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The potential of reversal agents for target-specific oral anticoagulants
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After more than 60 years of having only warfarin as an option for oral anticoagulation, several target-specific oral anticoagulants have entered the market.
These agents include a direct thrombin inhibitor, dabigatran (Pradaxa, Boehringer Ingelheim), and several Factor Xa inhibitors: apixaban (Eliquis, Bristol-Myers Squibb), edoxaban (Savaysa, Daiichi Sankyo) and rivaroxaban (Xarelto, Janssen Pharmaceuticals). The various benefits and limitations of each of these agents have been contested within the medical community. Specifically, a lack of a specific reversal agent is one persisting area of contention.
Predictably, manufacturers are scrambling to develop antidotes. In October, idarucizumab (Praxbind, Boehringer Ingelheim), a reversal agent specific to dabigatran, was approved by the FDA, but there is still no specific agents for Factor Xa inhibitor reversal. However, andexanet alfa (AnXa, Portola Pharmaceuticals) has been granted orphan drug status as breakthrough therapy by the FDA for expedited approval for the reversal of FXa inhibitors, low–molecular-weight heparin (LMWH) and heparin. See Table below for a list of current reversal agents that are available or in the pipeline.
Idarucizumab approved
Idarucizumab was approved in October 2015, 6 months after receiving breakthrough designation from the FDA for the reversal of dabigatran for patients requiring emergency or urgent procedures or those with life-threatening or uncontrollable bleeding. It is a humanized monoclonal antibody fragment that binds to free and thrombin-bound dabigatran directly.
Interim analysis of the phase 3 RE-VERSE AD study indicated that a 5-g dose reversed increased clotting time in 88% to 90% of patients; effects were seen as quickly as immediately after the infusion. Only one thrombotic adverse event was reported. However, patients who receive this agent will still have their underlying indication for anticoagulation, increasing the risk for a thromboembolic event once reversed.
Although it was not reported in any patients treated in RE-VERSE AD, antibody therapy does carry a risk of immunogenicity, and prior studies did identify a small percent (1% and 4%, respectively) of pre-existing and treatment-emergent antibodies in plasma samples.
Idarucizumab is available in a 2.5 g/50 mL vial (average wholesale price, $2,100 per vial). The recommended dose (5 g) may be given as two consecutive infusions from the vials or via one syringe. Vials should be stored in the refrigerator and the drug administered through dedicated line within 1 hour of removal from vial.
Given the price and risk, albeit low, for thromboembolic events, it would be prudent to reserve this agent for only those emergent or life-threatening situations. In light of dabigatran’s short half-life (12 to 17 hours), otherwise healthy patients may be best treated with observation and supportive care until the drug is renally cleared.
Current reversal strategies
Currently, supportive care is the mainstay of therapy for rapid reversal. The half-lives of apixaban, rivaroxaban and edoxaban are 5 to 14 hours, although the full anticoagulant effect may persist for nearly 24 hours after the last dose. Due to high protein binding, rivaroxaban and apixaban are not dialyzable. Although edoxaban is approximately 50% protein bound, the efficacy of dialysis has not been established.
*New agent is being studied for reversal of low–molecular-weight heparin (LMWH), unfractionated heparin (UFH)
** New agent being studied for reversal of LMWH, UFH and fondaparinux
*** Nonspecific reversal strategy, limited data available
Other agents cited in the literature to reverse the effects of Factor Xa inhibitors, including prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (aPCC) and recombinant Factor VIIa, have been used anecdotally. These agents have been studied in vitro, in animals and in healthy patients, but have not been proven safe and effective in clinical trials studying patients with active bleeding.
Modified human Factor Xa: Andexanet alfa
Andexanet alfa is a recombinant protein that structurally mimics Factor Xa, but is rendered inactive due to the absence of a gamma-carboxyglutamic acid domain and a serine residue mutation. These changes allow the molecule to bind to direct Factor Xa inhibitors and LMWH-activated antithrombin III (ATIII). It is being studied as a continuous IV infusion and bolus.
A continuous infusion of andexanet alfa in rats anticoagulated with rivaroxaban decreased the free unbound concentration of the Factor Xa inhibitor, which bound to the antidote in a 1:1 ratio. Further tests indicated a normalization of prothrombin time and no formation of antibodies. Because andexanet alfa also has an affinity for ATIII, tests were completed in rats anticoagulated with enoxaparin and fondaparinux. There was a decrease in anti-Factor Xa activity and blood loss in rats anticoagulated with enoxaparin.
Additional preclinical studies in human plasma confirmed the interaction between andexanet alfa and rivaroxaban, which is hypothesized to increase thrombin generation, thereby potentiating anticoagulation reversal. To date, animal studies showed that andexanet alfa, but not four-factor PCC, reversed blood loss and normalized thrombin generation, prothrombin time and activated partial thromboplastin time.
