Tag Archives: anticoagulation

Complications, Pharmacy

Direct Oral Anticoagulant (DOAC) Reversal: Part 2

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In the previous post, I reviewed some basic information on DOAC reversal. Five years ago, it was costly and questionably effective. So what has happened in the meantime?

In this post, I’ll review a big trial the pharma company was excited about and make a few comments.

ANNEXA-I Study

This study sought to evaluate the hemostatic effect of Andexanet administration in patients taking a Factor Xa inhibitor who suffered an intracranial hemorrhage.

Key points in this study:

  • It was a five-year, multicenter, randomized controlled trial
  • Subjects had to have taken their medication within 15 hours of the event, had an intracranial hemorrhage identified by CT within 12 hours of symptoms, and randomized in the study within two hours after the scan
  • There were 263 patients reversed with Andexanet and 267 with “usual care,” which was not clearly defined aside from administration of prothrombin complex concentrate (PCC)
  • Traumatic ICH was only present in about 13% of subjects, and the average volume was about 10 mL. Most were intracerebral hemorrhages (90%), with 5% or less being subdural hematomas.
  • Andexanet treatment was associated with increased “hemostatic efficacy,” a combination variable consisting of volume change, change in NIH Stroke Scale score, and no need for rescue therapy within 12 hours.   There was also decreased hematoma volume change by 3.8mm (12%), an increased number of thrombotic events (10% vs. 6%), and an increased number of ischemic strokes (6.5% vs. 1.5%) at 30 days. There was no difference in deaths at 30 days.
  • Hemostatic efficacy was highest in intracerebral hemorrhages and nearly ineffective for subdural hematomas
  • Hemostatic efficacy was significantly higher than that of patients who received PCC in the “usual care” arm, but it was no better than usual care without PCC (?)

Bottom line: Wow! That’s a lot of numbers. The company was excited because the trial was stopped early due to “superior [hemostatic] efficacy vs usual care.” Basically, what they are saying is that the combination of hematoma size, stroke scale, and lack of need for other rescue therapy was significantly lower in patients treated with andexanet alfa. 

But is this meaningful in trauma? There are several issues, IMHO:

  • The study was not powered to detect mortality or functional outcome differences, which is what we trauma people are really interested in
  • The primary outcome (hemostatic efficacy) was powered mainly by hematoma size change, which is not of any clear clinical significance
  • There were some shenanigans from company involvement in the study design, with several protocol amendments that occurred
  • It was not clear what “usual care” consisted of other than PCC administration in some patients
  • There was no information on costs

In my next post, I’ll cite several systemic reviews and meta-analyses to come to some final conclusions about this drug.

Reference: Andexanet for factor xa Inhibitor–Associated acute intracerebral hemorrhage. N Engl J Med. 2024;390(19):1745-1755.

Pharmacy

Direct Oral Anticoagulant (DOAC) Reversal: Part 1

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A new class of anticoagulants, the direct oral anticoagulants (DOACs), were introduced in 2010.  I started writing about them more than five years ago and was initially pessimistic about their safety profile in patients with head injuries. However, reversal agents and/or protocols were introduced, and the literature has borne out the fact that they appear to be safer than the old stand-by warfarin.

The most recent DOAC reversal agent, Andexxa (andexanet alfa), was approved in 2018. Today, I will republish a post on this agent five years ago and a year after the FDA approved it.  In my next post, I’ll refresh and update the trial data and cost, and review several systemic reviews with meta-analyses to come up with a consensus on its usefulness.

Here’s the repost:

Two classes of direct oral anticoagulant drugs (DOACs) are currently available: direct thrombin and Factor Xa inhibitors. Andexxa was designed to reverse the latter by providing a lookalike of Factor Xa to selectively bind to apixaban (Eliquis) and rivaroxaban (Xarelto).

The Austrian consensus paper I previously discussed recommended giving Andexxa to patients taking apixaban or rivaroxaban if it was not possible to show that the drugs were non-therapeutic. This means that reversal should be considered if your lab could not measure anti-Factor Xa levels promptly and the patient was known to be taking one of these agents.

Sounds cut and dried, right? Your patient is taking a Factor Xa inhibitor, and they are bleeding, so give the reversal agent. Unfortunately, it’s much more complicated than that.

