Noreversaban?

05 Nov
November 5, 2015

Noreversaban?We have written about the new Non-Vitamin K Oral Anti Coagulants (NOACs). Many have jokingly referred to them as the “Noreversabans.” Taking these drugs is a high risk, high reward type of decision. While we recognize the benefits of quick anticoagulation without a need to bridge, as well as being more stable and having less interactions than Coumadin, these drugs are dangerous with serious bleeding concerns. Recently, Dabigatran was likened to “Dancing with the Devil”. For those of us in EM and Critical Care practice, there are no good options for reversing these agents. Once taken there is no turning back… until now?

There is a game changing drug, Idarucizumab, now FDA approved as of October 16, 2015 for the reversal of the new NOAC Dabigatran. Lets take a look at the drug, its road to approval, and what evidence we are dealing with to date. At the end, we will give you a skeptical, evidence based evaluation and balance it with a humble commitment to how we would move forward given the data in true REBEL style.

Idarucizumab was developed by Boehringer Ingeleim. Yes, the same company that brought us Dabigatran, its intended target. They are trying to tame the very beast they created. Its kinda’ like the dentist who sells candy out of the candy shop beside his or her dental practice that will then gladly treat your cavity. Quite a lucrative business model? It is being marketed with the trade name “Praxbind “ to be used for reversal of Pradaxa, the brand name for Dabigatran. Idarucizumab is a direct antibody to Dabigatran, which renders it inactive. This antibody is some 300 times more attractive (binding affinity) to Dabigatran than thrombin, Dabigatran’s intended clinical target for anticoagulation.

This drug was first tested out on 236 healthy volunteers that were not taking Dabigatran in two studies and found to have negligible side effects [1][2]. It was then given to 47 healthy male volunteers who were first loaded with Dabigatran and then given the reversal agent Idarucizumab. They monitored a whole host of blood and drug levels and found that Idarucizumab reversed the most meaningful lab values in minutes, publishing results in the Lancet this summer [3].

Next, the RE-VERSE AD study by Pollack et al, started enrolling patients in an ongoing, multicenter, international, prospective cohort study [4]. They published preliminary, early results this summer in NEJM after enrolling 90 patients (average age of 76 years) who were taking Dabigatran mostly for A-fib (86/90) and divided them up into two groups. The primary endpoint was reversal at 4hrs post infusion using Dilute Thrombin Time and Ecarin Clotting Time and a secondary outcome of clinical hemostasis.

They divided the 90 patients up into 51 patients in Group A with life threatening bleeds (the ones we care most about) and 39 in Group B with non life threatening bleeds. Of the 51 patients with life threatening bleeds, they were only able to assess laboratory coagulation parameters in 40 patients (11 patients, at the point of initial inclusion, had sub therapeutic Dabigatran levels). At 4 hrs, 100% of patients with life threatening bleeds were reversed by Idarucizumab and most had normalization of lab parameters within 30 minutes.

There were only 35 of 51 patients that could undergo evaluation for ongoing clinical bleeding, the secondary endpoint. Many had intracranial hemorrhage, retroperitoneal or GI bleeding to name a few. They could not do serial hourly CTs or endoscopy to detect real time cessation of bleeding and therefore could only comment on clinical bleeding cessation in 35 total patients. This is really what we care about. In this group it took on average 11.4 hrs to reach clinical hemostasis.

It should be noted that the half life of Dabigatran is 12-14 hrs in patients with normal renal function. 11 hours is much longer than we would hope to see an “antidote” work for hemostasis. Would they have bled as long without Dabigatran on board? Would patients on therapeutic Dabigatran have bled as long without administering the proposed antidote Idarucizumab? This study did not answer these questions.

Of the 51 life threating bleeding patients, nine died, three of them from bleeding. The others died of forms of respiratory failure and one of “general health deterioration” (whatever that means). Since there was no comparison group, the results cannot be judged to be equal or superior to other existing expert recommendations that currently exist such as 4 factor PCC, aPCC (FEIBA) or placebo [5][6].

Complications from this reversal agent were reported to be low. The data from the healthy volunteer study seemed to show a low side effect profile with no patients having any serious adverse events from Idarucizumab infusion in any of the studies. Post reversal thrombosis occurred in five patients.

The Good:

  1. The hypothesis of an antibody binding antidote seems to be philosophically safer than trying to balance anticoagulation drugs with the infusion of hypercoagulable therapies. Hypothetically speaking, although not formally proven, this antibody may have less thrombotic complications than more thrombotic reversal options of coagulation complex concentrates such as PCC and aPCC.
  2. We like that it was done in actual patients in the population we are interested in studying.
  3. Being a multicenter and international study is good, and adds a component of diversity which makes the results more generalizable.
  4. The side effects of Idarucizumab seem to be low in healthy volunteers and in the cohort of actively bleeding patients.

