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Date: July 29, 2024

Reference: Connolly SJ et al (ANNEXA-I investigators) Andexanet for Factor Xa Inhibitor–Associated Acute Intracerebral Hemorrhage. NEJM May 2024

Guest Skeptic: Dr. Vasisht Srinivasan is an Emergency Medicine physician and neurointensivist at the University of Washington and Harborview Medical Center in Seattle, WA. He is an assistant professor in Emergency Medicine, Neurology, and Neurosurgery at the School of Medicine at the University of Washington.

Case: A 65-year-old man is brought into the emergency department (ED) by emergency medical services (EMS) after his family saw him slump over at the dinner table. He was confused, slurring his speech, and had trouble moving his right side. Initial evaluation by medics revealed right arm weakness, a right facial droop, and decreased responsiveness. When he arrives at your ED, the family tells you he was doing fine until dinner. A code stroke is activated, and a CT head shows a left basal ganglia hemorrhage with no vascular lesions on CT angiography. Vital signs show a blood pressure (BP) of 190/110, heart rate (HR) 117 and irregularly irregular, respiratory rate (RR) 18, SpO2 99% on room air. You ask the patient’s family about any other medical conditions, and they report he has high blood pressure and atrial fibrillation. He takes metoprolol and apixaban and last took his medications that morning about eight hours before. As you begin to lower his blood pressure, you start thinking about reversal agents for his anticoagulation.

Background: In hemorrhagic stroke, the ABCs for resuscitation remain the same, but can also be categorized as:

  • Airway Management: This is an important aspect for patients with a poor neurologic exam or those who are not protecting their airways.
  • Blood Pressure Control: There is a lot of debate about the aggressiveness of blood pressure lowering. Numerous trials have attempted to determine the optimal blood pressure target to balance the two goals of minimizing hemorrhage expansion and limiting brain ischemia.
    • INTERACT-2 demonstrated that in patients with ICH, intensive lowering of blood pressure did not result in a significant reduction in the rate of the primary outcome of death or severe disability (SGEM#73).
    • ATACH-2 showed that intensive blood pressure reduction (SBP 110-139 mm Hg) does not provide benefit over standard blood pressure reduction (SBP 140-179 mm Hg) in patients with acute intracerebral hemorrhage (SGEM#172).
    • INTERACT-3 reported the odds of a poor functional outcome were lower in the goal-directed intensive care bundle group compared to usual care (SGEM#413).
  • Coagulopathy Reversal: It makes pathophysiologic sense that patients who take anticoagulants should have the drug rapidly reversed to prevent worsening hemorrhage and poor outcomes. However, the evidence regarding the impact of anticoagulation reversal on patient-oriented outcomes such as decreased mortality or improved neurologic function in patients with acute hemorrhagic stroke is mixed and somewhat limited.
    • Reversal of Warfarin: Freeman et al. (2004) found that recombinant factor VIIa can rapidly reverse warfarin anticoagulation in cases of acute intracranial hemorrhage, but the study did not conclusively demonstrate a reduction in mortality or an improvement in functional outcomes.
    • Direct Oral Anticoagulants (DOACs): Compared to warfarin, DOACs like dabigatran, apixaban, and rivaroxaban have shown lower rates of ICH in randomized controlled trials. However, the management of ICH in the setting of DOAC use remains complex. Hemodialysis can help clear dabigatran, and activated charcoal may be used for recent ingestion. Prothrombin complex concentrate (PCC) may offer some benefit in reversing DOAC-related hemorrhage.

The 2022 AHA/ASA guidelines give several recommendations on blood pressure lowering and coagulopathy reversal along with an algorithm.

