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December 01, 2009
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New Oral Anticoagulants for Thromboprophylaxis After Total Hip or Knee Arthroplasty

Abstract

Patients undergoing total hip or knee arthroplasty are at increased risk of venous thromboembolism (VTE). The long-term sequelae of VTE, such as post-thrombotic syndrome or pulmonary hypertension, can be debilitating with severe morbidity. Conventional anticoagulants have several shortcomings: for example, warfarin requires regular coagulation monitoring and low-molecular-weight heparins are inconvenient to use because they require subcutaneous administration. The development of new anticoagulants has focused on 2 classes of compounds: direct thrombin inhibitors and direct factor Xa inhibitors. These new oral agents have shown efficacy in large randomized clinical trials and offer new, more convenient options for anticoagulation.

Patients undergoing total hip or total knee arthroplasty (THA and TKA, respectively) are at an increased risk for venous thromboembolism (VTE) (comprising deep venous thrombosis [DVT] and pulmonary embolism [PE]) that persists for at least 2 to 3 months after surgery.1 In the absence of thromboprophylaxis, the incidence of venographically confirmed DVT is 42% to 57% after THA and 41% to 85% after TKA, whereas that of PE is 0.9% to 28% after THA and 1.5% to 10% after TKA.1

The long-term sequelae of VTE can be debilitating. Post-thrombotic syndrome, involving pain, swelling, and skin changes in the affected extremity, occurs in approximately a quarter of patients within 3 years of an episode of DVT.2,3 Chronic pulmonary hypertension, a complication of PE, is estimated to occur in up to 3.8% of patients within 2 years of the acute event.4 Last, patients who have survived VTE are at elevated risk for subsequent potentially fatal episodes.2 Therefore, preventing VTE in the setting of THA or TKA is vital to both short- and long-term term survival and long-term quality of life.

Anticoagulants currently used to prevent VTE include the oral vitamin K antagonist warfarin, low-molecular-weight heparins (LMWHs) such as enoxaparin and dalteparin, and fondaparinux, a synthetic pentasaccharide.1 Each has its drawbacks, such as the requirement for routine outpatient coagulation monitoring with warfarin to ensure that patients’ international normalized ratios remain within the target range of 2.0 to 3.0,5 and the need for parenteral administration of both LMWHs and fondaparinux,6 rendering them inconvenient in the outpatient setting.7

To address these drawbacks, anticoagulant research has focused on developing new oral agents that do not require routine coagulation monitoring or dose adjustment, that have minimal food and drug interactions, and that offer an improved risk:benefit ratio profile. Two classes of compounds, direct thrombin inhibitors (DTIs) and direct factor Xa inhibitors, have been studied most extensively. This review gives an overview of some of the new anticoagulants in development and discusses findings of recent phase 3 trials.

Mode of Action

Conventional vs. Novel Anticoagulants

The coagulation cascade is illustrated in the Figure. At the juncture of the extrinsic and intrinsic pathways, factor Xa, as part of the prothrombinase complex, converts prothrombin (factor II) to thrombin (factor IIa). Thrombin, in turn, catalyzes conversion of fibrinogen to fibrin, the final step in the coagulation cascade.

Warfarin and other coumarin derivatives act by inhibiting synthesis of the vitamin K-dependent clotting factors II, VII, IX, and X, and thus act at multiple sites in the cascade.5 Binding to antithrombin,6 LMWHs indirectly enhance inactivation of factor Xa and, to a lesser extent, factor IIa. Fondaparinux, a synthetic pentasaccharide that closely resembles the minimal antithrombin binding sequence of heparin,8 also binds to antithrombin, indirectly enhancing inactivation of factor Xa (but not factor IIa).6

Figure: The coagulation cascade and activity of anticoagulants

Figure: The coagulation cascade and activity of anticoagulants.
Abbreviations: AT, antithrombin; LMWH, low-molecular-weight heparin.

