Does FEIBA Work for NOACs?

“Maybe”?

The novel oral anticoagulants – dabigatran, rivaroxaban, apixaban, edoxaban – have spread in use quite rapidly. There is weak evidence supporting the use of idarucizumab for emergency reversal of dabigatran, and even weaker evidence regarding the use of adenxanet alfa. Prothrombin concentrate complexes seem to be efficacious for the Factor Xa inhibitors – but what about factor eight inhibitor bypassing agent?

This small case series from Pittsburgh addresses this question in the least helpful fashion: 11 patients and no comparison group. These 11 patients, most of whom were on rivaroxaban, received 20mg/kg of FEIBA for emergency reversal of anticoagulation in the setting of traumatic intracranial hemorrhage. The authors report 6 of these 11 had stable ICH on repeat CT following initial diagnosis, and, therefore, FEIBA is a potentially safe reversal option.

Of course, the full accounting requires us to mention the remainder of patients had radiographic progression of their injuries despite FEIBA. Most injuries were minor and not expected to have elevated 30-day mortality – and, unsurprisingly then, most survived. In the patients demonstrating substantial derangement of laboratory measures of coagulation, most showed profound improvement of the PT following FEIBA administration. Two patients also suffered subsequent thromboembolic events.

So, yes, FEIBA may be a treatment option for the Factor Xa inhibitors – but this hardly supports routine use outside a study setting as these authors seem to be doing.

“Factor Eight Inhibitor Bypassing Agent (FEIBA) for Reversal of Target-Specific Oral Anticoagulants in Life-Threatening Intracranial Bleeding”

https://www.ncbi.nlm.nih.gov/pubmed/28007364

No Guidance for Calf Clots from CACTUS

Treatment evidence regarding venous thromboembolism is not particularly sparse – except what to do about calf VTE. The most robust evidence is three decades old, and of little use for generalizing to modern diagnostic methods and direct oral anticoagulants.

This, then, is the CACTUS trial – a randomized, double-blind, placebo-controlled trial examining the need for treatment of isolated calf DVT with subcutaneous nadroparin. The primary outcome was a composite measure of extension of calf DVT to proximal veins, contralateral DVT, or symptomatic pulmonary embolism. Safety endpoints were bleeding, death, and treatment-related adverse events.

Sadly, this evidence is mostly bereft of guidance. Over the six-year course of this trial, they screened 746 patients and only enrolled 259 – 50% of their goal sample. There were four (3.3%) VTE in the nadroparin group compared with seven (5.4%) in the placebo cohort, and these differences failed to reach statistical significance. Furthermore, clinically significant bleeding occurred in one patient in the nadroparin group, along with one clinically significant adverse medication reaction (heparin-induced thrombocytopenia). Thus, the authors conclude: “Nadroparin was not superior to placebo in reducing the risk of proximal extension or venous thromboembolic events in low-risk outpatients with symptomatic calf DVT, but did increase the risk of bleeding.”

However, half the patients enrolled had deep muscular DVT, further reducing the risk profile of their already grossly underpowered cohort. Thus, the question remains open – and probably the most relevant evidence would come from an adequately powered trial comparing the natural course of disease to both oral antiplatelet agents and direct oral anticoagulants.
“Anticoagulant therapy for symptomatic calf deep vein thrombosis (CACTUS): a randomised, double-blind, placebo-controlled trial”

https://www.ncbi.nlm.nih.gov/pubmed/27836513

Thanks to Tom Deloughery (@bloodman) for his insights!

Which is Safer – Rivaroxaban or Dabigatran (or Neither?)

The world of anticoagulation turned upside-down with dabigatran, and continued with the Factor Xa inhibitors: rivaroxaban, apixaban, and edoxaban. While RE-LY and its ilk showed, in the settings of controlled clinical trials, that these new agents were potentially superior, or at least non-inferior, to warfarin – which is best? Do we have any idea?

Unfortunately, such comparative effectiveness work is sadly lacking, and we are forced to try and glean safety data indirectly following approval. This study pools Medicare beneficiaries using the new agents for stroke prevention in the setting of nonvalvular atrial fibrillation, and attempts to observe “real world” outcomes.

