Meeting News CoveragePerspective

ANNEXA-4: Reversal agent effective in patients with acute major bleeding after Factor Xa inhibitor use

Andexanet alfa, a novel reversal agent, was effective at stopping acute major bleeding in patients taking Factor Xa inhibitors, according to results from the ANNEXA-4 study.

Stuart J. Connolly, MD, from the Population Health Research Institute, McMaster University, Hamilton, Ontario, and colleagues conducted a prospective study of 67 patients with acute major bleeding within 18 hours of taking a Factor Xa inhibitors. The most common uses of Factor Xa inhibitors are for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, and for treatment and prevention of venous thromboembolism.

Stuart J. Connolly

The researchers presented the findings at the European Society of Cardiology Congress and published them in the New England Journal of Medicine.

“Until now, we did not have experience [with andexanet alfa] in acutely bleeding patients,” Mark Crowther, MD, also from the Population Health Research Institute at McMaster University, said in a press release. “This preliminary report of the ongoing ANNEXA-4 study shows us that andexanet rapidly reverses anti-Factor Xa activity in acutely bleeding patients and this is associated with excellent or good hemostasis in most.”

Mark Crowther, MD, MSc

Mark Crowther

All patients received a bolus of andexanet alfa (AndexXa, Portola Pharmaceuticals) followed by a 2-hour infusion of the agent. Andexanet alfa is not yet approved for use in the United States; earlier in August, the FDA wrote Portola that it will not approve the agent until it receives more information about certain manufacturing issues and clinical indications. No reversal agent for Factor Xa inhibitors has been approved by the FDA.

“The letter from the FDA [said] they need more data, which we are happy to provide,” researcher Truman J. Milling, MD, research director, Ascension Seton Dell Medical School Stroke Institute, Austin, Texas, told Cardiology Today. “Hopefully we can get the agency to a comfort level for approving the drug, because there is a dire need for it in the clinical arena.” He noted some doctors and patients have a “psychological barrier” to using newer oral anticoagulants, which are as effective as warfarin and may be safer, but do not have a reversal agent.

“That has led to underuse of anticoagulation in general, and because of that, there are a couple of hundred thousand unnecessary strokes per year,” he said.

The average age of the patient population was 77 years and most had advanced CVD.

The outcomes of interest were measures of anti-Factor Xa activity and clinical hemostatic efficacy at 12 hours. Patients were followed for an additional 30 days.

The 47 patients evaluated for the efficacy endpoint had confirmed severe bleeding and a baseline value of ≥ 75 ng/mL for anti-factor Xa activity; it was ≥ 0.5 IU/mL in those who received enoxaparin.

In most cases, bleeding was gastrointestinal or intracranial, Connolly and colleagues reported.

After administration of the bolus, median anti-Factor Xa activity fell 89% (95% CI, 58-94) in those who took rivaroxaban (Xarelto, Janssen Pharmaceuticals) and 93% (95% CI, 87-94) in those who took apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), according to the researchers, who reported that those figures were sustained during the 2-hour administration of the drug.

At 4 hours post-infusion, those who took rivaroxaban showed a relative decrease from baseline of anti-Factor Xa activity of 39%; the figure was 30% in those who took apixaban, according to the researchers.

Truman J. Milling

 At 12 hours post-infusion, 79% of the patients in the efficacy cohort had clinical hemostasis adjudicated as excellent or good.

“The interim results were reassuring that [andexanet alfa] does work, despite the chaos in the body that exists when there is a major hemorrhage scenario,” Milling told Cardiology Today. “We have more work to do to enroll more patients and finish examining the safety and efficacy outcomes in the larger cohort.”

At 30 days, 18% of the overall cohort had thrombotic events, according to the researchers. “This rate of events is not unexpected considering the thrombotic potential of the patients and the fact that in most of them, anticoagulation was discontinued at the time of bleeding and not restarted,” Connolly said in the release. – by Erik Swain

References:

Connolly SJ, et al. Hot Line: Preventive Strategies 2. Presented at: European Society of Cardiology Congress; Aug. 27-31, 2016; Rome.

Disclosure: The study was funded by Portola Pharmaceuticals. Connolly reports consulting for, receiving royalties from and holding equity in Portola; receiving grant support from Boston Scientific; and receiving grant support and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb and Sanofi Aventis. Crowther reports receiving personal fees and nonfinancial support from Portola, and reports financial ties with AbbVie, AKP America, Alexion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Celgene, Daiichi Sankyo, Janssen, LEO Pharmaceuticals, Octapharma, Ortho Clinical Diagnostics, Pfizer and Shire. Milling reports receiving an honorarium from the Public Health Research Institute at McMaster University for serving on the executive committee of the ANNEXA-4 trial.

 

Andexanet alfa, a novel reversal agent, was effective at stopping acute major bleeding in patients taking Factor Xa inhibitors, according to results from the ANNEXA-4 study.

Stuart J. Connolly, MD, from the Population Health Research Institute, McMaster University, Hamilton, Ontario, and colleagues conducted a prospective study of 67 patients with acute major bleeding within 18 hours of taking a Factor Xa inhibitors. The most common uses of Factor Xa inhibitors are for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, and for treatment and prevention of venous thromboembolism.

Stuart J. Connolly

The researchers presented the findings at the European Society of Cardiology Congress and published them in the New England Journal of Medicine.

“Until now, we did not have experience [with andexanet alfa] in acutely bleeding patients,” Mark Crowther, MD, also from the Population Health Research Institute at McMaster University, said in a press release. “This preliminary report of the ongoing ANNEXA-4 study shows us that andexanet rapidly reverses anti-Factor Xa activity in acutely bleeding patients and this is associated with excellent or good hemostasis in most.”