In contradistinction to warfarin, LMWHs, and fondaparinux, the novel oral anticoagulants are direct and specific inhibitors of single clotting factors, whether thrombin or factor Xa.9

Dabigatran, Apixaban, and Rivaroxaban

Of the new oral anticoagulants, the DTI dabigatran and direct factor Xa inhibitors apixaban and rivaroxaban are farthest in clinical development for preventing VTE after THA and TKA. Table 1 summarizes salient pharmacodynamic and pharmacokinetic properties of these 3 agents.10-22 Oral bioavailabilities range from 6% for dabigatran etexilate, the prodrug of dabigatran, to 80% for rivaroxaban. Half-lives range from 9 hours for rivaroxaban (which may be prolonged to 12 hours in older adults) to as much as 17 hours for dabigatran. Whereas only 25% of the absorbed dose of apixaban is renally cleared, 80% of dabigatran is excreted in the urine. All of these agents carry a low risk for clinically relevant drug–drug interactions.

Table 1: Pharmacokinetic and Pharmacodynamic Properties of Apixaban, Dabigatran, and Rivaroxaban

Dabigatran

Three completed double-blind, randomized, phase 3 trials have been reported for dabigatran: 2 in TKA and 1 in THA. In the RE–MODEL trial of 2076 patients undergoing TKA, 2 doses of dabigatran (150 mg and 220 mg once daily, initiated with a half-dose 1 to 4 hours after surgery) were compared with the European regimen of enoxaparin 40 mg subcutaneously once daily (initiated on the evening before surgery) for 6 to 10 days.23 Both dabigatran doses proved noninferior to enoxaparin: the primary efficacy endpoint, which was the composite of total (ie, venographic and symptomatic) VTE and death during treatment, occurred in 40.5% of the dabigatran 150-mg group and in 36.4% of patients in the dabigatran 220-mg group, and in 37.7% of patients in the enoxaparin group. Incidences of major VTE (the composite of proximal DVT and death) were similar in the 3 groups. Major bleeding rates were also similar: 1.3% and 1.5% in the dabigatran 150- and 220-mg groups, respectively, vs. 1.3% in the enoxaparin group. Clinically relevant nonmajor bleeding (which included wound hematoma >100 cm2)24 occurred in 6.8% of those in the dabigatran 150-mg group, 5.9% of those in the dabigatran 220-mg group, and 5.3% of those in the enoxaparin group. Bleeding leading to reoperation occurred in 1 patient receiving dabigatran 150 mg, 3 patients receiving dabigatran 220 mg, and 1 patient receiving enoxaparin. There were no significant differences among the 3 groups in other measures of safety.

In the RE–MOBILIZE study, dabigatran 150 mg and 220 mg (initiated 6 to 12 hours after surgery) were compared with the North American regimen of enoxaparin 30 mg subcutaneously twice daily (initiated 12 to 24 hours after surgery) for 12 to 15 days in 3016 patients undergoing TKA.25 Mandatory bilateral venography was performed within 12 hours of the last dose of study medication. In 1896 patients included in the primary efficacy analysis, both doses of dabigatran proved inferior to enoxaparin: the primary composite efficacy endpoint of total VTE (defined in RE–MODEL) and death during treatment occurred in 25.3% of enoxaparin-treated patients compared with 33.7% of patients in the dabigatran 150-mg group (absolute risk difference [ARD], 8.4%; 95% CI, 3.4-13.3; P<.001) and 31.1% of patients in the dabigatran 220-mg group (ARD, 5.8%; 95% CI, 0.8-10.8;P=.024). Rates of major, clinically relevant nonmajor bleeding, and surgical site bleeding did not differ significantly among the 3 groups.

RE–NOVATE was a trial of extended thromboprophylaxis for 28 to 35 days in 3493 patients undergoing THA.26 As in RE–MODEL,25 dabigatran 150 mg or 220 mg once daily (initiated with a half-dose 1 to 4 hours after surgery) was compared with enoxaparin 40 mg subcutaneously (initiated the night before surgery). Both doses of dabigatran were noninferior to enoxaparin; the primary efficacy endpoint (the composite of total VTE and death) occurred in 8.6% of patients in the dabigatran 150-mg group, 6% of patients in the dabigatran 220-mg group and 6.7% of patients in the enoxaparin group. Rates of major bleeding, clinically relevant nonmajor bleeding, and wound complication did not differ significantly among the treatment groups. Incidences of other adverse events were comparable.

