Factor Xa Inhibitors

Factor Xa represents an attractive target for antithrombotic drugs as blockade of factor Xa permits inhibition of both the extrinsic and intrinsic coagulation pathways. Several factor Xa inhibitors, such as rivaroxaban, apixaban and edoxaban, have been approved for certain conditions, and are also in clinical development for other indications.

Rivaroxaban

Rivaroxaban (Fig. 3.1) is a novel factor Xa inhibitor that exhibits predictable pharmacokinetics, with high oral bioavailability, rapid onset of action (achieves maximum plasma concentration in 1.5–2.0 h), and no known food interactions [1] (see Table 2.1). The drug has a dual mode of elimination: two-thirds of it is metabolized by the liver (mostly via CYP3A4 and CYP2J2), with no major or active circulating metabolites identified, and one-third is excreted unchanged by the kidneys. Elimination of rivaroxaban from plasma occurs with a terminal half-life of 5–9 h in young individuals, and with a terminal half-life of 12–13 h in subjects aged

>75 years [2]. Available data indicate that body weight, age, and gender do not have a clinically relevant effect on the

Figure 3.1 Rivaroxaban

pharmacokinetics and pharmacodynamics of rivaroxaban, and it thus can be administered in fixed doses without coagulation monitoring. Rivaroxaban has minimal drug interactions (eg, with naproxen, acetylsalicylic acid, clopidogrel, or digoxin) [1] and its predictable pharmacokinetics and pharmacodynamics allow use of rivaroxaban without regular laboratory monitoring. Although no specific antidote is known for rivaroxaban, preclinical data suggested that recombinant factor VIIa and activated prothrombin complex concentrate may reverse the effects of high-dose rivaroxaban [3–5]. The clinical development programs for rivaroxaban are outlined in Table 3.1 [6–23].

Venous Thromboembolism Prevention following Joint Surgery

Four completed phase II efficacy and safety studies of rivaroxaban for the prevention of venous thromboembolism (VTE) in patients undergoing elective total hip replacement (THR) and total knee replacement (TKR) (n = 2907 patients) have demonstrated comparable efficacy and safety of rivaroxaban and conventional management with subcutaneous enoxaparin [6–9, 24]. Efficacy was assessed as a composite of

Table 3.1 Clinical development program from rivaroxaban

Table 3.1 (continued)

Enoxaparin (8101)

AF atrial fibrillation, LMWH low-molecular-weight heparin, VKA

vitamin K antagonist, VTE venous thromboembolism

any deep vein thrombosis (DVT) (proximal or distal), nonfatal objectively confirmed pulmonary embolism (PE) and all-cause mortality; safety was judged on the basis of major hemorrhage incidence. A pooled analysis of two of these studies confirmed non-inferiority of rivaroxaban in patients undergoing elective THR or TKR, with no significant dose-response relationship for efficacy but with a significant dose-related increase for the primary safety endpoint (P < 0.001), a total daily dose of 5–20 mg being the optimal dose range (Fig. 3.2) [9, 25].

Consequently, a fixed dose of rivaroxaban 10 mg qd was selected to be used in the phase III RECORD (REgulation of Coagulation in ORthopedic surgery to prevent DVT and PE) program (Table 3.2) [9–12]. The RECORD program included four large trials that recruited more than 12,500 patients undergoing elective THR or TKR. All RECORD trials have the composite primary efficacy endpoint of DVT,

Figure 3.2 Dose-response relationships between rivaroxaban and primary efficacy and safety endpoint. Results for the prevention of venous thromboembolism after major orthopedic surgery. DVT deep vein thrombosis, PE pulmonary embolism (Reproduced with permission from Eriksson et al. [8])

nonfatal PE, or all-cause mortality, and the main secondary efficacy endpoint was major VTE. The primary safety endpoint was major hemorrhage. These studies had no upper age limit and allowed recruitment of patients with mild or moderate hepatic impairment.

