Apixaban: A Novel Oral Inhibitor of Factor Xa

Edith Nutescu, Pharm.D., FCCP

Disclosures

Am J Health Syst Pharm. 2012;69(13):1113-1126. 

In This Article

Efficacy and Safety

VTE Prophylaxis in Major Orthopedic Surgery

The efficacy and safety of apixaban for VTE prophylaxis in major orthopedic surgery have been evaluated in one Phase II trial and three Phase III trials.

Phase II Trial APROPOS was a multicenter, randomized, double-blind, dose-response study including 1238 patients who had elective total knee replacement. Patients were randomized to receive (1) one of six dosages of oral apixaban (5, 10, or 20 mg once daily or 2.5, 5, or 10 mg twice daily) starting 12–24 hours after surgery, (2) enoxaparin sodium 30 mg subcutaneously twice daily (North American regimen) starting 12–24 hours after surgery, or (3) open-label warfarin (dosage adjusted to achieve an INR of 2.0–3.0) starting on the evening of surgery.[47] Patients were treated for 10–14 days, at the end of which mandatory venography was performed. Study results showed that all apixaban-treated groups had lower rates of the primary efficacy outcome (total VTE events and all-cause mortality) than did either comparator. The primary outcome rates with apixaban 2.5 mg twice daily and 5 mg once daily were 9.0% and 11.3%, respectively, compared with 15.6% in the enoxaparin group and 26.6% in the warfarin group (p = 0.09 for the once- and twice-daily regimens combined versus warfarin or enoxaparin, p = 0.19 for the once-daily apixaban regimens, and p = 0.13 for the twice-daily apixaban regimens). The frequency of major bleeding (primary safety outcome) ranged from 0% in the group receiving apixaban 2.5 mg twice daily to 3.3% of patients receiving apixaban 20 mg once daily, compared with 0% in the enoxaparin and warfarin groups. There was a significant dose-related increase in the frequency of total adjudicated bleeding events with once-daily (p = 0.01) and twice-daily (p = 0.02) apixaban dosing. Based on exposure–clinical outcome modeling, apixaban 2.5 mg twice daily appeared to offer the most favorable risk:benefit profile and was selected for Phase III trials in VTE prevention.[48]

Phase III Trials The Phase III surgical thromboprophylaxis program for apixaban consisted of two multicenter, randomized, double-blind trials of patients undergoing total knee replacement (ADVANCE-1[49] and ADVANCE-2[50]), with a treatment duration of 10–14 days, and one multicenter, randomized, double-blind trial including patients undergoing total hip replacement (ADVANCE-3[51]), with a treatment duration of 35 days followed by assessment with bilateral venography ( Table 1 ). The primary efficacy outcome in each of these studies was a composite of asymptomatic and symptomatic deep vein thrombosis, nonfatal pulmonary embolism, and all-cause mortality during treatment. The primary safety outcome was major and nonmajor bleeding during the treatment period or within 2 days of discontinuing study medication.

ADVANCE-1 In ADVANCE-1, 3195 patients undergoing elective total knee replacement were randomized to receive oral apixaban 2.5 mg twice daily or enoxaparin sodium 30 mg subcutaneously twice daily (North American regimen for enoxaparin), with each started 12–24 hours after surgery.[49] The primary efficacy outcome occurred in 9.0% of patients in the apixaban group and 8.8% of patients in the enoxaparin group (relative risk [RR], 1.02; 95% confidence interval [CI], 0.78–1.32; p = 0.06 for noninferiority) (Figure 1). Thus, apixaban did not meet the prespecified noninferiority criterion when compared with enoxaparin. Results for the primary endpoint in this study indicated that the number needed to harm for apixaban was 719. A potential contributing factor was that the rate of primary events was much lower in the enoxaparin patients in ADVANCE-1 than had been observed in the patients receiving enoxaparin (16%) in the Phase II APROPOS study.[47] Major bleeding occurred in 0.7% of patients receiving apixaban compared with 1.4% of patients receiving enoxaparin (p = 0.053). The composite of major bleeding and clinically relevant nonmajor bleeding occurred in 2.9% of patients in the apixaban group and 4.3% in the enoxaparin group (p = 0.03) (Figure 1). Results from this study indicated that the number needed to treat (NNT) to prevent one episode of major bleeding or clinically relevant nonmajor bleeding with apixaban was 72. The authors of this study concluded that while apixaban did not meet the pre-specified noninferiority criterion, its efficacy was similar to that of enoxaparin, with potentially lower rates of clinically relevant bleeding.

Figure 1.