In a preplanned pooled analysis of these 3 trials,27 major VTE and VTE- related death occurred in 3.8% of patients in the 150-mg dabigatran etexilate group, 3% of patients in the 220-mg dabigatran etexilate group, and 3.3% of patients in the enoxaparin group. Major and clinically relevant nonmajor bleeding occurred with similar frequency in all groups, and there were no significant differences among the treatment groups in the incidence of liver enzyme elevations or acute coronary events.

Apixaban

In the ADVANCE–1 trial, apixaban (2.5 mg twice daily, started 12 to 24 hours after surgery) was compared in a double-blind, double-dummy fashion with the North American enoxaparin regimen of enoxaparin (30 mg subcutaneously every 12 hours started 12 to 24 hours after surgery) for the prevention of VTE in 3195 patients undergoing TKA.28 Treatment continued for 10 to 14 days, at which time bilateral venography was performed. The primary efficacy endpoint was the composite of symptomatic and asymptomatic DVT, PE, and all-cause death during treatment. The rate of the primary efficacy endpoint for apixaban was numerically similar to that for enoxaparin (9% vs. 8.9%; P=.064), but did not meet the prespecified statistical criteria for noninferiority. Rates of major bleeding were 0.7% in the apixaban group vs. 1.4% in the enoxaparin group (P=.054).

The ADVANCE–2 study compared apixaban 2.5 mg twice daily initiated 12 to 24 hours after wound closure with enoxaparin 40 mg subcutaneously once daily initiated the night before surgery in 3057 patients undergoing TKA.29 Treatment was continued through bilateral venography at 12±2 days. The primary composite efficacy endpoint (ie, DVT by venography; symptomatic, objectively confirmed DVT or PE; and death from any cause during the treatment period) occurred in 15.1% of apixaban-treated patients and 24.4% of enoxaparin-treated patients (ARD, –9.3%; 95% CI, –12.7 to –5.8; one-sided P<.001). Major VTE, defined as the composite of proximal DVT, symptomatic nonfatal PE, and VTE- related death, occurred in 1.1% and 2.2% of apixaban- and enoxaparin-treated patients, respectively (RR 0.50; 95% CI, 0.26-0.97, one-sided P=.019). Clinically relevant bleeding (major or clinically relevant nonmajor bleeding) occurred in 3.5% and 4.8% of patients given apixaban and enoxaparin, respectively (P=.09).

Rivaroxaban

Rivaroxaban and enoxaparin have been compared for thromboprophylaxis in 4 randomized, double-blind phase 3 trials—2 in THA (RECORD1 and 2) and 2 in TKA (RECORD3 and 4). The primary efficacy endpoint in each was the composite of symptomatic and asymptomatic DVT (detected by mandatory venography at the end of the treatment period), nonfatal PE, and all-cause mortality during the specified treatment period. In each trial, rivaroxaban was started 6 to 8 hours after wound closure.

RECORD1, a trial of extended thromboprophylaxis, compared enoxaparin 40 mg subcutaneously once daily (initiated the night before surgery) with rivaroxaban 10 mg in 4541 patients undergoing THA.30 Treatment was continued for 31 to 39 days, at which time patients underwent bilateral venography. Rivaroxaban was significantly more effective than enoxaparin, with the primary endpoint occurring in 1.1% and 3.7% of rivaroxaban- and enoxaparin-treated patients, respectively (ARR, 2.6%; 95% CI, 1.5-3.7; P<.001). Major VTE (ie, the composite of proximal DVT, nonfatal PE, or death from VTE) occurred in 0.2% of patients in the rivaroxaban group compared with 2% of patients in the enoxaparin group (ARR, 1.7; 95% CI, 1-2.5; P<.001), whereas major bleeding occurred in 0.3% and 0.1% of rivaroxaban- and enoxaparin-treated patients, respectively (P=.18). Bleeding leading to reoperation occurred in few patients (0.1% of patients in the rivaroxaban group and <0.1% of patients in the enoxaparin group). Postoperative wound infection occurred in 0.4% of patients in both groups and hemorrhagic wound complication (the composite of excessive wound hematoma and surgical site bleeding) occurred in 1.5% and 1.7% of the rivaroxaban and enoxaparin groups, respectively. Numbers of patients with liver enzyme elevations (increased alanine aminotransferase levels up to 3 times the upper limit of the normal range) were similar between groups. Incidences of acute coronary events during prophylaxis were low in both groups.

