ANNEXA-4 Published: Anti-Factor Xa Antidote Stops Major Bleeding

Deborah Brauser

February 15, 2019

HONOLULU — Andexanet alfa (Andexxa, Portola Pharmaceuticals) is effective and relatively safe in stopping the acute major bleeding that can sometimes arise when taking factor Xa inhibitors, new research suggests.

Although preliminary results from the ANNEXA-4 trial, which assessed the reversal agent, were previously released, the full study report was published online February 7 in the New England Journal of Medicine to coincide with its presentation here at the International Stroke Conference (ISC) 2019.

The nonrandomized, open-label study included more than 300 patients with acute major bleeding associated with the use of factor Xa inhibitors. Among patients who had earlier received either apixaban (Eliquis, Bristol-Myers Squibb) or rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals), those who received an andexanet bolus showed a 92% reduction from baseline in anti–factor Xa activity, thereby meeting the co-primary efficacy outcome.

Among the 249 patients assessed for hemostatic efficacy, 82% showed excellent or good clinical hemostasis 12 hours after an andexanet infusion — meeting the second co-primary outcome.

"Reductions in anti–factor Xa activity was not predictive of hemostatic efficacy overall but was modestly predictive in patients with intracranial hemorrhage," the investigators report.

Safety results showed that 10% of the participants experienced a thrombotic event within 30 days and that 14% died.

Dr Truman Milling Jr

"There's now a reversal agent for all the anticoagulants," senior author Truman J. Milling Jr, MD, associate professor in the Department of Neurology and the Department of Surgery and Perioperative Care at the Dell Medical School at the University of Texas at Austin, told Medscape Medical News.

"For the practicing emergency physician who deals with bleeding pretty regularly and has seen bad cases of anticoagulant-associated bleeding, that's a comfort," said Milling, who is also from the Seton Dell Medical School Stroke Institute.

FDA-Approved Reversal Agent

Andexanet alfa, a modified and recombinant form of factor Xa, was designed to "rapidly neutralize the anticoagulant effects" of factor Xa inhibitors at times of acute bleeding, the investigators note.

These types of inhibitors "have a favorable benefit-risk profile for the treatment and prevention of thrombotic events but may cause or worsen acute major bleeding, with substantial morbidity and mortality," they add.

As reported by Medscape Medical News, the US Food and Drug Administration (FDA) approved the agent in May 2018 under its Accelerated Approval Program. It's indicated to reverse the inhibitors' anticoagulation effects as needed because of life-threatening or uncontrolled bleeding. The agent is currently under review by the European Medicines Agency.

The factor Xa inhibitors, a relatively new class of anticoagulants, "have really become blockbuster drugs with millions of US people taking them. But until recently, there was no way to really turn them off when people started bleeding," Milling said.

"It's not like the drugs are overly dangerous," he added. "They're much safer than the old drug warfarin, but bleeding can happen, so this new drug was developed specifically to turn that blood thinner off to prevent major bleeding."

The ANNEXA-4 investigators enrolled 352 adult patients (53% men; mean age, 77 years) at 63 centers in North America and Europe between April 2015 and June 2018.

Individuals with only intracranial hemorrhage (ICH) were enrolled from July 2016 to September 2017 "to enrich the study with these patients" (65%), the researchers report.

From September 2017 to June 2018, enrollment was opened to patients with all types of bleeding except those with musculoskeletal, intra-articular, or visible bleeding. The primary site of bleeding was gastrointestinal (GI) in 26% of the patients.

Decreased Bleeding

All participants had received within 18 hours of presentation to an emergency department (ED) any dose of rivaroxaban (n = 128; mean daily dose, 20 mg), apixaban (n = 194; mean daily dose, 10 mg), or edoxaban (Sayvasa, Saiichy Sankyo) (n = 10); or enoxaparin (Lovenox, Sanofi) at a dose of at least 1 mg/kg of body weight/day (n = 20). The most common indication for use of the factor Xa inhibitors was atrial fibrillation (80%).

At the centers, the patients received either a 400-mg bolus of andexanet followed by a 4-mg/min infusion of the agent for 2 hours or an 800-mg bolus followed by an 8-mg/min infusion for 2 hours. The decision as to whether to follow the low-dose or the high-dose protocol for a given patient was based on type, timing, and amount of the last factor Xa inhibitor received.

The mean time from presentation at the ED to initial andexanet treatment was 4.8 hours.

Results showed that anti–factor Xa activity decreased from a median of 149.7 ng/mL at baseline to 11.1 ng/mL after the andexanet bolus for those who had received apixaban (95% confidence interval [CI] for reduction, 91% – 93%) and from 211.8 ng/mL to 14.2 ng/mL for those who had received rivaroxaban (95% CI for reduction, 88% – 94%).

In addition, those who received enoxaparin showed a decrease in activity from 0.48 IU/mL at baseline to 0.15 IU/mL after the bolus (75% reduction; 95% CI, 66% – 79%).

In 204 of 249 patients, excellent or good hemostatic efficacy was judged to have occurred at 12 hours (82%; 95% CI, 77% – 87%). Of these 204 patients, 84% demonstrated "excellent" efficacy. Subgroup analyses indicated that 85% of those with GI bleeding showed excellent or good efficacy, as did 80% of those with intracranial bleeding.

Only four of the 10 patients who received edoxaban were included in the efficacy analysis; results for this specific group were not released.

