A Q&A on Risk, Management of Bleeding-Related Hospitalizations

March 30, 2020

The American Journal of Managed Care® (AJMC® ) interviewed Craig I. Coleman, PharmD, University of Connecticut, School of Pharmacy/Hartford Hospital Evidence-Based Practice Center, on bleeding-related hospitalizations in both patients at high thrombotic risk and those administered andexanet alfa or 4-Factor prothrombin complex concentrate (4FPCC).

The American Journal of Managed Care® (AJMC® ) interviewed Craig I. Coleman, PharmD, University of Connecticut, School of Pharmacy/Hartford Hospital Evidence-Based Practice Center, on bleeding-related hospitalizations in both patients at high thrombotic risk and those administered andexanet alfa or 4-Factor prothrombin complex concentrate (4FPCC). Coleman presented 2 abstracts, titled “Management of Oral Factor Xa Inhibitor Bleeding-Related Hospitalizations with Andexanet Alfa or 4-Factor Prothrombin Complex Concentrate,” and “Outcomes Associated with Bleeding-Related Hospitalizations in Patients at High Thrombotic Risk Findings from the Nationwide Readmission Database.”

The abstracts were released through the American College of Cardiology (ACC) and World Congress of Cardiology (WCC) Annual Meeting—ACC.20/WCC Virtual Experience.

AJMC®: Can you discuss how patients at high thrombotic risk may be more prone to readmissions for bleeding-related issues?

Coleman: Patients at high risk for thrombosis, including those with atrial fibrillation and those experiencing an acute venous thromboembolic event are at high risk of thrombotic events. The way we treat these patients is to use oral anticoagulants (now frequently, oral factor Xa inhibitors like rivaroxaban or apixaban) to prevent thrombosis/clots. As with any anticoagulant, the use of oral factor Xa inhibitors carry bleeding as a possible adverse event, and such bleeds can be severe (resulting in the need for hospitalization) or life-threatening.

AJMC®: In your findings to be presented at the virtual ACC/WCC annual meeting, you discover that patients at high thrombotic risk who were hospitalized for intracranial hemorrhage (ICH) exhibited higher rates of mortality. What differentiates ICH from other site bleeds? (e.g. gastrointestinal, genitourinary).

Coleman: While ICH is a somewhat rare consequence of anticoagulation, and even less common for users (about 50% less) of oral factor Xa inhibitors compared to older therapies such as warfarin, they are associated with a high degree of morbidity (long term neurologic deficit) and mortality. Much like a clot that gets to the brain (an ischemic stroke), a bleed in the brain can be equally as devastating to a patient. In fact, we often refer to ICHs in many cases as “hemorrhagic strokes”. As bleeds in the brain grow (we call it hematoma expansion), they put pressure on the brainstem, disrupting the body’s regulation of heart rate, breathing, blood pressure, autonomic functions.

AJMC®: In another study you will be presenting at ACC/WCC, 31.8% of patients with bleeding related hospitalizations were administered either 4FPCC or andexanet to manage oral factor Xa inhibitor (oFXaI) associated bleeding. Can you explain how 4FPCC and andexanet differ in managing oFXaI associated bleeding?

Coleman: Andexanet alfa is a biologic agent, a recombinant modified version of human activated factor X (FXa). Oral factor Xa inhibitors bind to andexanet alfa with the same affinity as to natural FXa. As a result, in the presence of andexanet alfa natural FXa is partially freed up allowing it to help form clot. It acts as a decoy receptor and the only specific reversal agent to manage oral factor Xa inhibitor related bleeding.

4-factor prothrombin complex concentrate is a medication made up of blood clotting factors II, VII, IX and X, and is only approved in the US for reversal of warfarin. Besides its use being “off-label”, there are a few concerns with 4FPCC including whether it contains enough factor Xa in it to properly reverse oral factor Xa inhibitors. It is also thought to be thrombogenic (may result in an increased risk of clotting events, not just management/slowing of bleeding).

So andexanet alfa is a drug-specific reversal agent, while 4F-PCC is a replenishment/infusion of clotting factors. While no randomized head-to-head trials of these 2 management strategies has been undertaken, data being presented by Dr. Ander Cohen at this ACC meeting provides some of the best comparative effectiveness data we have to date (abstract #1213-209). It suggests andexanet alfa was associated with less 30-day mortality than PCCs when used to treated oral factor Xa inhibitor-associated bleeding.

AJMC®: Why may physicians continue to use 4FPCC in managing oFXaI associated bleeding?

Coleman: This is an interesting question and one that my group would like to perform additional research to answer. There are probably a number of factors that play into the decision. There is accessibility to consider, as not every hospital has both agents on formulary. The type of bleed comes into play as well, with ICH likely more often treated with andexanet alfa than bleeds associated with less morbidity and mortality. Physicians familiarity with using each of the agents (4F-PCC has been available longer, albeit not approved for reversal of newer oral anticoagulants). Cost of treatment.

AJMC®: What are some common mistakes taken by physicians in managing oFXaI associated bleeding in patients?

Coleman: From my perspective, improvement in the management of oral factor Xa inhibitors could be made by 1) getting a good history regarding patients’ dose and time of last apixaban or rivaroxaban use. These agents have a short half-life/duration of activity and often neither agent is really needed; 2) follow the guidelines from various organizations that have a stake in care of these patients (ACC/AHA, ESC, CHEST, ISTH, etc.).