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Direct factor Xa inhibitors for the prevention of venous thromboembolism


28 July, 2010  

The latest types of anticoagulant – inhibitors of factor Xa and thrombin – have proved very successful in clinical trials of patients undergoing major orthopaedic surgery on the hip and knee

Serge Motte
MD, PhD
Head of thrombosis
and antithrombotic
treatment clinic
Department of vascular
diseases
Hôpital Erasme
– Université Libre de
Bruxelles
Brussels, Belgium

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are two manifestations of the same disease called venous thromboembolism (VTE). VTE is a common complication of surgery, and the need for appropriate pharmacological thromboprophylaxis in different surgical settings is increasingly recognised. Current prophylactic anticoagulants include
low-dose subcutaneous unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH), fondaparinux and warfarin. These agents have been shown to be effective in different patient groups.[1] However, they have some drawbacks. UFH is a mixture of glycosaminoglycan molecules
derived from animals that acts as an anticoagulant by binding to antithrombin.[2]

Need for new anticoagulants
The interaction with antithrombin is mediated by a unique pentasaccharide sequence and results in accelerating the rate at which antithrombin inhibits clotting factors, particularly thrombin and activated factor X (factor Xa). UFH has two
main drawbacks. First, prophylactic dose UFH should be administered subcutaneously every 12 or eight hours. Second, UFH can induce thrombocytopenia.
LMWHs are produced by enzymatic or depolymerisation of UFH. They are now widely used because they are more convenient to administer than low-dose UFH, since they can be given once
daily.[1,2] They are the reference standard used in most trials evaluating new antithrombotic agents for the prevention of VTE. The drawbacks are:

  • The subcutaneous route of administration that can be inconvenient in cases of prolonged treatment.
  • The risk of accumulation in patients with severe renal function impairment.
  • The potential risk of heparin-induced thrombocytopenia.
  • Cost – in particular if a nurse is required for subcutaneous administration.

Current therapies
Fondaparinux is a synthetic analogue of the pentasaccharide
sequence of heparins and, like UFH and LMWHs, acts as an anticoagulant by binding antithrombin. It is administered subcutaneously once daily and is cleared like LMWHs by
the renal route. It has been shown to be highly efficacious for the prevention of VTE in high-risk orthopaedic patients, in general surgery patients and in acutely ill medical patients. Limitations of fondaparinux are the cost and the risk of accumulation in patients with severe renal function
impairment.
Vitamin K antagonists such as warfarin are the sole available oral anticoagulants that remain as an alternative to subcutaneous heparins.[3] The advantages of vitamin K antagonists are their oral administration and low cost. Their drawback is that laboratory monitoring is required for appropriate dosage because their therapeutic window is narrow. Main expected properties for new anticoagulants are selectivity for a specific target, predictable anticoagulant response avoiding lab monitoring and rapid reversibility in case of bleeding or urgent surgery. Finally, the oral route of administration is more convenient than the subcutaneous route, in particular when VTE prophylaxis has to be prolonged at home after discharge.

Therapies in development
Several different compounds targeting a specific  enzyme in the coagulation pathways are currently under development. As factor Xa and thrombin are two key enzymes essential for the propagation and amplification of blood coagulation, most
of the compounds that have been developed and are at the most advanced stage of clinical development are targeted against one of these two enzymes. All most promising anticoagulants bind directly to their specific target and block its interaction with substrates.
Potential advantages of direct inhibitors over indirect inhibitors are the production of a more predictable anticoagulant response and the absence of interaction with platelets.
In general, the same robust development programme is under way or planned for most new drugs. Phase II dose-finding studies are conducted to determine the optimal combination of efficacy and safety. Then large phase III studies are conducted
to assess the efficacy and the safety of the new drug compared with the reference standard in the same indication. The two therapeutic strategies – inhibition of thrombin generation by
factor Xa inhibitors or direct thrombin inhibition of thrombin activity – are currently under development in parallel. Whether the efficacy and the safety of both classes of agents are similar will remain controversial until head-to-head clinical
trials are conducted.
Two direct factor Xa inhibitors, rivaroxaban and apixaban, are at the most advanced stage of clinical development in patients undergoing major orthopaedic surgery. The rationale for factor Xa inhibition is that factor Xa is a pivotal enzyme for amplification in the coagulation process. Direct factor Xa inhibitors are specific, competitive inhibitors of free and fibrin-bound factor Xa activity, resulting in inhibition of prothrombinase activity and subsequently in inhibition
of thrombin generation.

Advanced-stage therapies Rivaroxaban
Rivaroxaban has high bioavailability, rapid onset of action and predictable dose-proportional pharmacokinetics and pharmacodynamics with a half-life of five to nine hours in healthy subjects. It is excreted via both the renal and faecal/
biliary routes. A robust phase II programme was conducted to determine the optimal combination of efficacy and safety of rivaroxaban for the prevention of VTE in patients undergoing
major orthopaedic surgery. Three phase II double-blind, randomised dose-finding studies were performed. Two of these studies evaluated a twice-a-day dose regimen and the third study evaluated a once-a-day dose regimen.[4-6]
These studies showed that the incidences of the primary end-point (the composite of the incidence of any DVT [mandatory venography], objectively confirmed nonfatal pulmonary embolism and all-cause mortality) with rivaroxaban
were similar to or lower than those with enoxaparin. A significant dose-response relationship was observed between rivaroxaban and major postoperative bleeding. Following these studies, a 10mg once-a-day dose regimen that provided
the optimal combination of efficacy and safety was selected for investigation in the phase III programme.
The phase III programme included four separated clinical trials (the RECORD studies) comparing rivaroxaban at 10mg once daily with once daily or twice daily enoxaparin after hip or
knee arthroplasty.[7-10] All these studies used the same primary efficacy end-point as that used in the phase II studies described above. The primary safety end-point was major bleeding. In the RECORD1 trial, rivaroxaban was compared
to enoxaparin 40mg once daily, both study drugs given for 35 days in patients undergoing hip arthroplasty. The primary efficacy end-point occurred in 1.1% and 3.7% in the rivaroxaban group respectively (absolute risk reduction 2.6%,
95%CI: 1.5-3.7%), demonstrating that rivaroxaban
was superior to enoxaparin.
In the RECORD2 study that was also conducted in patients undergoing hip arthroplasty, rivaroxaban given for 35 days was compared with enoxaparin 40mg once daily given for 12 days. As in the record1 study, rivaroxaban compared with enoxaparin significantly reduced the incidence of the primary efficacy end-point from 9.3% to 2.0% (absolute risk reduction 7.3%,
95%CI: 5.2-9.4%). Interestingly, the reduction in any DVT (asymptomatic and symptomatic) with rivaroxaban was  associated with a parallel reduction in symptomatic VTE.
In the RECORD3 trial, rivaroxaban was compared with enoxaparin 40mg once daily, given for ten to 14 days in patients undergoing knee arthroplasty. The incidence of the primary efficacy end-point was 9.6% in the rivaroxaban
group and 18.9% in the enoxaparin group (absolute risk reduction 9.2%, 95%CI: 5.9-12.4%). As in the RECORD2 trial, rivaroxaban compared with enoxaparin also significantly reduced the incidence of major and symptomatic VTE. Finally, in the RECORD4 trial including 3,148 patients undergoing knee arthroplasty, rivaroxaban was also demonstrated to be more effective than enoxaparin 30mg twice daily for ten to 14 days.
In all four studies, bleeding rates did not differ significantly between the two groups.

Apixaban
Apixaban is a related factor Xa inhibitor under development. It is a highly selective and potent inhibitor of both free and  prothrombinase-bound factor Xa. A double-blind phase II study for the prevention of VTE in 1,217 patients undergoing total knee replacement (TKR) compared six doses of oral apixaban (5,10 or 20mg given as a single or a twice daily divided dose) with openlabel enoxaparin or warfarin for ten to 14 days.[11]
The incidence of the primary efficacy endpoint (composite of DVT, non-fatal PE and allcause mortality) in all apixaban groups was lower than in the enoxaparin and warfarin groups. Following that study, a dose of 2.5mg twice daily that provided a promising benefit-risk profile was selected for investigation in a phase III trial including 3,195 patients undergoing knee arthroplasty. [12] Apixaban was compared with 30mg of
enoxaparin subcutaneously every 12 hours, both started 12 to 24 hours after surgery and given for ten to 14 days. The incidence of the primary efficacy endpoint was 9.0% and 8.8% with apixaban and enoxaparin respectively (relative risk, 1.02;
95%CI: 0.78 to 1.32). As far as the safety profile is concerned, apixaban was associated with lower rates of clinically relevant bleeding. Other phase III trials in patients undergoing joint replacement are ongoing.

Promising future
New oral anticoagulant agents appear very promising, in particular because of the convenience of their use. These agents appear safe in the prevention of postoperative VTE after major orthopaedic surgery. The oral factor Xa inhibitor rivaroxaban has completed phase III development for thromboprophylaxis in major knee and hip surgery and has been approved by the European Commission for use in this indication. Apixaban has entered late-phase development. Although these new oral anticoagulants appear promising, some issues need to be clarified. Extrapolation of clinical trial data to actual clinical practice should be done carefully because there are some differences between patients included in trials and real-life patients. In particular, patients with clinically significant liver disease, severe impairment of renal function (creatinine clearance <30ml per minute) and those considered at high risk of bleeding were excluded. Most studies showed that the incidence of safety outcomes, including major bleeding, was low and not significantly different in both the new study drugs and the reference competitor groups. However, trials were powered to demonstrate non-inferiority on efficacy but not to demonstrate non-inferiority on safety. Further data on exposure in more patients, in particular in fragile patients, are needed to definitely confirm drug safety. Another issue is the rapid reversibility in case of bleeding or urgent surgery. There is no specific antidote that antagonises the effect of both rivaroxaban and apixaban as well as for any new oral anticoagulant. In case of life-threatening bleeding or urgent surgery, administration of prothrombin concentrate or recombinant factor VIIa may be considered. However, no clinical data are available concerning this recommendation.

References
1. Geerts WH et al. Chest. 2008;133(6 Suppl):381S-453S.
2. Hirsh J et al. Chest. 2008;133(6 Suppl):141S-159S.
3. Ansell J et al. Chest. 2008;133(6 Suppl):160S-198S.
4. Turpie AG et al. J Thromb Haemost.2005;3:2479–86.
5. Eriksson BI et al. J Thromb Haemost.2006;4:121–8.
6. Eriksson BI et al. Circulation. 2006;114:2374-81.
7. Eriksson BI et al. N Engl J Med. 2008;358:2765-75.
8. Kakkar AK et al. Lancet. 2008;372:31-9.
9. Lassen M R et al. N Engl J Med. 2008;358:2776-86.
10. Turpie A G et al. Lancet. 2009;373(9676):1673-80.
11. Lassen MR et al. J Thromb Haemost.2007;5:2368-75.
12. Lassen MR et al. N Engl J Med. 2009;361:594-604.