  • Blood Pressure Lowering:
    • “In patients with spontaneous ICH in whom acute BP lowering is considered, initiating treatment within 2 hours and reaching target within 1 hour can be beneficial to reduce the risk of HE and improve functional outcome” (Class 2a; LoE C-LD)
    • “In patients with spontaneous ICH of mild to moderate severity presenting with SBP between 150 and 220 mmHg, acute lowering of SBP to a target of 140 mmHg with the goal of maintaining in the range of 130 to 150 mmHg is safe and may be reasonable for improving functional outcomes.” (Class 2b; LoE B-RP)
    • “In patients with spontaneous ICH presenting with large or severe ICH or those requiring surgical decompression, the safety and efficacy of intensive BP lowering are not well established.” (Class 2b; LoE C-LD)
  • Reversal:
    • In patients with VKA-associated spontaneous ICH and INR ≥2.0, 4-factor (4-F) prothrombin complex concentrate (PCC) is recommended in preference to fresh-frozen plasma (FFP) to achieve rapid correction of INR and limit HE. (Class I; LoE B-R)
    • In patients with direct factor Xa inhibitor-associated spontaneous ICH, andexanet alfa is reasonable to reverse the anticoagulant effect of factor Xa inhibitors. (Class 2a; LoE B-NR)
    • In patients with direct factor Xa inhibitor-associated spontaneous ICH, a 4-F PCC or activated PCC (aPCC) may be considered to improve hemostasis. (Class 2b; LoE B-NR)
    • In patients with dabigatran- or factor Xa inhibitor-associated spontaneous ICH, when the DOAC agent was taken within the previous few hours, activated charcoal may be reasonable to prevent absorption of the DOAC. (Class 2b; LoE C-LD)
    • In patients with dabigatran-associated spontaneous ICH, when idarucizumab is not available, aPCC or PCCs may be considered to improve hemostasis. (Class 2b; LoE C-LD)
    • In patients with dabigatran-associated spontaneous ICH, when idarucizumab is not available, renal replacement therapy (RRT) may be considered to reduce dabigatran concentration. (Class 2b; LoE C-LD)
    • In patients with unfractionated heparin (UFH)-associated spontaneous ICH, intravenous protamine is reasonable to reverse the anticoagulant effect of heparin. (Class 2a; LoE C-LD)
    • In patients with low-molecular-weight heparin (LMWH)-associated spontaneous ICH, intravenous protamine may be considered to partially reverse the anticoagulant effect of heparin. (Class 2b; LoE C-LD)

Today’s episode centers on “C”, and how best to reverse the direct oral anticoagulants (DOACs) (e.g. apixaban, rivaroxaban, edoxaban) that are direct factor Xa inhibitors.

The most common agent for anticoagulant reversal was initially fresh frozen plasma (FFP).  Over time, prothrombin complex concentrate (PCC) began to be used, with 3-factor and 4-factor variants, offering high concentrations of clotting factors in a small volume.  4-factor PCC has now largely supplanted FFP to reverse vitamin K antagonists (VKA) (e.g. warfarin). 

As newer anticoagulants were developed, specific agents soon followed for directed reversal of those agents. For example, the direct thrombin inhibitor has a targeted reversal agent, idarucizumab.  We have looked at the evidence for idarucizumab on SGEM#139 and our bottom line at that time was idarucizumab is here (USA) and probably works but its patient-oriented efficacy and safety are still pending.

When rivaroxaban was first released in 2008 in Europe and Canada, the best reversal agent was still unknown.  With time, PCC became utilized and had effectiveness against DOACs, finding its way into national guidelines [Fonteral et al NCC Guidelines 2016]. 

In 2018, andexanet alfa came to market as a targeted agent to reverse rivaroxaban and apixaban.  The ANNEXA-4 trial demonstrated reduced anti-factor-Xa activity.[1]  However, this agent was incredibly expensive which significantly limited its use.  We reviewed this on SGEM#251 and our bottom line was that the routine use of andexanet alfa in the management of bleeding patients on factor Xa-inhibitors cannot be recommended at this time.

There were reports of increased thrombotic events with andexanet alfa which raised questions about its safety profile.  Finally, by this point, most centers had been using 4-factor PCC for DOAC reversal with good effect [2,3] and did not see the need to add this medication to their formulary, particularly one with a significant cost and without strong data demonstrating effectiveness.

Clinical Question: In patients with intracranial hemorrhage, is andexanet alfa superior to usual care?

Reference: Connolly SJ et al (ANNEXA-I investigators) Andexanet for Factor Xa Inhibitor–Associated Acute Intracerebral Hemorrhage.  NEJM May 2024