Human studies
The results of the phase 2 and 3 studies have yet to be published; however, conference presentation abstracts and press releases by the manufacturer, Portola Pharmaceuticals, have reported positive outcomes. Phase 2, double blind, placebo-controlled trials assessing the efficacy of various andexanet alfa doses in otherwise healthy adults anticoagulated with apixaban, edoxaban and rivaroxaban are ongoing.
Thus far, boluses of 600 mg and 900 mg followed by 1-hour infusion at 8 mg/minute decreased anti-Factor Xa activity of edoxaban in a dose-dependent manner. The 52% to 73% reduction was seen immediately after the bolus dose and remained stable throughout the infusion. Similarly, 210-mg and 420-mg bolus doses in patients anticoagulated with rivaroxaban exhibited a dose-dependent reduction in anti-Factor Xa activity of 20% and 53%, respectively, which persisted for 2 hours.
This same protocol was employed in patients treated with enoxaparin 30 mg subcutaneously for 6 days and resulted in resumption of thrombin generation and reduction of anti-Factor Xa activity immediately after the bolus dose and 2 to 3 hours thereafter. Similar results were identified in patients anticoagulated with apixaban for 6 days before being administered andexanet alfa 420 mg bolus followed by a 4-mg/minute infusion for 45 or 120 minutes. A statistically significant 90% reduction in anti-Factor Xa activity was detected (P < .0001) regardless of duration of infusion. Furthermore, thrombin generation was normalized for 2 hours after completion of the infusion. None of the aforementioned studies reported severe thrombotic adverse events; a small number of mild infusion-related reactions were reported.
According to press releases, preliminary results of the phase 3 studies yielded statistically significant positive results as well. These studies, titled ANNEXA-A and ANNEXA-R, which are ongoing, use similar methods to assess the safety and efficacy of andexanet alfa in healthy patients anticoagulated with apixaban and rivaroxaban, respectively. Investigators are enrolling patients aged 50 to 75 years, allowing better extrapolation to the populations typically prescribed target-specific oral anticoagulants.
In part 1, the treatment group is administered an 800-mg bolus of andexanet alfa. In part 2, a 2-hour continuous infusion at 4 mg/minute is administered after the bolus dose. Patients will be followed for 43 days for safety analysis.
Results for part 1 of ANNEXA-R indicate that the andexanet alfa group had more patients with a 90% or greater reduction in anti-Factor Xa activity (P < .0001), and a lower free rivaroxaban level (P < .0001). Additionally, patients in the treatment group achieved normal thrombin generation within 10 minutes of the dose.
Preliminary results were presented at the American College of Cardiology Annual Scientific Session in March 2015. Both part 1 and 2 of the ANNEXA-A study have been described via press release. Results of part 2 indicate that 93.5% of the anti-Factor Xa activity in the treatment group was reversed after the bolus dose, and the reversal was maintained throughout the duration of the infusion for a final reversal of 92.7% of activity (P < .0001). Similar to ANNEXA-R part 1, there was a significant reduction in unbound apixaban and increased thrombin generation. No significant adverse effects were reported.
Future use
Besides completion and publication of the phase 3 trials described above, studies in humans comparing new antidotes to PCC, aPCC and recombinant Factor VIIa are needed to determine the best recommendation for future use.
Given the rapid onset and short duration of andexanet alfa and lack of serious and thrombotic adverse effects in clinical trials thus far, it may be a game changer for anticoagulation reversal and further increase the utilization of Factor Xa inhibitors.
- References:
- Crowther M, Crowther MA. Arterioscler Thromb Vasc Bio. 2015;doi:10.1161/ATVBAHA.114.303402.
- Crowther M, et al. A phase 2, randomized, double blind, placebo-controlled trial demonstrating reversal of edoxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), a universal antidote for Factor Xa (FXa) inhibitors. Presented at: 56th Annual Meeting of the American Society of Hematology; Dec. 6-9, 2014; San Francisco.
- Crowther M, et al. Blood. 2013;122:3636.
- Lu G, et al. Interaction of andexanet alfa, a universal antidote to FXa inhibitors, with tissue factor pathway inhibitor enhances reversal of FXa inhibitor-induced anticoagulants. Presented at: 25th Congress of the International Society of Thrombosis and Haemostasis; June 20-25, 2015; Toronto.
- Lu G, et al. Nat Med. 2013;doi:10.1038/nm.3102.
- Pine P, et al. Andexanet alfa but not four-factor prothrombin complex concentrate reverses rivaroxaban-induced anticoagulation as measured by reduction in blood loss in a rabbit liver laceration model. Presented at: 56th Annual Meeting of the American Society of Hematology; Dec. 6-9, 2014; San Francisco.
- For more information:
- Amanda M. Morrill, PharmD, BCPS, and Kristine C. Willett, PharmD, FASHP, are both assistant professors in the department of pharmacy practice at Massachusetts College of Pharmacy and Health Sciences, Manchester, New Hampshire.
Disclosures: The authors report no relevant financial disclosures.