Posted: June 25, 2019

On May 9-11, 2019 the Hemostasis Thrombosis Research Society (HTRS) and North American Foundation of Thrombosis and Hemostasis (NAFTH) met in New Orleans, LA for a large Clotting and Bleeding Clam Bake of clinical and research information sharing.

The first large exchange of information was that the two societies of HTRS/NAFTH would now merge under the banner of the HTRS for future meetings and business. This will result in more beneficial exchange of supporting collaborative research.

The first education session was a lively discussion on DOAC Reversal in a Bleeding Patient: Yes or No.

A case was presented of a subject suffering from a hemorrhage while undergoing a colostomy.

The audience was asked to vote via meeting APP as to whether they would use the anti-Xa reversal agent for a subject experiencing a severe hemorrhage while on an anti-Xa medication. The reversal agent in question to be used was Andexanet-alfa. The primary questions are: do the lab results correlate with the bleeding? Is the reversal agent really necessary?

The Pro reversal position was defended by Dr. Deborah Siegal, MD, MSc, FRCPC, Assistant Professor, Division of Hematology and Thromboembolism, Department of Medicine, Investigator, Population Health Research Institute, McMaster University, Hamilton, Ontario. The title of her presentation was DOAC reversal: the case for “Yes.”

Her talking points were the following:

  • Bleeding is the major complication of DOACs and all anticoagulants including the Vitamin K agonists (VKA’s) like warfarin
  • Major bleeding is associated with a risk of death
  • DOACs are reversible
  • Reversal agents are available
  • Reversal will improve clinical outcomes (at least in some patients)

I noticed that her last bullet said in some patients. When talking about reversal of DOACs the medical community is still conflicted about when to reverse the medications. We don’t yet have a reference range that tells us when we should reverse a DOAC or if the laboratory values in a subject that is bleeding will really do anything other than let the healthcare team know that the drug is present and is it safe or not to reverse the suspected DOAC problem.

She noted that anticoagulants don’t cause bleeding but they make bleeding worse. She cited Dr. Mark Crowther, MD, with this quote. She then quoted Dr. Clive Kearon, MD on his “First Rule of Thrombosis,” “Don’t anticoagulate a bleeding patient.”

Dr. Siegal then made the points stated below:

When to Consider Using an Antidote in a Bleeding Patient:

  • Life-threatening (e.g. hemodynamic compromise)
  • Critical organ (e.g. intracranial)
  • Severe ongoing bleeding
  • Expected long delay in restoration of normal hemostasis (over-anticoagulation, renal failure)

Dr. Siegal then brought up the following issues for reasons on why reverse the DOAC present that is causing the bleeding:

  • Remove anticoagulant effect
  • Facilitate definitive interventions (endoscopy/surgery)
  • Reduce complications of bleeding
  • Anemia, transfusion, ICU admission, prolonged admission
  • Save lives?

It was stated that GI bleeding is not a benign condition. She highlighted a couple of studies on using reversal agents for bleeding in dabigatran

REVERSE-AD GI Bleed Cohort (idarucizumab for dabigatran reversal) Hemostasis 69% Median time to bleeding cessation 2.4 hrs (2.0-3.9 Mortality – 30 days – 90 days 11% 15% Van der Wall Circulation 2019; Siegal Circulation 2019).

The second study was the ANNEXA 4 study using Andexanet alfa.

ANNEXA-4: Hemostasis and Corrected Anti-Xa Activity Connolly et al. NEJM 2019. Acute major bleeding ≤ 18 hours of last dose of apixaban, rivaroxaban, edoxaban, enoxaparin Efficacy n=254, Safety n=352 82% achieved good/excellent hemostasis within 12 hrs

Limitations of Data = Uncertainty in Lack of comparator group

  • Hemostatic efficacy
  • Thrombotic events
  • Mortality

Therefore, does the Harm outweigh the benefits to use the reversal agents.

Dr. Siegal then summarized using PCC vs Andexanet alfa in 3 different studies: