Question & Answer

Q: On May 3, the Food and Drug Administration (FDA) approved a drug that reverses the anticoagulant effect of apixaban (ELIQUIS) and rivaroxaban (XARELTO). Does this alter your classification of these two drugs as Do Not Use?

A: Our Do Not Use classification for apixaban[1] and rivaroxaban[2] remains the same despite the FDA’s recent approval of andexanet (ANDEXXA), an antidote for reversing the anticoagulation (blood-thinning) effect of these two new anticoagulants when needed due to life-threatening or uncontrolled bleeding.[3]

Andexanet’s approval was based on small trials that enrolled healthy volunteers and on preliminary results from an ongoing phase 3 trial with no control group that is enrolling subjects with acute major bleeding who recently were prescribed a new oral anticoagulant.[4]

Furthermore, the FDA approved andexanet under the accelerated review mechanism, which permitted the drugmaker to use a surrogate endpoint (change in blood thinning activity) rather than a proven — and much more important — clinical endpoint (such as resolution of serious bleeding and death) in these trials.[5],[6]

The agency’s own clinical reviewers were similarly concerned about the lack of evidence from andexanet’s ongoing trial that the surrogate endpoint correlates with resolution of bleeding. These reviewers also characterized the trial’s preliminary results as "not conclusive."[7]

Importantly, andexanet’s label carries a black-box warning — the strongest warning that the FDA can require — for serious and life-threatening adverse events, including blood clots in the arteries and veins, cardiac arrest, ischemic events (such as heart attack and ischemic stroke) and sudden death.[8]

The FDA’s clinical reviewers concluded that the uncertainty regarding the clinical benefit in combination with concern about the safety of andexanet result in an unfavorable overall benefit-risk profile for this drug.[9] Yet the director of the FDA office responsible for the review of the drug decided to override this conclusion and approved andexanet, arguing, in part, that andexanet’s risks are “mitigated by the [warnings on the drug’s] label.”[10]

As a condition of continued approval, the FDA required andexanet’s maker to conduct a postmarketing trial to provide “much more reliable data” about both the benefits and risks of andexanet in patients with life-threatening or uncontrolled intracerebral hemorrhage (bleeding inside the brain).[11]

For all of the aforementioned reasons, and due to other reasons that we outlined in our June 2018 and April 2016 issues of Worst Pills, Best Pills News, we continue to classify apixaban and rivaroxaban as Do Not Use drugs. Instead, we continue to recommend warfarin (COUMADIN, JANTOVEN) over all of the new oral anticoagulant drugs.

References

[1]Is XARELTO really the 'right move' for patients with blood clots or risk for stroke? Worst Pills, Best Pills News. April 2016. /newsletters/view/1026. Accessed June 13, 2018.

[2]Do Not Use the new oral blood thinner apixaban (ELIQUIS). Worst Pills, Best Pills News. June 2018. /newsletters/view/1202. Accessed June 13, 2018.

[3]Portola Pharmaceuticals, Inc. Label: andexanet (ANDEXXA). 2018. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM606687.pdf. Accessed July 5, 2018.

[4]Ibid.

[5]Food and Drug Administration. Accelerated approval letter for coagulation factor Xa (recombinant), inactivated-zhzo (BL125586/0). May 3, 2018. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM606693.pdf. Accessed July 5, 2018.

[6]Portola Pharmaceuticals, Inc. Label: andexanet (ANDEXXA). 2018. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM606687.pdf. Accessed July 5, 2018.

[7]Food and Drug Administration. Summary basis for regulatory action for ANDEXXA/coagulation factor Xa (recombinant), inactivated-zhzo. May 3, 2018. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM610006.pdf. Accessed July 5, 2018.

[8]Portola Pharmaceuticals, Inc. Label: andexanet (ANDEXXA). 2018. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM606687.pdf. Accessed July 5, 2018.

[9]Food and Drug Administration. Memorandum: Director, Office of Tissues and Advanced Therapies re. coagulation factor Xa (recombinant), inactivated-zhzo (ANDEXXA). May 2, 2018. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM610007.pdf. Accessed July 5, 2018.

[10]Ibid.

[11]Food and Drug Administration. Memorandum: Director, Office of Tissues and Advanced Therapies re. coagulation factor Xa (recombinant), inactivated-zhzo (ANDEXXA). May 2, 2018. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM610007.pdf. Accessed July 5, 2018.