  • Population: Patients with an ICH who were taking a factor Xa inhibitor, with the last dose taken within 15 hours before randomization. Initially, any ICH was included, but mid-enrollment, a protocol amendment was implemented which restricted enrollment to only patients with acute intracerebral hemorrhage (not subdural or subarachnoid hemorrhage). A second protocol amendment restricted patients based on time; initially, patients were allowed to be enrolled if their scan was done within 12 hours of the onset of bleeding symptoms, and the protocol changed this to 6 hours.
    • Exclusions: Glasgow Coma Scale score < 7, NIH Stroke Scale score > 35, planned surgery within 12 hours post-enrollment, thrombotic event within 2 weeks before enrollment and hematoma volume < 0.5 ml or > 60 ml.
  • Intervention: Andexanet alfa either at a high-dose or low-dose bolus followed by a 2-hour infusion.
  • Comparison: Usual care. This was defined as the intention to use PCC.  The first protocol amendment stratified patients who were to receive usual care based on the time since onset of symptoms to the baseline imaging (< 180 minutes or ≥ 180 minutes)
  • Outcome:
    • Primary Outcome: Hemostatic efficacy (defined as expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the NIHSS score of less than 7 points at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours).
    • Secondary Outcomes: Percent change in anti-factor Xa activity 2 hours post randomization; modified Rankin Scale (mRS) score at 30 days; thrombotic events; death.
  • Type of Study: Unmasked randomized controlled trial

Authors’ Conclusions: “Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke.”

Quality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. No
  2. The patients were adequately randomized. Yes 
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). Unsure
  6. The patients in both groups were similar with respect to prognostic factors. No 
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No
  8. All groups were treated equally except for the intervention. Yes
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. No 
  12. Financial conflicts of interest. The trial was sponsored by Alexion AstraZeneca Rare Disease, and confidentiality agreements existed between the sponsor and the authors. The agreement between the Principal Investigator and the Sponsor (or its agents) that restricts the PI’s rights to discuss or publish trial results after the trial is completed. A medical writer whose services were paid for by Alexion assisted with an earlier version of the Methods section. Multiple authors declared conflicts of interest, with some being employees of the funding company.

Results: They enrolled 530 patients with a mean age of 79 years and 46% female. Close to 90% had a history of atrial fibrillation, 21% had a previous stroke and 13% had a previous myocardial infarction. The most frequently used factor Xa inhibitor was Apixaban (~60%). The baseline median hematoma volume was 10ml and the median NIHSS score was 9.

Key Result: The Andexanet group achieve more hemostatic efficacy and had more thrombotic events compared to the usual care group.

  • Primary Outcome: Hemostatic efficacy occurred in 67% of the andexanet group and 53% in the usual care group. Adjusted difference of 13.4% (95% CI; 4.6 to 22.2; p = 0.003).
  • Secondary Outcomes: 
    • Percent change in anti-factor Xa activity during first 2 hours post-randomization -94.5% vs -26.9% (p<0.001)
    • Modified Rankin scale at 30 days: 28% had mRS 0-3 vs 31% in the usual care group (not statistically significant)
    • Thrombotic events: 10.3% vs 5.6% (p = 0.048)
    • Ischemic stroke: 6.5% vs 1.5%
    • Death: 27.8% vs 25.5% (p = 0.51)

1. Protocol Changes: There were three protocol changes mid-study. The first restricted enrollment from 12 hours to 6 hours from onset to baseline scan, and limited patients to ICH only. It also increased the enrollment from 440 to 900, and an interim analysis was planned for 450 patients.  However, a different stopping rule was also introduced at 450 patients with a significance level of p < 0.031, rather than the initial p < 0.001. These changes make me more skeptical of the trial in general.

2. Duration of Follow-Up: 90-day mortality/outcomes is the usual duration of follow-up in other ICH trials. It’s unclear why the authors chose a 30-day timeline for follow-up.

3. Trial Ended Early: Stopping trials early for benefit can over-inflate the point estimate of the effect size. This is due to the concept of regression to the mean. Data oscillates around the true value. What goes up must also come down. We are looking for the “truth” defined as the best point estimate of an observed effect size with a confidence interval around the point estimate. Stopping a trial early can result in wider confidence intervals and less certainty.

Montori et al did a systematic review and meta-analysis of 143 randomized control trials that were stopped early for benefit and almost two-thirds were industry-sponsored.[4]  This trial had significant sponsorship from industry. The trial was funded by Alexion AstraZeneca and previously by Portola and Alexion Pharmaceuticals. Portola and Alexion provided andexanet free of charge. The trial was designed primarily by the first author who had declared conflicts of interest and two employees of Portola. A medical writer was also paid for by Alexion to assist with the writing of an earlier version of the methods section.  Multiple authors reported financial conflicts of interest with pharma. An interim stopping rule was implemented with the analysis  performed by an unblinded statistician affiliated with the funded institute.