  • The half-life of Andexxa is much shorter than that of the drugs it reverses. The reversal effect of Andexxa begins to wear off two hours after administration and is gone by four hours. On the other hand, the half-life of rivaroxaban is 10+ hours in the elderly. The half-life of apixaban is even longer, 12 hours. This means that it is likely that multiple doses of Andexxa would be necessary to maintain reversal.
  • There are no studies comparing the use of Andexxa with the current standard of care (prothrombin complex concentrate, PCC). The ANNEXA-4 study tried to do this. It was a single-arm observational study with 352 subjects. These patients were given Andexxa if major bleeding occurred within 18 hours of their DOAC dose. Two-thirds of the patients had intracranial bleeding. All were given a bolus followed by a two-hour drip. All showed dramatic drops in anti-Factor Xa levels, and 82% of patients had good or excellent hemorrhage control. However, 15% died, and 10% developed thrombotic complications.
  • The FDA clinical reviewers recommended against approval due to the lack of evidence for clinical efficacy. The director for the Office of Tissues and Advanced Therapies overruled the reviewers and allowed approval until a definitive study was completed. So far, there have been no justifiable claims that Andexxa is superior to PCC.
  • To be fair, PCC has not been compared to placebo either. So, we don’t really know how useful it is when treating bleeding after DOAC administration.
  • Andexxa is very expensive. Old literature showed a single dose price of $49,500, which has been revised downward. Effective October 2019, Medicare agreed to reimburse a hospital about $18,000 for Andexxa over and above the DRG for the patient’s care. Remember, two doses may be needed due to the long half-life of the Factor Xa inhibitors. This comes to about $36,000, which is much higher than the cost for PCC (about $4,000).

Bottom line: Any hospital considering adding Andexxa to their formulary should pay attention to all the factors listed above and do the math for themselves. Given the growing number of patients placed on DOACs, the financial and clinical impact will continue to grow. Is the cost and risk of this therapy justified by the meager clinical efficacy data available?

References:

  1. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. NEJM 380(14):1326-1335, 2019.
  2. Key Points to Consider When Evaluating Andexxa for Formulary Addition. Neurocrit Care epub ahead of print, 22 Oct 2019.
Pharmacy

Best Of EAST #4: 4-Factor PCC vs Andexanet Alfa For Factor Xa Inhibitor Reversal

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Falls are by far the most common mechanism of injuries in US trauma centers these days. They typically occur in elderly patients, and a growing number are on some type of oral anticoagulant for their medical conditions. And the number of these patients who are taking a DOAC (direct thrombin inhibitor or factor Xa antagonist) is rising quickly.

Unfortunately, most of the DOACs do not have good reversal agents, and they are very, very expensive. Specifically, Andexanet Alfa, the antidote for rivaroxaban and apixaban used to cost in excess of $50,000 per dose. This has come down over time to “only” $22,000 per dose. Unfortunately, the half-life is much shorter than the agent it is neutralizing, frequently requiring two doses. And the kicker is that there are no studies definitively showing that Andexanet Alfa improves mortality when used for CNS hemorrhage.

Prothrombin complex concentrate (PCC) has been used for reversal of these agents as well. Its efficacy is also not well known. The group at George Washington University is presenting an abstract comparing it against Andexanet Alfa (AA) for reversal of either of the Factor Xa inhibitors (rivaroxaban, apixaban). They performed a multicenter study involving 10 trauma centers. The endpoints studied were number of transfusions, mortality, and ICU length of stay.

Here are the factoids:

  • From a total of 263 patients, 77 received AA and 186 received PCC
  • Only 4% of patients received a second dose of AA despite its short half-life
  • There was no significant difference in the number of PRBCs transfused
  • The authors stated that the mortality was significantly lower with PCC but the p value in the data table provided was = 0.05
  • They also stated that the ICU LOS was significantly lower with PCC (1.2 vs 1.5 days, p = 0.04)

The authors concluded that PCC is non-inferior to AA for reversal in bleeding trauma patients. They recommended a randomized study be done.

Bottom line: The first thing for you to know is that I have never been impressed with the data on Andexanet Alfa. Which means I have to be very careful and aware of my own cognitive bias. In practice, this means I can’t just look at the study title or abstract and be happy that it meets my confirmation bias. I have to make a conscious effort to critically read the paper or abstract and see if it really does mean what I want it to mean, or if I need to change my opinion.