In the entire patient population, there was no significant association between hemostatic efficacy and reduction in anti–factor Xa activity (area under the curve [AUC], 0.53; 95% CI, 0.44 – 0.62). However, the magnitude of activity reduction was a significant predictor of hemostatic efficacy in the patients with ICH (AUC, 0.64; 95% CI, 0.53 – 0.74).

Thrombotic Events, Deaths

In the safety analyses, 34 patients experienced at least one thrombotic event during the 30-day follow-up. Of these, 11 had an event within 5 days of receiving the bolus, 11 had an event between 6 and 14 days after the bolus, and 12 had an event between 15 and 30 days after the bolus.

"Thrombotic events at 30 days were in the expected range for the study population," Milling told meeting attendees.

Ischemic stroke, deep-vein thrombosis, myocardial infarction, and pulmonary embolus occurred in 14, 13, seven, and five of the patients, respectively. One patient also had a transient ischemic attack, and two patients experienced a nonsevere infusion reaction.

Of the 49 patients who died within 30 days, 35 died from cardiovascular causes. Among those with ICH, the mortality rate was 15.0%; among those with GI bleeding, it was 11.1%.

Full oral anticoagulation was restarted in 100 patients (28%) by the 30-day mark. After these restarts, no thrombotic events were reported.

"The study supported the May 2018 FDA approval of andexanet alfa, now the only approved agent for patients taking rivaroxaban and apixaban when urgent reversal is needed," Milling said in a press release.

The investigators note that the "most important limitation" of the study is that there was no randomized comparison with a control group. They write that at study initiation, it was decided that such a trial would present both logistic and ethical challenges — especially risks from being assigned to placebo for such a vulnerable population.

Nevertheless, "continued use of unapproved agents, despite a lack of rigorous clinical data, has changed the equipoise for a trial," the researchers write. They add that the sponsor is planning to start a randomized trial later in 2019.

According to, the new study will be conducted in patients with acute ICH who present within 12 hours of symptom onset and within 15 hours of taking an oral factor Xa inhibitor. The estimated enrollment is 440 patients.

"What We Expected"

After the presentation, session moderator Louise McCullough, MD, PhD, professor and chair of neurology at the McGovern Medical School at UT Health, Houston, Texas, told Medscape Medical News that the findings "were exactly what we expected them to be."

Dr Louise McCullough

"It reversed bleeding, and it reversed bleeding quickly and efficiently," said McCullough, who is also vice-chair of the ISC 2019 program committee. "Obviously there were some procoagulant effects, but if somebody is having life-threatening bleeding, whether it's peripheral or in the head, you want to stop it as soon as possible."

She added that this agent gives clinicians an option for the patients who are taking oral anticoagulants "that you can't reverse other ways. I'd say it's an effective therapy and another tool in our toolbox, especially for polytrauma and ICH. But it is expensive."

Dr Larry Goldstein

Also asked to comment, Larry Goldstein, MD, professor and chair of the Department of Neurology and codirector of the Kentucky Neuroscience Institute at the University of Kentucky, Lexington, noted to Medscape Medical News that the inhibitor drugs are being used more and more frequently in place of warfarin for patients with atrial fibrillation or deep vein thrombosis.

"The problem is that if those patients would bleed, we didn't have a way of effectively and quickly reversing that anticoagulation. We had processes for that for patients on warfarin, but not a good way to do this for patients on these anti-Xa drugs," he said.

Comparator Concerns

Goldstein, who was not involved with the current research, is also a spokesperson for the American Heart Association. He voiced concern that the study predominantly used a surrogate measure.

"That was the reversal of the anti–factor Xa activity. The issue with it is that there's no control group," he said.

"They indicated that it would have been logistically and ethically difficult to do the study with a control arm. However, they potentially could have used 4-factor concentrate, which is the currently available treatment that's used in these types of patients, as a control. And then they could have tried to determine whether this new approach is more efficacious than that," Goldstein said.

He added that treatment options are "potentially important" for these patients. "The hypothesis is that if you can effectively and rapidly reverse the anticoagulant effect of these drugs, we'd limit the amount of bleeding and improve functional outcome. But without a control group, whether reversing level of anticoagulation improves patient outcome, we don't know."

Goldstein also noted that although the investigators report that the rate of thrombotic events was in the range they expected, "without concurrent controls, that's a very difficult hypothesis to prove."

"We were leery about doing this trial because there was no standard of care to compare it to," Milling admitted. "The inhibitors were new, the reversal agent was even newer, and nobody could agree on what to compare it to," he told Medscape Medical News when asked about these issues.

However, Milling noted that the next step, "and it's in the FDA approval letter," is to design and carry out a randomized trial of andexanet vs "usual care."

"That, in many environments, will be prothrombin complex concentrate; and there are variable forms of that: 4-factor, 3-factor, activated, inactivated. Depending on where you practice, different people use different things," he said.

The study was funded by Portola Pharmaceuticals. Milling reports having served as a consultant/advisory board member for Octapharma and Portola, being on the speakers' bureau for Janssen, and receiving honoraria from CSL Behring. Disclosures for the other study authors are fully listed in the original article. McCullough and Goldstein report no relevant financial relationships.

International Stroke Conference (ISC) 2019: Abstract LB7. Presented February 7, 2019.

N Engl J Med. Published online February 7, 2019. Abstract

Follow Deborah Brauser on Twitter: @MedscapeDeb

For more Medscape Neurology news, join us on Facebook and Twitter


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.