Summary of efficacy and safety of apixaban in ADVANCE trials.49–51 The enoxaparin sodium dosage was 30 mg twice daily subcutaneously in ADVANCE-1 or 40 mg once daily subcutaneously in ADVANCE-2 and ADVANCE-3. VTE = venous thromboembolism, CRNM = clinically relevant nonmajor, RR = relative risk, Diff = difference, TKR = total knee replacement, THR = total hip replacement.

ADVANCE-2 In ADVANCE-2, 3057 patients undergoing elective total knee replacement were randomized to receive either apixaban 2.5 mg twice daily started 12–24 hours after surgery or enoxaparin sodium 40 mg subcutaneously once daily started 12 hours before surgery (European regimen for enoxaparin).[50] The primary efficacy outcome occurred in 15% of patients receiving apixaban versus 24% of those receiving enoxaparin (RR, 0.62; 95% CI, 0.51–0.74; p < 0.0001 for noninferiority and for superiority) (Figure 1). Efficacy results for the primary endpoint in this trial indicated that the NNT for apixaban was 14. The frequency of major bleeding was 0.6% for the apixaban group and 0.9% for the enoxaparin group (p = 0.301). Major or clinically relevant nonmajor bleeding occurred in 3.5% of patients receiving apixaban and 4.8% of those treated with enoxaparin (p = 0.09) (Figure 1). The NNT for apixaban to prevent one episode of major bleeding or clinically relevant nonmajor bleeding was 81. Thus, results from ADVANCE-2 suggest a similar or greater efficacy of apixaban versus enoxaparin, when the European regimen of enoxaparin was used, for VTE prevention without increased bleeding.

ADVANCE-3 In ADVANCE-3, 5407 patients undergoing total hip replacement were randomized to receive either apixaban 2.5 mg orally twice daily started 12–24 hours after surgery or enoxaparin sodium 40 mg subcutaneously once daily started 12 hours before surgery.[51] The primary efficacy outcome was reported for 1.4% of patients treated with apixaban and 3.9% of those who received enoxaparin (RR, 0.36; 95% CI, 0.22–0.54; p < 0.001 for noninferiority and for superiority) (Figure 1). Efficacy results for the primary efficacy endpoint in this trial indicated an NNT of 41. Major bleeding was reported for 0.8% of patients treated with apixaban versus 0.7% of those who received enoxaparin (p = 0.54). Major or clinically relevant nonmajor bleeding occurred in 4.8% and 5.0% of the apixaban- and enoxaparin-treated patients, respectively (p = 0.72) (Figure 1). Results from this trial indicated an NNT of 469 for apixaban to prevent one episode of major bleeding or clinically relevant nonmajor bleeding.

Considered together, results from the studies of apixaban for VTE prophylaxis after total knee replacement or total hip replacement demonstrated that apixaban was superior to enoxaparin sodium 40 mg once daily but not to enoxaparin sodium 30 mg twice daily for the prevention of VTE. Safety results indicated significantly less bleeding with apixaban compared with enoxaparin sodium 30 mg twice daily but not with enoxaparin sodium 40 mg once daily. Notably, the majority of events contributing to the primary endpoint in each of these studies were asymptomatic VTEs. For example, in ADVANCE-3, 27 events contributed to the primary endpoint composite for apixaban compared with 74 for enoxaparin, but symptomatic VTE or death from VTE comprised only 4 events for apixaban and 10 events for enoxaparin. The patterns of results were similar in both ADVANCE-1 and ADVANCE-2.[49,50]

VTE Prevention in Patients Hospitalized With Acute Medical Illness

Despite the fact that patients hospitalized with acute medical illness are at risk for VTE, prophylaxis against VTE is underutilized.[52] Results from one large-scale analysis indicated that the risk for VTE was approximately 1% in a sample of acutely ill patients who were hospitalized for longer than 2 days.[53] The American College of Chest Physicians has recommended that such patients receive thromboprophylaxis with LMWH, low-dose unfractionated heparin, or fondaparinux, and it recognized that the risk for VTE may extend beyond the time of hospital discharge.[54] This view is supported by results of the EXCLAIM trial, which found that extending the duration of enoxaparin administration from 10 to 28 days in acutely ill medical patients with reduced mobility decreased the frequency of VTE compared with placebo from 4.0% to 2.5%, while increasing major bleeding from 0.3% to 0.8%.[55]

ADOPT was a Phase III trial that compared the effectiveness of apixaban 2.5 mg twice daily for 30 days with standard enoxaparin therapy for the prevention of VTE in patients hospitalized with acute illness ( Table 2 ).[56] The primary efficacy outcome (composite endpoint of death related to VTE, pulmonary embolism, symptomatic deep vein thrombosis, or asymptomatic proximal leg deep vein thrombosis detected by ultrasonography on day 30) among evaluable patients occurred in 2.71% of patients in the apixaban group and 3.06% of patients in the enoxaparin group (RR, 0.87; 95% CI, 0.62–1.23; p = 0.44). The primary safety outcome of major bleeding occurred in 0.47% and 0.19% of patients in the apixaban and enoxaparin groups, respectively (RR, 2.58; 95% CI, 1.02–7.24; p = 0.04).