The Bad:

  1. Significant bias. The same company who makes the drug Dabigatran is also the same company producing the proposed antidote Idarucizumab. The Glund and Pollack studies were industry sponsored and conducted by investigators with a myriad of conflicts of interest.
  2. This study is vastly underpowered. The small numbers of enrolled patients is hard to create the level of evidence that would warrant a major change in clinical practice. If we only look at the life threatening bleeding patients, we are left with 51 patients. Then remove the 16 that they were unable to assess clinical bleeding, we are left with 35 patients. These are small numbers. More enrolled patients would be nice to see.
  3. This study was a prospective cohort study that was not blinded and not randomized or compared with other treatment modalities to see if in fact the proposed therapy under question is superior to other therapies or placebo.
  4. 11 patients had sub therapeutic levels of Dabigatran upon arrival that should have been excluded from the study.  Including these patients could falsely over-inflate the results of the study.

The Truth:

We can say that Idarucizumab hypothetically shows promise as being a potentially good strategy for reversing Dabigatran in patients requiring reversal. Based on the existing limited data, it seems safe to administer to patients. Reversal of Dabigatran by Idarucizumab must be studied in larger numbers of patients by unbiased investigators and in comparison to other competing strategies recommended by expert panels before it can be deemed the hands down reversal agent of choice for Dabigatran. Further work needs to be done to bring the level of evidence beyond what we judge to be level C.  Based on this level of evidence we can only give this a IIb recommendation. Then again, the competing strategies and evidence for management of the life threatening bleeding patient on Dabigatran are equally if not less convincing and promising than Idarucizumab.

Clinical Bottom Line: For now, if we had to choose to give this medicine to a loved one who was needing emergent reversal for a serious life threatening bleed, we are between a rock and a hard place. We may be forced to use this therapy despite limited evidence at this time.

References:

  1. Glund S, Moschetti V, Norris S, et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost 2015;113:943-51. PMID: 25789661
  2. Glund S, Stangier J, Schmohl M, et al. Idarucizumab, a specific antidote for dabigatran: immediate, complete and sustained reversal of dabigatran induced anticoagulation in elderly and renally impaired subjects. Blood 2014;124:344. [Abstract]
  3. Glund S, Stangier J, Schmohl M, et al.Safety, tolerability, and efficacy of Idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet 2015 June 15. PMID: 26088268
  4. Pollack CV et al. Idarucizumab for Dabigatran Reversal. N Engl J Med. 2015 Aug 6;373(6):511-20. doi: 10.1056/NEJMoa1502000. Epub 2015 Jun 22. PMID: 26095746
  5. Siegal DM, Cuker A (2013) Reversal of novel oral anticoagulants in patients with major bleeding. J Thromb Thrombolysis 35(3): 391–398. PMID: 23389753
  6. Siegal DM. Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents. J Thromb Thrombolysis. 2015 Apr;39(3):395-402. doi: 10.1007/s11239-015-1167-9. PMID: 25586208

For More on This Topic Checkout:

  1. Ryan Radecki at EMLit of Note: Let’s Reverse – Dabigatran
  2. David Slessor at The Bottom Line: Idarucizumab for Dabigatran Reversal
  3. Ken Milne at The SGEM: SGEM#139 – One Thing Leads to Another – Idarucizumab for Dabigatran Reversal?
  4. Dan Silva at CORE EM: Idarucizumab for Reversal of Dabigatran

Post Peer Reviewed By: Matt Astin (Twitter: @mastinmd)

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Scott Wieters

REBEL EM Guest Contributor and Author
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8 replies
  1. Cole says:

    Even the generic name for Praxbind pokes fun at prescribers of dabigatran, idarucizumab [can be] pronounced “I-Dare-You-Sissy-Mab”, essentially taunting anyone who prescribes dabigatran. I see Praxbind being useful for quasi-urgent ortho procedures, grandma broke hip situations; because it’d be pretty useless in someone experiencing serious hemorrhaging (I’d still give it, but you’d need something more definitive to stop the bleeding – simply removing dabigatran isn’t enough). And I love how your post calls even that into question.
    Sell the poison and the “antidote”, great marketing plan if it wasn’t so insidious.
    Maybe andexanet alfa will give us more of what we need.