There are also ethical concerns about stopping trials early.[5] Guidelines exist to help researchers decide if stopping their trial early is appropriate. It appears these investigators did not follow the guidelines.[6] Ultimately, the COIs and stopping the trial early increases my skepticism around this publication.

4. Definition of the Primary Outcome: The authors defined their primary outcome with three parts:

  •  A change in hematoma volume of 20% or less (excellent efficacy) or 35% or less (good efficacy) within 12 hours of baseline
  • NIHSS score increase less than 7 points at 12 hours
  • Receipt of no rescue therapies (including andexanet, PCC, or surgery) within 3 to 12 hours after randomization

 While the primary outcome was statistically significant, when broken down into the components, only the hematoma volume change ≤ 35% was significant; the other two components were not.  These results mirror the previous ANNEXA-4 trial where receipt of a DOAC reversal agent did indeed reduce hematoma expansion in the setting of DOAC-induced coagulopathy.  However, the patient-centred subcomponents (NIHSS change, need for rescue therapy) did not seem to change.

5. Disease-Oriented Outcome (Hematoma Volume): The median hematoma volumes in this trial were 10.5 mL (4.1 – 24.9) in the andexanet group and 9.0 mL (3.1 – 22.8) in the usual care group. These are relatively small hemorrhages, with a low risk of significant neurologic decline or poor functional outcome. In other words, it is unlikely this small DOO will result in an important POO.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree that andexanet alfa does prevent the expansion of the hemorrhage, but this does not translate into true patient-centred outcomes such as improved survival or less neurologic disability.  There is also a real concern for increased thrombotic events when using andexanet alfa.

SGEM Bottom Line: The routine use of andexanet alfa in the management of intracranial hemorrhage patients on factor Xa-inhibitors cannot be recommended at this time.

Case Resolution: Your hospital does not have andexanet alfa on the formulary, so you administer the appropriate dose of 4-factor PCC.  The patient was admitted to the neurointensive care unit, and his repeat CT scan was unchanged.

Dr. Vasisht Srinivasan

Clinical Application: The potential benefit of this drug is a disease-oriented outcome (DOO) and not a patient-oriented outcome (POO). There was also potential harm with a statistically significant increase in thrombotic events. Add that to the price of this drug and it does not look like a superior option to PCC.

What Do I Tell the Patient?  You are having a stroke – this is the kind that is caused by bleeding in the brain.  Because you are on blood thinners, you need medication to reverse the actions of those medications so you can form blood clots to stop the bleeding.  There are several choices based on the medication that you take and neither one seems to be dramatically better or worse than the other.  We will be giving you the one we use at this hospital now.

 Keener Kontest: Last week’s winner was Dr. Steven Stelts from New Zealand. He knew the Olympic flag has five rings representing the five inhabited continents of the world: Africa, the Americas, Asia, Europe, and Oceania.

Listen to the SGEM podcast for this week’s question. If you know, then send an email to thesgem@gmail.com with “keener” in the subject line. The first correct answer will receive a shoutout on the next SGEM episode.  

Other FOAMed:

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

  1. Connolly et al; ANNEXA-4 Investigators. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. NEJM 2019
  2. Smith MN, Deloney L, Carter C, Weant KA, Eriksson EA. Safety, efficacy, and cost of four-factor prothrombin complex concentrate (4F-PCC) in patients with factor Xa inhibitor-related bleeding: a retrospective study. J Thromb Thrombolysis. 2019 Aug;48(2):250-255. doi: 10.1007/s11239-019-01846-5. PMID: 30941571.
  3. Pham H, Medford WG, Horst S, Levesque M, Ragoonanan D, Price C, Colbassani H, Piper K, Chastain K. Andexanet alfa versus four-factor prothrombin complex concentrate for the reversal of apixaban- or rivaroxaban-associated intracranial hemorrhages. Am J Emerg Med. 2022 May;55:38-44. doi: 10.1016/j.ajem.2022.02.029. Epub 2022 Feb 24. PMID: 35272069.
  4. Montori et al. Randomized trials stopped early for benefit: a systematic review. JAMA. 2005
  5. Mueller PS, Montori VM, Bassler D, Koenig BA, Guyatt GH. Ethical issues in stopping randomized trials early because of apparent benefit. Ann Intern Med. 2007 Jun
  6. Tyson, J.E., Pedroza, C., Wallace, D. et al. Stopping guidelines for an effectiveness trial: what should the protocol specify?. Trials 17, 240 (2016)