This abstract doesn’t really satisfy my confirmation bias. The title states that PCC is not inferior to AA. I would certainly like to believe that. But in order to safely say that, it is vitally important that a power analysis is performed to ensure that enough patients are present in both treatment groups to confidently state that there was no difference. If the number of patients is too small, significance can’t be detected and non-inferiority cannot be confirmed.

The body of the abstract claims that mortality was significantly lower in the PCC group, although the table states that the p value was 0.05, which technically is not significant. The difference in mortality numbers is impressive (PCC mortality 20% vs 32% for AA) so why the significance issue?

And one note about significance. Be careful not to conflate statistical significance with real-life significance. ICU length of stay in this study was statistically significantly shorter in the PCC group (1.2 vs 1.5 days) but I doubt that a difference of 7 hours in the ICU is clinically relevant.

Here are my questions for the authors and presenter:

  • Did you have enough patients in the study to assure that the PCC treatment was actually non-inferior? Please show us your power analysis.
  • What were the inclusion criteria for the study? This will help us understand the patient group better. Were these primarily head bleeds, actual external or intra-cavity hemorrhage?
  • Please clarify the significance claim for mortality. The raw percentages are impressively different, but the P value is not significant.
  • Could the low rate of administering a second dose of AA have influenced the outcomes? As mentioned above, the half-life of the antidote is much shorter than that of the DOAC. Perhaps giving a second dose is actually needed and could have moved the results in favor of AA.

This is a thought-provoking abstract for me. Let’s see if you can either confirm or refute my opinion on AA!

Reference: 4-FACTOR PROTHROMBIN COMPLEX CONCENTRATE IS NOT INFERIOR TO ANDEXANET ALFA FOR THE REVERSAL OF FACTOR XA INHIBITORS: AN EAST MULTICENTER STUDY. EAST 25th ASA, oral abstract #15.

Abstracts, CNS, Complications

Best Of EAST #8: Early vs Late Full Anticoagulation In TBI

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Trauma professionals are always reluctant to anticoagulate TBI patients with demonstrated blood in their head. In recent years, we’ve become more comfortable providing prophylactic doses of low molecular weight heparin after a suitable period. This is typically 24-48 hours after a stable head CT in patients with select types of intracranial hemorrhage (ICH) who are at increased risk for venous thromboembolism.

But what about therapeutic dose anticoagulation in these patients? Let’s say that you have a patient with ICH who has developed a significant pulmonary embolism (PE)? Is is safe to give full dose anticoagulation? And if so, when?

The group at Shock Trauma in Baltimore attempted to answer this in one of the EAST Quick Shot presentations scheduled for this week. The did a retrospective review of 4.5 years of their own data on these patients. They specifically selected patients who had both ICH and PE and compared those who received full anticoagulation within 7 days of injury vs those who were dosed after 7 days. Outcomes studied included death, interventions for worsening ICH, and pulmonary complications.

Here are the factoids:

  • A total of 50 patients had both ICH and PE, but only the 46 who received therapeutic anticoagulation were analyzed
  • 19 patients (41%) received early anticoagulation, and 27 received it late (59%)
  • There were 4 deaths in the early group (2 from the PE, 1 from multi-system organ failure, 1 from the TBI) vs none in the late group, and this was statistically significant
  • 3 patients in the early group (18%) vs 2 in the late group (7%) had an increase in their ICH (p=0.3), and none required intervention

The authors concluded that their study failed to show any instances of clinically significant progression of ICH after anticoagulation, and that it is not associated with worse outcomes, even if started early. Thus they recommend that ICH should not preclude full anticoagulation, even early after injury.

My comment: I always say that you shouldn’t let one paper change your practice. Even a really good one. In order to ensure that you are providing the best care, more work must always be done to confirm (or refute) the findings of any provocative research. And this little Quick Shot, with little opportunity for questions from the audience, should definitely not change it!

The major issues to consider here are common ones: 

  • This was a retrospective study and it does not appear that any guideline was followed to determine who got early vs late anticoagulation. So who knows what kind of selection bias was occurring and how the surgeon decided to prescribe anticoagulation? It’s very possible that patients with a “bad CT” were put into the late group, and the not so bad ones in the early group. This would bias the results toward better outcomes in the early anticoagulation group.
  • It’s also a very small study that is extremely underpowered. The authors comment on the fact that the outcomes of the early group were not worse than the late group. However, looking at their sample size (46) shows that they would only be able to show differences if they were about 5x worse in the early group. They would realistically need about 350 total patients to truly show that the groups behaved the same. Their small numbers also preclude saying that there were no ICH progressions. There very well could have been if 300 more patients were added to the series.
  • And isn’t death a significant outcome? The authors indicated that 2 of the 4 deaths were a result of the PE. Yet there was a significant association (p=0.02) of increased death in the early anticoagulation patients that can’t be discounted.