    Reply
  2. Jason W. Wilson, MD, FAAEM says:

    Hello Dr. Wieters-

    I wanted to provide a few thoughts I had in response to not just your blog post, but also a few more related blog posts that have appeared following the FDA approval of the dabigatran reversal agent. I appreciate and enjoy the R.E.B.E.L. EM blog. I am involved in anticoagulation research every day and these are just some thoughts I had from both research experiences as well as from patient/clinical experiences.

    Idarucizumab [PRAXBIND] is a medication that will likely be used most by emergency medicine physicians and surgeons (although, I should say, used or potentially used, because, as we will see below, many scenarios do not actually end up requiring reversal). However, the drug is very new and there will be a lot of questions as emergency medicine physicians and surgeons begin to get a grasp on the mechanism, drug effects/side effects and gain a generalized comfort level with the medication. The bottom line is that more and more patients will be older and have atrial fibrillation in the coming years, requiring anticoagulation.

    There have been a number of recent blog posts (1,2,3), which is expected and appropriate, in the EM landscape, that have reviewed Idarucizumab. I wanted to take a few minutes to contribute to that discussion and to also clear up a couple of potential fallacies in the interpretation of the data by these blog authors and community. Again, this is not an argument against a healthy discussion of a new drug for use in emergency medicine and the skepticism of a scientific lens is encouraged.

    The increased safety profile and improved time in therapeutic range make any of the NOACs superior to VKA. Remember that even in controlled study environments, patients only achieve anticoagulation with Coumadin at best 60% of the time – and probably much less in our patient population as many of my patients on Coumadin have an INR < 2 or are actually supertherapeutic (think about your own clinical ED practice). Sometimes we forget as EM physicians (due to our own biases that occur after we see a patient die in front of us from a spontaneous ICH) that the probability of a devastating stroke in a patient with a high CHADS2 score is overwhelmingly a poorer option then the < 2% chance of a bleed (that only has a small percentage chance of that 2% to actually be life threatening as most of these bleeds are GI bleeds on all of the NOACs). In addition, now that the labels across the NOACs have been harmonized, there is a true decrease seen in the chance for a patient to experience a life threatening intracranial bleed (RR < 1 and CI 5%). However, I have no idea if this is even attributable to the drug (Do 5% of all patients get headaches?) and I don’t think this adverse event is significantly dangerous. In RE-VERSE AD other associated adverse events have been hypokalemia, constipation, delirium and pyrexia. But remember – these are SICK ICU PATIENTS! What ICU patients don’t have these associated signs? In a study like RE-VERSE AD, the PI is required to report any type of symptom development after receipt of the study drug, even if it is unlikely to have been caused by that drug.

    I like the fact that the drug does not appear to hurt my patients. Now, I still don’t know that it will help my patient with the life threatening bleed, but it certainly doesn’t hurt to at least get the dabigatran portion of that bleed out of the equation – especially in trauma or cases where I want to convince a surgeon to take a patient to the OR! I at least know that the drug does what it is designed to do (lower levels of dabigatran and coagulation parameters including aPTT).

    I will say though, the results from Group B (patients who needed an emergent surgery) are most intriguing as they do hint at a patient safety outcome. In that group, the operating surgeon was asked, “Did the patient have a normal amount of bleeding or the amount of bleeding you would expect in an anticoagulated patient?”. The surgeons stated that 92% of the patients had normal levels of intraoperative bleeding. There are some arguments that the Lancet and NEJM studies are biased because the study is industry sponsored and because many of the investigators also serve as consultants for Boehringer-Ingelheim. I will discuss the flaws in making that assumption below but, either way, the surgeons were not part of the study and were not involved in any of the funding or sponsorship and provided a neutral interpretation, with a patient oriented outcome, of the drug effects.

    Also, the analysis of patients in the interim analysis only included the patients that had a therapeutic level of dabigatran at the time of enrollment. A couple of the blogs above criticized the inclusion of patients without therapeutic dabigatran levels but I do think this criticism, perhaps, results from a misunderstanding about that inclusion criteria and is also unfair to the real-time practicing emergency physician. Meaning, while the patients were allowed entry into the study based on clinical decision, patients with levels of dabigatran lower than the therapeutic range were excluded from analysis of the the effects of Idarucizumab. This mimics our world – we don’t know the patient’s dabigatran level (for better or worse – that is a whole separate conversation) – and most of use would want to reverse a patient on dabigatran with a life threatening bleed or to help get them to the OR emergently without waiting for a, likely send-off, test to come back measuring dabigatran level.

    I was the PI on two large bleed registry studies at our site and we have looked at essentially every bleed that came through the ED or occurred in the hospital among the NOAC patient population since their inception. There are two things that are striking about these bleeds: 1. Most of the patients that developed a bleed also had a concomitant illness occurring at the same time (sepsis, AKI, etc) and 2. Most of the patients that developed a bleed did not have a life threatening bleed that would require reversal. I think we have overestimated the dangers of these drugs compared to other medications we prescribe for some time and the improved safety profile of any of the NOACs compared to a VKA is an improvement for our patients.