Mark Crowther, MD, MSc

Mark Crowther

All patients received a bolus of andexanet alfa (AndexXa, Portola Pharmaceuticals) followed by a 2-hour infusion of the agent. Andexanet alfa is not yet approved for use in the United States; earlier in August, the FDA wrote Portola that it will not approve the agent until it receives more information about certain manufacturing issues and clinical indications. No reversal agent for Factor Xa inhibitors has been approved by the FDA.

“The letter from the FDA [said] they need more data, which we are happy to provide,” researcher Truman J. Milling, MD, research director, Ascension Seton Dell Medical School Stroke Institute, Austin, Texas, told Cardiology Today. “Hopefully we can get the agency to a comfort level for approving the drug, because there is a dire need for it in the clinical arena.” He noted some doctors and patients have a “psychological barrier” to using newer oral anticoagulants, which are as effective as warfarin and may be safer, but do not have a reversal agent.

“That has led to underuse of anticoagulation in general, and because of that, there are a couple of hundred thousand unnecessary strokes per year,” he said.

The average age of the patient population was 77 years and most had advanced CVD.

The outcomes of interest were measures of anti-Factor Xa activity and clinical hemostatic efficacy at 12 hours. Patients were followed for an additional 30 days.

The 47 patients evaluated for the efficacy endpoint had confirmed severe bleeding and a baseline value of ≥ 75 ng/mL for anti-factor Xa activity; it was ≥ 0.5 IU/mL in those who received enoxaparin.

In most cases, bleeding was gastrointestinal or intracranial, Connolly and colleagues reported.

After administration of the bolus, median anti-Factor Xa activity fell 89% (95% CI, 58-94) in those who took rivaroxaban (Xarelto, Janssen Pharmaceuticals) and 93% (95% CI, 87-94) in those who took apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), according to the researchers, who reported that those figures were sustained during the 2-hour administration of the drug.

At 4 hours post-infusion, those who took rivaroxaban showed a relative decrease from baseline of anti-Factor Xa activity of 39%; the figure was 30% in those who took apixaban, according to the researchers.

Truman J. Milling

 At 12 hours post-infusion, 79% of the patients in the efficacy cohort had clinical hemostasis adjudicated as excellent or good.

“The interim results were reassuring that [andexanet alfa] does work, despite the chaos in the body that exists when there is a major hemorrhage scenario,” Milling told Cardiology Today. “We have more work to do to enroll more patients and finish examining the safety and efficacy outcomes in the larger cohort.”

At 30 days, 18% of the overall cohort had thrombotic events, according to the researchers. “This rate of events is not unexpected considering the thrombotic potential of the patients and the fact that in most of them, anticoagulation was discontinued at the time of bleeding and not restarted,” Connolly said in the release. – by Erik Swain

References:

Connolly SJ, et al. Hot Line: Preventive Strategies 2. Presented at: European Society of Cardiology Congress; Aug. 27-31, 2016; Rome.

Disclosure: The study was funded by Portola Pharmaceuticals. Connolly reports consulting for, receiving royalties from and holding equity in Portola; receiving grant support from Boston Scientific; and receiving grant support and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb and Sanofi Aventis. Crowther reports receiving personal fees and nonfinancial support from Portola, and reports financial ties with AbbVie, AKP America, Alexion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Celgene, Daiichi Sankyo, Janssen, LEO Pharmaceuticals, Octapharma, Ortho Clinical Diagnostics, Pfizer and Shire. Milling reports receiving an honorarium from the Public Health Research Institute at McMaster University for serving on the executive committee of the ANNEXA-4 trial.

 

    Perspective
    Gordon F. Tomaselli

    Gordon F. Tomaselli

    One reason why some people have chosen not to use selective oral anticoagulants is the absence of a reversal agent as with warfarin, where agents can be used to reverse the effect of vitamin K. These other drugs have a lot of advantages, but the absence of a reversal agent is considered a major disadvantage. This agent selectively attacks the drug itself and seemingly, relatively safely with respect to the risk for thrombosis afterward, seems to promote hemostasis if someone presents with a bleed. Most bleeds in this study were gastrointestinal, but there were a substantial number of intracranial bleeds as well.
    The real question is, while hemostasis can be achieved without much risk for thrombosis, but are outcomes improved? I don’t think we have an answer. It may be a difficult question to ask, because we’re dealing with a complication of a therapy, where the expectation in some cases is that the outcome will not be good, especially if there’s an intracranial bleed. In this study, many of the intracranial bleeds resulted in death. The bottom line is, those wouldn’t be helped by a reversal agent in any case. Many of those bleeds stop because of pressure from the anticoagulant in the brain, tamponading vessels that are bleeding.
    For those with life-threatening but not life-limiting bleeds, it will be important to see how they fare after getting reversal of an anticoagulant. The real key in lots of these patients is what is the source of bleeding, and what is the safety of restarting the anticoagulant?
    Having reversal agents in our armamentarium is good. It would be nice if there were a single agent that could reverse all the anticoagulant agents.
    The community has been waiting for a study like this, and it will be interesting to see how prescriptions for oral anticoagulants change; this has the potential to produce a spike in the use of these drugs, and doing so will also produce a bit of a spike in overall health care costs.

    • Gordon F. Tomaselli, MD, FAHA, FACC, FHRS
    • Chief of Cardiology, Johns Hopkins University School of Medicine Past President, American Heart Association

    Disclosures: Tomaselli reports no relevant financial disclosures.

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