The RECORD1 and the RECORD3 studies compared rivaroxaban 10 mg qd (starting 6–8 h after surgery) with enoxaparin 40 mg qd (starting the evening before surgery) both given for 31–39 days (extended prophylaxis) after THR (RECORD1) [9] or for 10–14 days (short-term prophylaxis) after TKR (RECORD3) [11]. In both studies treatment with rivaroxaban was significantly superior to enoxaparin for VTE

Table 3.2 Incidence of venous thromboembolism and hemorrhage in the RECORD program

Duration of

Total VTE

Major VTE

Symptomatic VTE

Major hemorrhage

CRNM

Trial

Regimen (qd)

treatment

(%) P

(%) P

(%) P

(%)

hemorrhage

RECORD1 (THR)

Rivaroxaban

10 mg

5 weeks

1.1 <0.001

0.2 <0.001

0.3 0.22

0.3

2.9

n = 4541 [9]

Enoxaparin 40 mg

5 weeks

3.7

2.0

0.5

0.1

2.4

RECORD2 (THR)

Rivaroxaban 10 mg

10–14

days

2.0 <0.0001

0.6 <0.0001

0.2 0.004

<0.1

3.3

n = 2509 [10]

Enoxaparin 40 mg

5 weeks

9.3

5.1

1.2

<0.1

2.7

RECORD3 (TKR)

Rivaroxaban 10 mg

10–14

days

9.6 <0.001

1.0 0.01

0.7 0.005

0.6

2.7

n = 2531 [11]

Enoxaparin 40 mg

10–14

days

18.9

2.6

2.0

0.5

2.3

RECORD4 (TKR)

Rivaroxaban 10 mg

10–14

days

6.6 0.012

1.2 0.124

0.7 0.187

0.7

NA

n = 3148 [12]

Enoxaparin 40 mg

10–14

days

10.1

2.0

1.2

0.3

NA

Data from [9–12]

CRNM clinically-relevant non-major, NA not available, qd once daily, THR total hip replacement, TKR total knee replacement, VTE venous thromboembolism

prevention (Table 3.2). Recognizing that current guidelines recommend extended prophylaxis for patients undergoing THR, although this is not done in many countries, the RECORD2 trial investigated the efficacy and safety of extended thromboprophylaxis with rivaroxaban (5 weeks) compared with short-term enoxaparin 40 mg qd for 10–14 days [10]. The study demonstrated that prolonged prophylaxis with rivaroxaban was associated with reduced incidence of VTE, including symptomatic events, after THR. Of note, despite administration of rivaroxaban for 3 weeks longer than enoxaparin, the rate of major hemorrhage at 5 weeks was low and similar in both groups.

In the RECORD4 trial rivaroxaban 10 mg was significantly more effective than the North American regimen of enoxaparin 30 mg bid (10–14 days) for the prevention of VTE in patients undergoing TKR, with similar rates of major hemorrhage for both treatments and no serious liver toxicity with rivaroxaban [12]. Thus, the superiority of rivaroxaban over enoxaparin for VTE prevention was demonstrated in all four studies, with a good safety profile. As a result, in 2008 rivaroxaban received approval in the European Union (EU) and in Canada for the prevention of VTE in patients undergoing elective THR or TKR surgery. In July 2011, the FDA approved rivaroxaban for prophylaxis of DVT in adults undergoing hip and knee replacement surgery.

The utility of rivaroxaban (10 mg qd for up to 5 weeks) for VTE prevention in hospitalized medically ill patients was assessed in the phase III MAGELLAN study, with shortterm enoxaparin (10 days followed by placebo) as the comparator [22]. At day 10, the primary efficacy outcome (composite asymptomatic proximal DVT, symptomatic DVT, symptomatic non-fatal PE and VTE-related death) occurred in 2.7 % of patients in both treatment groups, demonstrating the non-inferiority of rivaroxaban (P = 0.003). At study end (day 35) fewer patients treated with rivaroxaban had the primary outcome (4.4 % vs 5.7 %; P = 0.02 for superiority). However, there was an increase in the risk of clinically relevant bleeding in the rivaroxaban group (4.1 % vs 1.7 %; P < 0.0001) [23].

 
< Prev   CONTENTS   Next >