In RECORD2, extended prophylaxis with rivaroxaban 10 mg once daily for 31 to 39 days was compared with short-duration prophylaxis with enoxaparin 40 mg subcutaneously once daily for 10 to 14 days in 4541 patients undergoing THA.31 As in RECORD1, enoxaparin was initiated 12 hours before surgery, then restarted 6 to 8 hours after wound closure. A double-dummy design was used to ensure blinding during the trial (with enoxaparin-treated patients receiving both oral and injected placebo after the 12- to 14-day treatment course). Extended prophylaxis with rivaroxaban was significantly more effective than short-duration prophylaxis with enoxaparin, with the primary endpoint occurring in 2% and 9.3% of patients in the rivaroxaban and enoxaparin groups, respectively (absolute risk reduction, 7.3%; 95% CI, 1.5-3.7; P<.0001). Major bleeding occurred in a single patient in each group. Major VTE occurred in 0.2% and 2% of rivaroxaban- and enoxaparin-treated patients, respectively (ARR, 1.7%; 95% CI, 1-2.5; P<.001). Significantly fewer patients in the rivaroxaban group had symptomatic VTE than in the enoxaparin group (0.2% vs. 1.2%, respectively; P=.004). No patients experienced bleeding leading to reoperation. Rates of postoperative wound infection were similar in the 2 groups (0.7% in the rivaroxaban group and 0.5% in the enoxaparin group), as were rates of hemorrhagic wound complication (1.6% and 1.7% in the rivaroxaban- and enoxaparin-treated groups, respectively). Liver enzyme elevations were infrequent in both groups. As in RECORD1, incidences of acute coronary events were low and similar in the 2 groups.

RECORD3 compared rivaroxaban 10 mg once daily to enoxaparin 40 mg once daily in 2531 patients undergoing TKA. Each agent was given for 10 to 14 days with enoxaparin initiated 12 hours before surgery.32 Rivaroxaban was significantly more effective than enoxaparin, with the primary efficacy endpoint occurring in 9.6% and 18.9% of patients in the rivaroxaban and enoxaparin groups, respectively (ARR, 9.2%; 95% CI, 5.9-12.4; P<.001). Major bleeding rates did not differ significantly between groups (0.6% for rivaroxaban vs. 0.5% for enoxaparin; P=.77). Significantly fewer patients in the rivaroxaban group had symptomatic VTE than in the enoxaparin group (0.7% vs. 2%; P=.005). The incidence of bleeding leading to reoperation was similar between rivaroxaban and enoxaparin (0.4% versus 0.3%, respectively). Postoperative wound infection occurred in 0.6% of the rivaroxaban group and 0.9% of the enoxaparin group, and hemorrhagic wound complication occurred in 2% and 1.9%, respectively. Similar proportions of patients in the 2 groups had elevated levels of liver enzymes; acute coronary events occurred infrequently and with similar incidences in both groups.

In RECORD4, rivaroxaban 10 mg once daily was compared with enoxaparin 30 mg every 12 hours (initiated 12 to 24 hours after wound closure) for 10 to 14 days in 3148 patients undergoing TKA).33 As in RECORD3, rivaroxaban was significantly more effective than enoxaparin, the primary efficacy endpoint occurring in 6.9% and 10.1% of rivaroxaban- and enoxaparin-treated patients, respectively (ARR, 3.19%; 95% CI, 0.71-5.67; P=.012). There was, however, no significant difference between the groups in the incidence of major or symptomatic VTE.

