The Use of Direct Factor Xa Inhibitors in the Prevention of Thromboembolism after Joint Replacement

Bassam A. Masri, M.D., FRCSC
Professor and Head, Department of Orthopaedics
University of British Columbia
Vancouver, BC

Rivaroxaban is the first oral direct Factor Xa inhibitor approved in Canada for the prevention of venous thromboembolism (VTE) following elective total hip replacement (THR) and total knee replacement (TKR) surgery1. The purpose of this article is to review the available information on rivaroxaban.

Rivaroxaban is a highly selective direct inhibitor of Factor Xa, with no direct actions on thrombin or platelet aggregation. Dose finding studies have shown that a single 10 mg dose provides effective and well-tolerated prophylaxis with no need for coagulation monitoring1.

Clinical Data
The RECORD programme evaluated the efficacy and safety of rivaroxaban for the prevention of VTE following THR (RECORD1, 2) and TKR (RECORD3, 4). These four randomized, double-blind trials involved 12,729 patients in total2,3,4,5.

The dosage and time of first administration of rivaroxaban was consistent across all four studies with a single 10 mg tablet given once daily beginning 6-8 hours after wound closure. In RECORD1, 2, and 3, the control population received enoxaparin 40 mg subcutaneously (s.c.) once daily (o.d.) initiated the evening prior to surgery2,3,4. In RECORD4, rivaroxaban was compared to enoxaparin 30 mg s.c. twice daily (b.i.d.) starting 12-24 hours after surgery5.

In RECORD1, the objective was to compare the efficacy and safety of rivaroxaban with 40 mg enoxaparin when both drugs are administered for 31-39 days in patients undergoing THR. RECORD2 investigated the THR population and compared the efficacy and safety of extended duration prophylaxis with rivaroxaban (31 - 39 days) versus short duration enoxaparin (10 - 14 days) followed by placebo. In RECORD3 and 4, prophylaxis with both rivaroxaban and enoxaparin was continued for 10-14 days in patients undergoing TKR.

In all studies, the primary efficacy endpoint was total VTE defined as the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality up to the end of the treatment period. Important secondary outcomes included major VTE (proximal DVT, non-fatal PE and thromboembolic-related death), as well as symptomatic events. The primary safety endpoint was major bleeding. Hemorrhagic wound complications (hematoma, surgical-site bleeding) were captured separately.

The results of RECORD1 and 3 were recently published in the New England Journal of Medicine, RECORD2 was published in the Lancet. In all three trials, the rivaroxaban regimen was found to be superior to the enoxaparin regimens in the prevention of total VTE, with risk reductions ranging from 62% to 79%2,3,4. Also, rivaroxaban was significantly better than the enoxaparin regimens at reducing major VTE; risk reductions ranged from 62% to 88% (Figure 1). The results of RECORD4 were presented at EFORT 20085. These results will be published at a later date.

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RECORD2 is the largest trial to demonstrate that symptomatic VTE may be significantly reduced with extended duration anticoagulant prophylaxis. In patients receiving extended duration rivaroxaban, 0.2% had symptomatic VTE, which was significantly lower than for those receiving 10-14 days of enoxaparin followed by placebo: 1.2% (p=0.004).

Of great value to orthopaedic surgeons, symptomatic events were significantly reduced in RECORD3 (TKR) with rivaroxaban compared to enoxaparin (0.7% versus 2.0%, P=0.005). In RECORD1, the occurrence of symptomatic events was similar between treatments (0.3% versus 0.5%, P=NS).

Safety remains paramount on the minds of orthopaedic surgeons when considering anticoagulation. In this regard, there were no significant differences between the treatment groups in the major bleeding and overall bleeding rates in RECORD1, 2 and 3 2,3,4. Major bleeding ranged from 0.1-0.6% in the rivaroxaban group and 0.1-0.5% in the enoxaparin group2,3,4. Similarly, hemorrhagic wound complications were 2% or less in the three studies with no significant differences noted (Figure 2).

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With respect to symptomatic events and all-cause mortality, a pooled analysis of RECORD1, 2, and 3 at day 12+2 demonstrated a significant reduction in favour of rivaroxaban compared to enoxaparin (0.4% versus 0.8%, p=0.005) with similar rates of major bleeding events (0.2% versus 0.2%, p=NS)6.

 

Practical Considerations
Health Canada has approved rivaroxaban for 35 days in elective THR and 14 days in elective TKR.

Since only one-third of the active drug is eliminated by the kidneys, rivaroxaban can be given to individuals with mild renal impairment. It should be used with caution in those with moderate renal impairment (CrCl 30-49mL/min) concomitantly receiving other drugs which increase rivaroxaban plasma concentrations, and is not recommended in patients with severe renal impairment (CrCl below 30mL/min).

Important drug interactions exist between rivaroxaban and inhibitors of both cytochrome CYP3A4 and P-glycoprotein (e.g., ketoconazole, ritonavir). These medications may increase rivaroxaban plasma concentrations by a clinically relevant degree which may lead to an increased bleeding risk. There are no food interactions.

Conclusion
Rivaroxaban is a very promising agent for the prevention of VTE after THR and TKR surgery. Further studies are needed to address unresolved questions relating to severe renal impairment and other potential drug interactions. Nonetheless, the evidence to date has demonstrated that rivaroxaban is effective and well-tolerated in the great majority of patients undergoing these elective procedures. Moreover, rivaroxaban may further reduce VTE beyond our current standards of practice.

References

  1. Xarelto® (rivaroxaban) Product Monograph, Canada, September 10, 2008.
  2. Eriksson B.I. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358: 2765-2775.
  3. Kakkar A.K. et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008;372: 31-39.
  4. Lassen M.R. et al. Rivaroxaban versus enoxaprin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358: 2776-2786.
  5. Turpie A.G.G. et al. Rivaroxaban - an oral, direct Factor Xa inhibitor - versus enoxaparin for thromboprophylaxis after total knee replacement: RECORD4, a phase III study. Pathophysiol Haemost Thromb 2007/2008;36:Abstract O57.
  6. Turpie A.G.G. et al. A meta-analysis of three pivotal studies of rivaroxaban - a novel, oral, direct Factor Xa inhibitor - for thromboprophylaxis after orthopaedic surgery. Pathophysiol Haemost Thromb 2007/2008;36:A15.

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