The winner on stroke prevention: rivaroxaban, by a hair. The winner on bleeding: dabigatran, by a long shot, both intra-cranial and extra-cranial. Overall mortality, then, slightly favored dabigatran.

These data are retrospective and tortured by statistical matching methods, so their reliability is hardly bulletproof. What this does raise are more questions about the appropriate usage of these new agents – and further emphasizes the importance of prospectively performed patient-centered effectiveness research.

“Stroke, Bleeding, and Mortality Risks in Elderly Medicare Beneficiaries Treated With Dabigatran or Rivaroxaban for Nonvalvular Atrial Fibrillation”

http://archinte.jamanetwork.com/article.aspx?articleid=2560376

Imprecise Dosing of Liquid Medications

Many parents are overdosing their kids, study says”. Is this true? Are parents poisoning their own children, as the headline implies?

Of course not; this is not in fact a study regarding overdose incidence at all. It is, quite simply, a measurement precision study.

This study involves 2,110 parents randomly assigned to measure doses of liquid medication in various quantities using either a cup, a 0.2mL syringe, or a 0.5mL syringe. Approximately a quarter of parents were >20% off with their measurement, and 2.9% doubled the instructed dose. Taking these results as a surrogate for overdose depends on the therapeutic range for a medication – so, while the headline is not technically incorrect, the implication is an exaggeration.

With regard to measurement and dosing errors, there were a few important trends to note. Health literacy had a large influence on dosing errors – regardless of whether teaspoons or mL were used in the instructions. Then, the cup: avoid the cup when possible. Almost three-quarters of parents committed measurement or dosing errors when asked to provide a 2.5mL dose in the cup. Stick to the syringe and target round numbers (5mL) to minimize errors.

With regard to the premise of overdose – for medications with a wide therapeutic range, these data are not quite as clinically relevant. However, for high-risk medications, more time and effort should be taken to demonstrate proper dosing with parents.

“Liquid Medication Errors and Dosing Tools: A Randomized Controlled Experiment”
http://pediatrics.aappublications.org/content/early/2016/09/08/peds.2016-0357

But Where is the Antidote to the Poison @NEJM?

Andexanet alfa is the long-awaited antidote for the Factor Xa inhibitors – rivaroxaban, apixaban, edoxaban, and their ilk. This publication, featured at the European Stroke Congress and in the New England Journal of Medicine, is Portola’s latest update regarding its utility. Is it better than their previous update – their failure to receive initial FDA approval – or just another “incomplete” like their publication last fall?

This is ANNEXA-4, an open-label, single-group study purporting to evaluate the efficacy and safety of andexanet for clinical hemostasis in actively bleeding patients with concomitant use of Factor Xa inhibitors. Or, more specifically, these are interim results – the first 67 of 250 planned for enrollment. The clinical efficacy endpoint is a complex series of adjudicated judgements regarding the cessation of bleeding, hematoma expansion, or change in hematocrit, depending on the type of bleeding enrolled. The primary safety endpoint is death or thrombotic event within 30 days – stroke, myocardial infarction, venous thromboembolism, etc.

There is virtually nothing positive to relate here. The authors, of course, relate that somewhere around 80% of the 47 patients included in their efficacy analysis obtained “good” or “excellent” hemostasis with 12 hours following their andexanet infusion. But, these essentially arbitrary labels at a potentially clinically unimportant timepoint tells us virtually nothing regarding its value versus observation, or an alternative treatment such as prothrombin concentrate complexes.

On the negative side, the list is endless. There is the baffling offensiveness of publishing what amounts to a quarter of a trial in the New England Journal of Medicine.  The mean time to andexanet bolus was nearly 5 hours, raising concern regarding the acuity and severity of bleeding in enrolled patients.  The vague, patient-oriented endpoints are meaningless – with or without a comparator – and thus, this boils down to basically a pharmacokinetic observational study. Even then, the pharmacokinetics don’t appear terribly favorable – andexanet dramatically reduces Factor Xa activity during infusion, but pops back to therapeutic anticoagulation following cessation. A concerning 18% had thrombotic events within 30 days – but, again, without any control group, little can be concluded regarding safety.