    I am a practicing emergency medicine physician at a busy Level 1 trauma center with an EM residency program. I see sick patients just like you. I am also the site PI for the RE-VERSE AD study and a paid consultant for Boehringer (as well as their competitor, Janssen). I think sometimes it is easy to see that something is industry sponsored and forget this does not define a built in bias. Many of the investigators working on these studies have a passion for anticoagulation and the NOACs in general. There is a self-selecting set of people who follows the literature closely and establishes themselves, based on knowledge and patient experiences, as experts in the developing field. Most of those folks are involved with multiple competing brands of NOACs as the interest is in the underlying science and the progression of patient care. One of the blogs talked about above criticizes the NEJM for using an editorial from a physician that receives speaking fees from Boehringer. However, the same article goes on to state that the physician is paid by multiple companies and is an investigator on both the RE-VERSE AD study and the Portola Study (the competing Factor Xa inhibitor). Where is the bias if the investigator is working on reversal of all anticoagulants? Furthermore, who would you like to have fund these studies? Unfortunately, NIH does not have the money or incentive to fund numerous prospective, well-powered, large randomized control trials. Sure, we need to minimize bias, but these studies, with sick dying patients in front of us, do not have much room for bias as the investigators are not the providers that placed the patient on dabigatran to begin with and, any reasonable prudent emergency medicine physician also facing a dying bleeding patient would reach for a reversal agent with a reassuring safety profile.

    We should continue to apply the natural skepticism of scientific thinking but we should also allow the science to speak past our biases and fears of a new medication. Certainly, I am glad that we have expanded the target sample size and feel reassured that the RE-VERSE AD study will continue even with the commercially available product on shelves worldwide.

    1. Wieters, Scott. Noreversaban? R.E.B.E.L. EM. http://rebelem.com/noreversaban/
    2. Radecki, Ryan. Let’s Reverse: Dabigatran. http://www.emlitofnote.com/2015/06/lets-reverse-dabigatran.html
    3. Slessor, David. The Bottom Line. http://www.wessexics.com/The_Bottom_Line/Review/index.php?id=8687613125065193679
    4. Glund et al., 2015. Lancet. Safety, tolerability and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60732-2/abstract
    5. Pollock et al., 2015. NEJM. Idarucizumab for dabigatran reversal. http://www.nejm.org/doi/full/10.1056/NEJMoa1502000

    Thank you for all your hard work and the chance to post this reply!

    -Jason

    Reply
    • Salim Rezaie says:

      Hello Jason,
      TY so much for reading and leaving a comment on the blog. We encourage and enjoy conversation, because at the end of the day, all we are trying to do is improve patient care.
      In regards to your first point, I agree from a patient prevention standpoint NOACs are nice because they have great time to therapeutic range and safety profiles. But on the other hand when these patients bleed (even if <2%), we still don't truly have a great reversal agent.
      I am not sure I would say that the drug doesn't hurt our patients. We don't really know that to be a fact as the studies didn't really have a comparison arm. Also we are still really only talking about 35 patients where clinical endpoints were followed. Regardless of the fact the population was small, we have to be very careful looking at the results of studies looking at surrogate endpoints (i.e. lab markers) and saying this is fact in clinical parameters. Maybe its true maybe its not, but I don't think we can say the drug is safe or beneficial with the best current evidence that we have (i.e. What about risk of thrombosis from the medication vs placebo?). As for the surgeons being surveyed, do we know for a fact they were not approached or talked to about the study? Again, maybe they were, maybe they weren't, but that is not explicitly stated in the study.
      Finally, I don't disagree with you that if a study is industry sponsored it has built in bias. I think it makes many of us pay closer attention to methodology and details.
      In the end I don't know that I am a believer in Idarucizumab. Would love to see a comparison study with FEIBA vs Idarucizumab vs Placebo telling me which agent does a better job, with the least amount of harm. I don't have other reversal agents that can reverse Dabigatran in the urgent situation, with high levels of evidence. In this setting even though rare, at this point in time I will consider reaching for the medication if needed, but whether the medication is harmful or makes a clinical difference in patient care is still up in the air at this point in time with the best available evidence in my humble opinion. TY so much for reading and leaving your thoughts. I hope this stirs up some more conversation amongst other readers.

      Salim

      Reply
  3. S Merlaud says:

    Noreversabans ?
    What about Bloodygatran and Intoxabans ?

    Reply

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