Tag Archives: reversal

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, Head

Best of EAST #8: Reversing Antithrombotic Drugs After Severe TBI

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Falls are the most common mechanism of injury at a majority of trauma centers these days. And due to the escalating number of comorbidities in our older population, more and more are taking some kind of anticoagulant or antiplatelet medication. And as all trauma professionals know, falling down and failure to clot do not mix well.

A variety of reversal regimens have been developed, including Vitamin K, plasma or platelet infusion, prothrombin complex concentrate, andexxanet, or idarucizumab depending on the agent. But when it comes to evaluating the efficacy of these agents, there are two important questions that need to be answered:

  1. Does the regimen reverse or neutralize the offending agent?
    and more importantly
  2. Does the regimen have a positive effect, i.e. reduce mortality and/or complications?

This last question has been problematic, especially for the direct oral anticoagulant drugs (DOACs). They are very expensive, but there has been little, if any, evidence that they improve mortality.

A study from the University of Florida at Jacksonville, and sponsored by EAST was performed last year. It was a multi-center, prospective, observational study of data provided by 15 US trauma centers. They collected data on the agents used, reversal attempts, and comorbidities in injured patients taking these drugs, and analyzed for head injury severity and mortality.

Here are the factoids:

  • There were a total of 2913 patients in the study, 46% on aspirin (ASA), 13% taking ASA and a P2Y12 inhibitor (one of the -grels), 11% on warfarin, 4% on ASA + warfarin, 13.5% on a Factor Xa inhibitor, and 6% on a Xa inhibitor + ASA
  • Patients on platelet blockers (P2Y12 inhibitor) had the highest mean ISS at 9
  • Warfarin was associated with a higher abbreviated injury score (AIS) for head, 1.2
  • Controlling for ISS, comorbidities, ISS, and initial SBP, warfarin + ASA had the highest head ISS with an odds ratio of 2.1 (with the lower confidence interval value of 1.19)
  • Reversal of antiplatelet therapy with DDAVP was not successful, with no change in mortality (87% with reversal and 93% without)
  • Reversal of Xa inhibitors with plasma or PCC was also unsuccessful with a mortality of 100% with reversal and 95% without

The authors concluded that reversal attempts for antiplatelet therapy or Factor Xa inhibitors did not decrease mortality, and shared the observation that combination therapies posed the most risk for severity of head injury.

My comments: Remember, the first thing to do is look at the study group. The authors did not share the inclusion or exclusion criteria for the study in the abstract, so we are a little in the dark here.

The next item that makes this study difficult to interpret (and perform) is the fact that nearly a quarter are on combination therapy for their anticoagulation. So even though nearly 3,000 patients were studied, many of the medication subgroups had only a few hundred subjects. The aspirin group was the largest, with 1,338. This makes me wonder if the overall study had the statistical power to find subtle differences in their outcome measures and support the conclusions.

Now have a look at one of the results tables:

In reviewing the demographic data, the concept of statistical significance vs clinical significance quickly comes to mind. Somehow, age, ISS, head AIS, mortality, and SBP are significantly different between some of the groups. Yet if you examine the specific values across most of the rows, there is little difference (e.g SBP ranges from 137 to 147, ISS from 7-9, mortality from 2-7%). These are all clinically identical. The only row that means much to me is the top one telling how many patients are in a group.

Here are my questions for the authors and presenter:

  1. Tell us about the study design, especially the inclusion and exclusion criteria. Were there any? How might this have influenced the study group?
  2. Please comment on your perception of the statistical power of the study, especially with seven groups of patients, each with relatively small numbers.
  3. Do you have information on the variety of reversal agents used? Were there any standards? Could this have contributed to the mortality in some of the groups?
  4. Do you have any clinical recommendations based on your findings? If not, what is the next step in examining this group of patients?

My bottom line is that I’m not sure that this study has the power to show us any significant differences. And looking at the information table and logistic regression results (odds ratio confidence intervals close to 1), I’m not really able to learn anything new from it. I’m hoping to learn a lot from the live presentation!

Reference: EAST MCT: comparison of pre-injury antithrombotic use and reversal strategies among severe TBI patients. EAST 2021, Paper 19.

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.
Laboratory

How Much Plasma Does It Take To Reverse Warfarin?

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For decades, plasma (with vitamin K) was the mainstay for reversing warfarin. Over the past several years, prothrombin complex concentrates (PCC) have made inroads in the management of this problem because of its sheer speed of action.

There are two problems with plasma. First, most hospitals still have only fresh frozen plasma (FFP), and it takes 20-30 minutes to thaw. This adds some up-front time to administration. Then, it takes time to infuse the 250cc or so of volume in each unit. This may be 1 or 2 hours, depending on policy and patient tolerance of a bolus of colloid.

If it always just took one unit of plasma to correct the INR to a desirable range (typically 1.5-1.6), then the whole PCC conversation might be moot. You could potentially have the INR corrected in 30-60 minutes depending on your patient’s cardiovascular system.

But how many does it really take? A group at Eastern Virginia Medical School in Norfolk, VA looked at this problem and tried to come up with a mathematical formula. They examined a year of warfarin reversal data at their hospital. Patients with severe clotting disturbances (advanced cirrhosis, DIC) and those who received additional products (PCC or activated Factor VII) were excluded.

Using data from nearly 1,000 patients, the following formula was derived and validated:

∆ INR = (0.57 ∙ preINR) – 0.72

So a patient with an INR of 3.0 would be expected to show a decrease of 0.99 to about 2.0 after one unit. This formula can be used iteratively to figure out how many units will drop the INR to the goal range.

I don’t know about you, but I hate doing math in the middle of a trauma resuscitation. I need something quick and dirty. A physician from NYU Langone in NYC commented on the article, and derived a nice little table to simplify the process. He calculated the number of plasma units based on some common INR ranges, assuming that the goal was to get it down under 1.5. Here is the table:

Bottom line: This is a nice little piece of information to tuck into your pocket or phone. For patients inside the usual therapeutic values, it will take 2-3 units of plasma to reverse. For your average older human with average comorbidities, expect this to take 4-6 hours, not counting ordering, thawing, and delivery. If my definitions of “life-threatening bleeding” are met (see below), your patient may have significant adverse events during this time frame. So think very seriously about using PCC instead.

Related posts:

Reference: Fresh Frozen Plasma Dosing for Warfarin Reversal: A Practical Formula. Mayo Clin Proc 88(3):244-250, 2013.