Bottom line: It’s way too early to consider giving early anticoagulation to patients with ICH and pulmonary embolism. It may very well be shown to be acceptable, eventually. But not yet. And a much bigger prospective study will be required to confirm it.

Reference: Therapeutic anticoagulation in patients with traumatic brain injuries and pulmonary emboli. EAST Annual Assembly Quick Shot #7, 2020.

Pharmacy

Reversing Direct Oral Anticoagulants With Andexxa

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I just finished a summary of the Australian consensus paper regarding anticoagulants (and anti-platelet agents) in patients with hemorrhagic TBI. One of the issues addressed was reversal of these agents. Today I’m going to provide more specific information on one of the new reversal agents, Andexxa (recombinant Factor Xa, inactivated-zhzo).

First, maybe someone can help me here. What does zhzo mean? I’ve done a deep dive including a review of the FDA filings, and still can’t figure out what this is. I have a hard enough time with the thousands of something-umab monoclonal antibody products out there. Now we’re adding on a bunch of z’s to the end of drug names?

There are currently two classes of direct oral anticoagulant drugs (DOACs) available, direct thrombin inhibitors and Factor Xa inhibitors. Andexxa was designed to reverse the latter by providing a lookalike of Factor Xa to selectively bind to apixaban (Eliquis) and rivaroxaban (Xarelto).

The Austrian consensus paper I previously discussed recommended giving Andexxa in patients taking apixaban or rivaroxaban if it was not possible to show that the drugs were non-therapeutic. This means that if your lab could not measure anti-Factor Xa levels in a timely manner and the patient was known to be taking one of these agents, reversal should be considered.

Sounds cut and dried, right? Your patient is taking a Factor Xa inhibitor and they are bleeding, so give the reversal agent. Unfortunately, it’s much more complicated than that.

  • The half-life of Andexxa is much shorter than that of the drugs it reverses. The reversal effect of Andexxa begins to wear off two hours after administration, and is gone by four hours. On the other hand, the half life of rivaroxaban is 10+ hours in the elderly. The half-life of apixaban is even longer, 12 hours. This means that it is likely that multiple doses of Andexxa would be necessary to maintain reversal.
  • There are no studies comparing use of Andexxa with the current standard of care (prothrombin complex concentrate, PCC). The ANNEXA-4 study tried to do this. It was a single-arm observational study with 352 subjects. These patients were given Andexxa if major bleeding occurred within 18 hours of their DOAC dose. Two thirds of the patients had intracranial bleeding. All were given a bolus followed by a two hour drip. All showed dramatic drops in anti-Factor Xa levels, and 82% of patients had good or excellent control of hemorrhage. However, 15% died and 10% developed thrombotic complications.
  • The FDA clinical reviewers recommended against approval due to the lack of evidence for clinical efficacy. The director for the Office of Tissues and Advanced Therapies overruled the reviewers and allowed approval until such time a definitive study was completed. So far there have been no justifiable claims that Andexxa is superior to PCC.
  • To be fair, PCC has not been compared to placebo either. So we don’t really know how useful it is when treating bleeding after DOAC administration.
  • Andexxa is very expensive. Old literature showed a single dose price of $49,500 but this has been revised downward. Effective in October 2019, Medicare agreed to reimburse a hospital about $18,000 for Andexxa over and above the DRG for the patient’s care. Remember, due to the half life of the Factor Xa inhibitors, two doses may be needed. This comes to about $36,000, which is much higher than the cost for PCC (about $4,000).

Bottom line: Any hospital considering adding Andexxa to their formulary should pay attention to all of the factors listed above and do the math for themselves. Given the growing number of patients being placed on DOACs, the financial and clinical impact will continue to grow. Is the cost and risk of this therapy justified by the meager clinical efficacy data available?

References:

  1. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. NEJM 380(14):1326-1335, 2019.
  2. Key Points to Consider When Evaluating Andexxa for Formulary Addition. Neurocrit Care epub ahead of print, 22 Oct 2019.