Treatment of Symptomatic VTE

Traditional treatment of acute VTE entails administration of an injectable anticoagulant such as an LMWH for rapid initial activity, followed by a longer period of secondary prevention using a vitamin K antagonist.[63] Apixaban is being evaluated as a treatment option in patients with VTE.

Phase II Trial The Botticelli DVT study was a Phase II dose-ranging trial that investigated apixaban as a potential alternative to LMWH followed by a vitamin K antagonist for the treatment of patients with deep vein thrombosis.[64] The study enrolled 520 consecutive patients with symptomatic deep vein thrombosis who were randomized to receive 84–91 days of oral apixaban 5 mg twice daily, 10 mg twice daily, or 20 mg once daily or an LMWH followed by a vitamin K antagonist. The primary outcome—a composite of symptomatic recurrent VTE and asymptomatic deterioration of bilateral compression ultrasound or perfusion lung scan—occurred in 4.7% of the apixaban-treated patients (95% CI, 2.8–7.5%) versus 4.2% of those treated with LMWH and a vitamin K antagonist (95% CI, 1.4–9.6%). There was no evidence of a relationship between apixaban dose and efficacy. The composite of major and clinically relevant nonmajor bleeding occurred in 7.3% of the apixaban-treated patients (95% CI, 4.9–10.3%) and in 7.9% of patients who received LMWH and a vitamin K antagonist (95% CI, 3.9–14.1%). There was no evidence of a relationship between apixaban dose and bleeding.

Phase III Trials Assessment of apixaban for the treatment of VTE is being continued in the Phase III AMPLIFY trials ( Table 2 ).[57,58] In AMPLIFY, patients with VTE are randomized to either apixaban 10 mg orally twice daily for seven days followed by 5 mg twice daily or enoxaparin followed by warfarin for 6 months.[57] Enrollment as of October 2010 was 4816 patients, and study completion is expected in December 2012. The AMPLIFY-EXT trial is a comparison of apixaban 2.5 or 5 mg twice daily for 12 months versus placebo in patients who have completed usual treatment for symptomatic VTE.[58]

Stroke Prevention in Patients With AF

Although warfarin is effective for stroke prevention in patients with AF, it requires careful management to optimize efficacy and safety and is unsuitable for many patients. This limitation has been addressed with the approval of dabigatran for stroke prevention in patients with AF.[65] Apixaban has also been evaluated for stroke prevention in AF in two Phase III trials, one of which was recently completed. Both include patients with one or more additional stroke risk factors ( Table 2 ).

Phase III TrialsAVERROES AVERROES was a double-blind, double-dummy superiority trial of apixaban 5 mg orally twice daily (2.5 mg twice daily in selected patients) compared with aspirin 81–324 mg once daily in 5599 patients with AF and at least one risk factor for stroke who had not responded to or were unsuitable for vitamin K antagonist therapy.[59] The mean CHADS2 score (in which the presence of congestive heart failure, hypertension, age, diabetes mellitus, and previous stroke or transient ischemic attack are weighted to predict the risk of stroke) for the patients who received apixaban was 2.0 and that for those treated with warfarin was 2.1. Low-dose aspirin was selected as the comparator for apixaban in this study because it is still used as prophylaxis against ischemic stroke in a large number of patients[66] and is recommended in guidelines for AF patients who have a lower risk of stroke or who are deemed to be ineligible for a vitamin K antagonist.[67]

The primary efficacy outcome in AVERROES was stroke or systemic embolism, and the primary safety outcome was major bleeding.[68] Results from AVERROES showed that the annual rate of stroke or systemic embolism was significantly lower in the apixaban group versus the aspirin group (1.6% versus 3.7%; hazard ratio, 0.45; 95% CI, 0.32–0.62; p < 0.001). Efficacy results for this trial indicated that the NNT for apixaban was 45. The annual rate of major bleeding was slightly higher in the apixaban group, but this difference was not statistically significant (1.4% versus 1.2%; hazard ratio, 1.13; 95% CI, 0.74–1.75; p = 0.57). The rate of hemorrhagic stroke was 0.2% and 0.3% annually for the apixaban and aspirin treatment groups, respectively (p = 0.45).[69] Safety results from AVERROES indicated a number needed to harm of 590 for apixaban for one episode of major bleeding.