The incidence of major bleeding did not differ significantly between the groups (0.7% vs. 0.3% for the rivaroxaban and enoxaparin groups, respectively; P=.110). Bleeding leading to reoperation occurred in 0.3% of patients in the rivaroxaban group and in 0.1% of patients in the enoxaparin group. Rates of postoperative wound infection were similar (0.3% in the rivaroxaban group and 0.2% in the enoxaparin group), as were those of hemorrhagic wound complication (1.4% and 1.5%, respectively). Also as in RECORD1, 2, and 3, incidences of liver enzyme elevations and acute coronary events were low and similar in the 2 groups.

A prespecified analysis of data from RECORD1, 2, 3, and 434,35 considered 3 pools: the day 12±2 active treatment pool (the enoxaparin-controlled period common to all studies); the total treatment duration pool (the planned treatment period); and the total study duration pool (the period of treatment and follow-up). The total treatment duration and total study duration pools included data from the RECORD2 placebo phase.33

Rivaroxaban significantly reduced the incidence of symptomatic VTE and death compared with enoxaparin in the day 12±2 pool (0.47% vs. 0.97%; P=.001); the total treatment duration pool (0.57% vs. 1.32%; P<.001); and the total study duration pool (0.81% vs. 1.63%; P<.001). Rates of PE and death were significantly lower with rivaroxaban in the day 12±2 pool (0.19% vs. 0.39%; P=.049) and the total study duration pool (0.47% vs. 0.76%; P=.039). Rates of major bleeding with rivaroxaban were not significantly different from those with enoxaparin in any of the pools: for the day 12±2 pool, 0.34% vs. 0.21% (P=.175); for the total treatment duration pool, 0.39% vs. 0.21% (P=.076); and for total study duration pool, 0.44% vs. 0.27% (P=.135). The composite of major and clinically relevant nonmajor bleeding was, however, significantly different in the total treatment duration pool (3.19% for rivaroxaban vs. 2.55% for enoxaparin; P=.039), but not in the day 12±2 pool (2.85% for rivaroxaban vs. 2.45% for enoxaparin; P=.186) or in the total study duration pool, 3.35% vs. 2.76% (P=.064).

Other Classes of Compounds in Development

Other DTIs, factor Xa inhibitors, and other classes of compounds (eg, synthetic oligosaccharides and ultralow-molecular-weight heparins) are being studied for the prevention of VTE after THA and TKA. Betrixaban, edoxaban, YM150, semuloparin, AZD0837, and SR123781A are some of the compounds currently in phase 2 or 3 clinical trials.

Conclusion

New oral anticoagulants offer a more convenient route of administration and simpler dosing than warfarin or the parenteral anticoagulants LMWHs and fondaparinux, and, in the case of rivaroxaban, may offer more effective VTE prevention after THA and TKA. Unlike warfarin, they do not require regular coagulation monitoring and do not have as many food and drug interactions. Data from clinical trials have shown that DTIs and direct factor Xa inhibitors have favorable efficacy and safety profiles. Dabigatran and rivaroxaban are currently approved in Canada, the European Union, and other countries for the prevention of VTE after THA and TKA.

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Author

Dr Friedman is from the Department of Orthopaedic Surgery, Roper Hospital, and is also from the Department of Orthopaedic Surgery, Medical University of South Carolina, Charleston, South Carolina.

Dr Friedman is a consultant for Johnson & Johnson, Astellas Pharmaceuticals, Inc, and Boehringer Ingelheim, received research grants from Astellas Pharmaceuticals, Inc and Boehringer Ingelheim, and is on the speaker’s bureau for sanofi–aventis.

Correspondence should be addressed to: Richard J Friedman, MD, FRCSC, Charleston Orthopaedic Associates, 1012 Physicians Dr, Charleston, SC 29414.

doi: 10.3928/01477447-20091103-53