FDA approves edoxaban to reduce stroke risk, treat DVT and PE

Ido Weinberg, MD

From an efficacy standpoint, full-dose edoxaban has been found to be noninferior to warfarin in patients with nonvalvular AF and acute VTE. From a safety standpoint, there are two points to be made:

• Bleeding: In the Hokusai-VTE study, there was less clinically relevant major and minor bleeding in edoxaban-treated patients compared with patients assigned warfarin. There was no difference regarding major bleeds alone. Also, there was no mention of the outcome of these bleeds in patients receiving edoxaban vs. warfarin. In the ENGAGE-AF TIMI 48 study, both 60 mg and 30 mg of edoxaban were associated with less intracranial bleeding compared with warfarin.
• In patients who received edoxaban and had creatinine clearance >95 mL/min, it was less effective for stroke prevention. Such a signal was not observed in the Hokusai-VTE study. As a result of these data, the FDA issued a black box warning to avoid edoxaban in patients with creatinine clearance >95 mL/min and nonvalvular AF.

Also, edoxaban should not be stopped abruptly, because it may be associated with increased stroke risk.

Other safety issues are still being studied. Once prominent example is the use of edoxaban in patients with renal dysfunction.

There has not been a direct comparison between edoxaban and other novel oral anticoagulants. In my opinion, any statement regarding one of these medications as compared with others from a safety or efficacy standpoint cannot be made.

Edoxaban has two characteristics that may make it less desirable if novel oral anticoagulants are being considered in general. First, it should be started as a treatment for VTE only after a run-in phase with a parenteral agent. As there are other oral Factor Xa inhibitors such as rivaroxaban and apixaban that can be administered orally from day 1, there is currently no incentive to choose edoxaban in the general VTE population. Second, edoxaban has been found to be less effective in stroke prevention in patients with creatinine clearance >95 mL/min. Thus, in the majority of patients who have normal renal function, another novel oral anticoagulant may be a better choice.

Having said that, for patients with severe or high-risk PE, there are a lack of data concerning novel oral anticoagulant therapy and, thus, this group of medications has been avoided. Edoxaban has actually been administered in this patient population, perhaps because of the required parenteral anticoagulant administration preceding its administration. As such, it may definitely be an option for patients with PE and evidence of right ventricular dysfunction.

The matter of switching patients to novel oral anticoagulants or target-specific oral anticoagulants still requires clarification. There are data to suggest that overall novel oral anticoagulant therapy has a better safety profile compared with warfarin, with similar efficacy. However, novel oral anticoagulants are not devoid of downsides. First, the fact that their levels cannot be measured may prove problematic for some patients who want to have some verification of the fact that they are being treated effectively. Also, prior to procedures, operators would like to have proof that the medication level is safe. Furthermore, in patients who may have compliance issues, monitoring may serve as a means to increase compliance. Next, while novel oral anticoagulant-related bleeding seems to be less intracranial and result in equal or even less severe outcomes when compared with warfarin, the lack of an approved antidote makes them less appealing. Finally, the relatively short half-life of the novel oral anticoagulants results in lack of a lingering effect in the body. While this may be beneficial from a safety standpoint, it may actually be detrimental for patients at high thrombotic risk who tend to forget occasional doses of their medication.

The aforementioned statements are true regarding novel oral anticoagulants in general, and are overall true regarding edoxaban, although the volume of edoxaban-specific data is still relatively low. Nonetheless, edoxaban should be avoided in patients with AF and creatinine clearance >95 mL/min. There is no such warning regarding patients with venous VTE; however, this signal will have to be followed in this patient population as well.

In patients with VTE eligible for novel oral anticoagulants, there is no evidence to recommend one agent over another because the novel oral anticoagulants have never been compared in head-to-head trials. Nonetheless, suggestions can be provided based on the distinct pharmacologic profiles of the novel oral anticoagulants and the designs of the trials in which they were investigated. Thus, for patients with a creatinine clearance between 30 mL/min and 50 mL/min, an oral Factor Xa inhibitor may be a better choice than dabigatran because the Factor Xa inhibitors are less dependent on renal excretion. If edoxaban is chosen for such patients, the dose must be reduced from 60 mg to 30 mg once daily to maintain similar drug exposure. All novel oral anticoagulants should be avoided in patients with creatinine clearance <30 mL/min. Rivaroxaban or apixaban may be good choices for patients aged older than 75 years with reduced renal function (creatinine clearance, 30 mL/min to 50 mL/min), particularly women with low body weight, because the benefit-to-risk profile of these agents in frail patients is superior to that of conventional therapy. Such benefit as not been shown for edoxaban as of yet.

While there is no edoxaban-specific antidote, there has been a small phase 1 study showing that bleeding measures could be reversed in people who receive edoxaban and were administered 4 factor prothrombin complex concentrate. With further studies, this may or may not prove to be clinically relevant in patients who are receiving edoxaban and who present with a significant bleed.