ARISTOTLE ARISTOTLE was a randomized, double-blind study that compared apixaban (5 mg twice daily) with warfarin (target INR 2.0–3.0) in 18,201 patients with AF and at least one additional risk factor for stroke.[60,61] The mean CHADS2 score for patients in each treatment group was 2.1. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority. A secondary objective was to test for superiority for the primary outcome of major bleeding and death from any cause.[62,70] Patients were followed for a median of 1.8 years. The rate of the primary outcome was 1.27% per year for the patients treated with apixaban versus 1.60% per year for those who received warfarin (p < 0.001 for noninferiority, p = 0.01 for superiority). Efficacy results for the primary endpoint in this study indicated an NNT of 169 for apixaban to prevent the occurrence of one event comprising the primary endpoint. For patients treated with apixaban, the rate of major bleeding was 2.13% per year versus 3.09% per year for warfarin (p < 0.001). The rate of hemorrhagic stroke among patients who received apixaban was 0.24% per year versus 0.47% per year for the warfarin-treated group (p < 0.001). The values for all-cause mortality for the apixaban and warfarin groups were 3.52% and 3.94%, respectively (p = 0.047). Safety results from ARISTOTLE indicated an NNT of 67 for apixaban to prevent one episode of major bleeding (defined based on criteria established by the International Society of Thrombosis and Haemostasis [ISTH]).

ACS The use of anticoagulants for the prevention of ischemic events in post-ACS patients indicated some benefit before the development and extensive use of clopidogrel but was associated with a high risk of bleeding and was difficult to manage.[71,72] Results from the APPRAISE-1[42] and APPRAISE-2[73] trials have confirmed that the addition of an anticoagulant to current antiplatelet therapy is ineffective and associated with a high risk of bleeding.

APPRAISE-1 APPRAISE-1 was a Phase II double-blind, placebo-controlled, dose-ranging study of 1715 patients with recent ST- segment elevation or non-ST- segment elevation ACS.[42] These patients were randomized to receive six months of treatment with oral apixaban 2.5 mg twice daily, 10 mg once daily, 10 mg twice daily, 20 mg once daily, or placebo. Nearly all patients in this study received aspirin, 76% received clopidogrel, and 75% received dual-antiplatelet therapy. The two higher-dosage apixaban regimens (10 mg twice daily and 20 mg once daily) were discontinued because of excess total bleeding. Compared with placebo, apixaban 2.5 mg twice daily and 10 mg once daily resulted in a dose-dependent increase in major or clinically relevant nonmajor bleeding, as defined by ISTH (p = 0.09 and p = 0.005, respectively). For the secondary outcome, apixaban 2.5 mg twice daily and 10 mg once daily resulted in numerically lower rates of ischemic events (cardiovascular death, myocardial infarction, severe recurrent ischemia, or ischemic stroke) compared with placebo (p = 0.21 and p = 0.07, respectively). The increase in bleeding was more pronounced and the reduction in ischemic events was less evident in patients taking aspirin plus clopidogrel than in those taking aspirin alone.

Assessment of biomarkers in APPRAISE-1 indicated that all doses of apixaban reduced d-dimer and prothrombin activation fragment F1.2 levels compared with placebo and that these markers reached normal levels more rapidly with apixaban than with placebo.[74]

APPRAISE-2 APPRAISE-2, a Phase III study, evaluated apixaban 5 mg twice daily versus placebo in patients with recent ACS treated with antiplatelet monotherapy or dual-antiplatelet therapy.[73] The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban and a lack of benefit in preventing recurrent ischemic events. Efficacy results over a median follow-up of 241 days indicated that the composite endpoint of cardiovascular death, myocardial infarction, and ischemic stroke occurred in 7.5% of patients randomized to apixaban versus 7.9% of those assigned to placebo (p = 0.51). Major bleeding occurred in 1.3% of patients treated with at least one dose of apixaban versus 0.5% of those who received placebo (p = 0.001). Fatal bleeding occurred in 5 patients who received apixaban versus 0 patients receiving placebo. Intracranial bleeding occurred in significantly more patients in the apixaban group than in those treated with placebo (12 patients versus 3 patients, p = 0.03).

Additional Safety Findings

The adverse-event profiles for apixaban and comparators have been similar in studies conducted to date. Thrombocytopenia, myocardial infarction, and stroke were also uncommon and occurred no more frequently with apixaban than with comparators.[42,49,50,64] Elevation of liver enzymes was uncommon and similar in apixaban and comparator groups. Safety results from the two largest studies of apixaban completed to date, ADVANCE-3 and ARISTOTLE, are summarized in Table 3 .[51,61]

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