the patient who should have a vested interest in this interesting corollary.
On July 1, 2011 the FDA approved rivaroxaban (Xarelto®) to reduce the risk of deep vein thrombosis and pulmonary embolism following knee or hip replacement surgery.1 Of concern however is the ability to “balance the bleeding concerns”. This prompted a State-of-the-Art Review: Assessing the Safety Profiles of New Anticoagulants for Major Orthopedic Surgery Thromboprophylaxis2 with findings that the perceived safety profile and estimated bleeding risks of the new anticoagulants could be underestimated because of varying definitions for major bleeding outcomes across and within the clinical trials.
Published outcomes data comparing major bleeding between patients randomized to rivaroxaban or to enoxaparin were found to have a similar incidence. In addition, there were similar incidence rates cited for the combined end point of major and clinically relevant non-major bleeding events; hemorrhagic wound complications; and the proportion of patients receiving blood transfusions.
In the original citation2 the authors expressed concern that because the protocols did not include in their definitions of major bleeding—“bleeding at the site of surgery”—that this could potentially create difficulty in the accurate interpretation of the data. Despite this observation, the published results of the RECORD3,4 studies do indeed report “hemorrhagic wound complications” (defined as a composite of excessive wound hematoma and reported bleeding at the surgical site). The hemorrhagic wound complication rate was essentially the same for rivaroxaban versus the comparator (enoxaparin).
With the advent of rivaroxaban—and the published data, there has been demonstrated a reduction of risk of VTE—balanced against the concerns of bleeding which have been addressed. As to the patient and their interest—the daily cost of rivaroxaban will be considerably less than the comparator (branded or generic), and the ease of oral administration with rivaroxaban compared to subcutaneous low molecular weight heparin (LMWH) injections may be preferred.
Editor’s note from Henry I. Bussey, Pharm.D.: There are at least two other issues that some clinicians might consider before concluding that rivaroxaban is the preferred choice:
First, some clinicians believe that low molecular weight heparin (LMWH) is approximately twice as effective and just as safe if the first dose is given as a half dose at 4 to 8 hours postoperatively (rather than the usual approach in the U.S. of delaying the first postoperative dose for 12 to 24 hours). If such increased efficacy is the case, then one would expect similar protection from rivaroxaban and LMWH. Hull and colleagues5,6 presented evidence supporting improved efficacy with early postoperative dosing in hip replacement surgery and concluded that VTE was reduced by 43% to 55% without an increase in bleeding.
Second, warfarin (which is certain to be less expensive than rivaroxaban or LMWH) is rated as a “1A” choice for both total knee and total hip replacement surgery by the 8th Edition of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidenced-Based Clinical Practice Guidelines.7 Francis and colleagues8-10 have reported on pre-operative warfarin dosing schemes in which a modest but safe degree of anticoagulation is achieved pre-operatively and then adjusted upward post-operatively. This approach has achieved a low proximal DVT rate of 2% to 7%. Thrombosis and bleeding events in one study were found to be related to having INR values below or above the target range, respectively.10 As we and at least three other groups have reported, INR self-testing with online monitoring and management can substantially simplify achieving optimized warfarin management and dosing.11 It is possible that combining the warfarin “two step” approach with INR self-testing and online management could offer a more effective and cost-effective method of VTE prevention.
It would seem reasonable that partial dose LMWH early postoperatively and/or “two step” warfarin preoperatively would be prime areas for comparative effectiveness research; but funding of such research is likely to be problematic since neither LMWH nor warfarin appear to be “target rich” areas in so far as industry funding is concerned in the current commercial climate.
References
- fda.gov/NewsEvents/
Newsroom/PressAnnouncements/ucm261839.htm
- Hull R, Yusen RD, Bergqvist D. Assessing the safety profiles of new anticoagulants for major orthopedic surgery thromboprophylaxis. Clinical and Applied Thrombosis/Hemostasis. 2009; 15(4):377-388.
- Eriksson BI, Borris LC, Friedman RJ et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after Hip arthroplasty. N Engl J Med 2008; 358:2765-2775.
- Lassen MR, Ageno W, Borris LC et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee replacement. N Engl J Med 2008; 358(26):2776-2786.
- Hull RD, Pineo GF, Stein PD, et al. Timing of initial administration of low-molecular-weight heparin prophylaxis against deep vein thrombosis in patients following elective hip arthroplasty, A systematic review. Arch Intern Med. 2001; 161:1952-1960.
- Hull RD, Pineo GF, Francis C, et al. Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplasty patients: A double-blind, randomized comparison. Arch Intern Med. 2000; 160:2199-2207.
- Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:381S-453S.
- Francis CW, Marder VJ, Evarts CM, Yaukoolbodi S. Two-step warfarin therapy; Prevention of postoperative venous thrombosis without excessive bleeding. JAMA 1983; 249:374-378.
- Francis CW, Pellegrini VD, Marder VJ, et al. Comparison of warfarin and external pneumatic compression in prevention of venous thrombosis after total hip replacement. JAMA 1992; 267:2911-2915.
- Francis CW, Pellegrini VD Jr., Leibert KM, et al. Comparison of two warfarin regimens in the prevention of venous thrombosis following total knee replacement. Thrombosis and Haemostasis 1996; 75:706-11.
- Bussey HI. Transforming oral anticoagulation by combining international normalized ratio (INR) testing and online automated management. J Thromb Thrombolysis 2011; 31:265-274.
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