Comparison of Apixaban With Other New Oral Anticoagulants
With the emergence and approval of other new oral anticoagulants such as dabigatran and rivaroxaban, the role of and place in therapy for all of these new agents will have to be clearly delineated. Differentiation based on pharmacokinetic and clinical characteristics as well as cost will likely be the major factors contributing to the selection of the appropriate agent for individual patients.
The pharmacokinetic properties of apixaban, dabigatran, and rivaroxaban are summarized in Table 4 . The elimination half-life is 6–9 hours for rivaroxaban, 12–14 hours for dabigatran, and approximately 12 hours for apixaban. Apixaban and dabigatran have been dosed twice daily and rivaroxaban once daily in Phase III clinical trials to date. There appears to be less peak-to-trough variation with twice-daily dosing, but the clinical importance of this difference is not yet clear; however, once-daily dosing may be preferable from a patient adherence perspective.
There are differences in the pharmacokinetics of these three anticoagulants that may be clinically important. For example, higher proportions of dabigatran (approximately 80%) and rivaroxaban (67%) doses are excreted by the kidneys versus apixaban (25%) doses. In the United States, the approved dosages of dabigatran etexilate for the prevention of stroke in patients with AF are 150 mg orally twice daily for patients with a creatinine clearance of >30 mL/min and 75 mg orally twice daily for those with a creatinine clearance of 15–30 mL/min. In Europe, the recommended dosage of dabigatran for stroke prevention in patients with AF who have a creatinine clearance of >30 mL/min is the same as in the United States; however, dabigatran use is contraindicated in Europe for patients with a creatinine clearance of ≤30 mL/min.
The dabigatran etexilate dosage recommended in Europe for patients undergoing total knee replacement or total hip replacement is 220 mg once daily, reduced to 150 mg once daily for patients with a creatinine clearance of 30–50 mL/min or who are elderly (>75 years of age). Dabigatran etexilate is available as 75- and 150-mg capsules in the United States and as 75-, 110-, and 150-mg capsules in Europe.
The concomitant use of dabigatran with Pgp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided. Coadministration of dabigatran with Pgp inhibitors ketoconazole, verapamil, amiodarone, quinidine, and clarithromycin does not require dosage adjustments for dabigatran.
Rivaroxaban is a substrate of CYP3A4 and Pgp and is not recommended for patients receiving concomitant treatment with strong CYP3A4 and Pgp inhibitors such as ritonavir and ketoconazole (though fluconazole may have less effect on rivaroxaban pharmacokinetics). However, interactions with clarithromycin (a strong CYP3A4 inhibitor and moderate Pgp inhibitor) and erythromycin (moderate inhibitor of both) do not appear to be clinically relevant. Coadministration of rivaroxaban and strong Pgp and CYP3A4 inducers, such as rifampin, phenytoin, carbamazepine, and St. John's wort should be avoided. If these drugs must be coadministered, a rivaroxaban dose increase to 20 mg (i.e., two 10-mg tablets) should be considered.
Phase III trials of rivaroxaban and dabigatran in patients undergoing total hip replacement or total knee replacement have also been conducted. In terms of study design, the RECORD trials of rivaroxaban used a once-daily dose of rivaroxaban started six to eight hours after surgery. Results indicated a lower risk of VTE with rivaroxaban versus enoxaparin and a similar frequency of major bleeding. A pooled analysis of the three trials comparing oral rivaroxaban with enoxaparin sodium 40 mg subcutaneously once daily also found lower rates of symptomatic VTE and all-cause mortality with rivaroxaban than with enoxaparin and similar rates of major bleeding. However, different analyses have shown higher rates of major and clinically relevant nonmajor bleeding with rivaroxaban compared with enoxaparin. The approach in the dabigatran trials was to begin treatment one to four hours after surgery with a half dose and then to continue with the full dose twice daily. Two different doses were compared. In the RE-MOBILIZE study, both doses of dabigatran twice daily were inferior to enoxaparin sodium 30 mg twice daily for the prevention of VTE and all-cause mortality. In the RE-NOVATE, RE-NOVATE II, and RE-MODEL trials, dabigatran was noninferior to enoxaparin sodium 40 mg subcutaneously once daily for the primary efficacy outcome. In all three trials, the frequency of major bleeding was similar between treatments. This pattern of results was borne out in pooled analyses. For apixaban, efficacy and safety were generally well balanced: ADVANCE-1 showed numerically similar efficacy, though statistically noninferiority was not met, and lower bleeding rates than enoxaparin sodium 30 mg twice daily, while ADVANCE-2 and ADVANCE-3 showed superior efficacy against the 40-mg dose of enoxaparin sodium and similar rates of bleeding. In selecting specific agents for clinical use and various indications, these differences in efficacy and safety data must be considered in the context of the doses of comparator agents used in clinical trials to ensure appropriate dosing for the U.S.-based standards of care and timing of dosing around surgery.
The RE-LY trial showed that dabigatran etexilate 150 mg orally twice daily was significantly superior to warfarin in decreasing the risk for all-cause stroke (p < 0.01). The rate of hemorrhagic stroke was significantly lower in the dabigatran group than in the warfarin group. There was no significant difference between the major bleeding risks with this dabigatran dose and warfarin. Results from the ROCKET AF trial indicated that rivaroxaban 20 mg orally once daily was noninferior to warfarin in reducing all-cause stroke and non-central nervous system embolism in AF patients (p = 0.117), with a similar rate of major bleeding. A secondary, on-treatment analysis revealed the superiority of rivaroxaban over warfarin for this endpoint (p = 0.015). When considering these results for dabigatran and rivaroxaban, it is important to note that RE-LY was an open-label study, while ROCKET AF was a randomized double-blind trial. The potential effect of trial design on outcomes is underscored by results from the SPORTIF III and SPORTIF V trials.
It is difficult to compare the results for rivaroxaban from ROCKET AF with those for apixaban, because ROCKET AF included patients with a higher stroke risk (prior stroke or transient ischemic event or at least two other risk factors) than did AVERROES and ARISTOTLE. Nevertheless, apixaban was superior to warfarin in patients with AF who had at least one additional stroke risk factor. Only apixaban has been compared head-to-head with aspirin in patients not suitable for warfarin therapy, in AVERROES.
Rivaroxaban has also been evaluated for the treatment of VTE. In the EINSTEIN extension study, VTE risk was lower with rivaroxaban versus placebo and the rate of clinically relevant nonmajor bleeding was higher with rivaroxaban than with placebo. Results from the dabigatran RE-COVER trial for the treatment of acute VTE showed rates of recurrent VTE and major bleeding similar to those found with warfarin.