Finally, clearly, the NEJM has given up publishing the conflicts-of-interest for the authors because it would sum up to half the journal – this article directs the reader to the disclosure forms on the web. For the eagle-eyed reader, however, they can pick out this text as part of the author affiliations: “Portola Pharmaceuticals, San Francisco (J.T.C., A.G., M.D.B., G.L., P.B.C., S.G., J.L., B.L.W.)”. Yes, eight of the authors are employees of Portola Therapeutics, the manufacturer. Better even, are their ICJME form disclosures. John Curnutte, the Head of Research and Development, has checked the box stating he has no relevant conflicts of interest with the work under consideration for publication – but, you know, outside the submitted work he happens to be an employee for Portola. In fact, from what I can tell, every employee authoring this article declared they have no COI with the work under consideration for publication.

Inconceivable!

Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors
http://www.nejm.org/doi/full/10.1056/NEJMoa1607887

Save the FFP, Save the World

This is a trial that does a couple things I really love: it nails inappropriate usage of the International Normalized Ratio to the wall, while simultaneously offering a viable alternative.

The INR is intended for one thing and one thing only: monitoring anticoagulation with warfarin. The INR, as a proxy for the PT, has instead been utilized as a pointless and misleading instrument for screening adults for previously undiagnosed coagulopathy. The PT, in the correct, narrow clinical context, has value – the INR does not.

This trial beautifully illustrates this point. These are patients with severe cirrhosis and end-stage liver disease undergoing invasive procedures. With thirty patients in each group, they were randomized to either standard pre-procedure prophylactic transfusion per-protocol based on INR guidelines, or the necessity of blood product was determined via thromboelastography. In the standard care group, the mean INR was 2.01, and, thus, per protocol, the typical patient received an appropriate dose of 4 units of FFP for “correction”. In the TEG group, only a handful of patients were deemed to actually have a coagulopathy for which FFP was indicated. No patients in the TEG-guided cohort had procedure-related bleeding and identical numbers of patients needed red cell transfusions.

Transfusions are expensive and dangerous: transfusion-related circulatory overload, transfusion-related lung injury, various incompatabilities and allergic reactions are not terribly infrequent. They should be avoided whenever possible, and this study beautifully illustrates the disutility of the INR for screening for bleeding risk. ESLD patients have elevated INRs from their inability to synthesize Vitamin K-dependent clotting factors, but they also do not synthesize Protein C and S, and there are a variety of other compensatory mechanisms. These patients do not routinely need transfusions of FFP prior to procedures, despite most centers being replete with similar protocols.

“Thrombelastography-Guided Blood Product Use Before Invasive Procedures in Cirrhosis With Severe Coagulopathy: A Randomized, Controlled Trial”
http://www.ncbi.nlm.nih.gov/pubmed/26340411

Put the Platelets Away in ICH

Sometimes, medical practice in the setting of uncertainty simply turns out to be futile and low-value.

This is one of those times where we’ve probably been at least futile, and possibly harmful.

Life-threatening or critical intracranial bleeding in the setting of concomitant antiplatelet therapy frequently offers a dire prognosis.  As part of our standard “don’t just stand there!” approach in Emergency Medicine, patients with ICH in this setting are frequently transfused platelets in an effort to provide untainted clotting substrate.  This practice, however, has never been reinforced by substantiated evidence, and the pharmacokinetics of the antiplatelet agents suggests this strategy is unlikely to be efficacious.

This is the PATCH trial, a randomized, open-label trial conducted at 60 hospitals between 2009 and 2015, investigating the utility of platelet transfusion in the setting of ICH.  Patients with normal baseline functional status and ICH while taking aspirin, clopidogrel, or dipyridamole were eligible for inclusion.  Specific excluded ICH were epidural or subdural hematomas, significant intraventricular blood, surgical intervention planned, or those in which death appeared imminent.  Treating clinicians could not be blinded to study arm allocation, but follow-up assessors and data analysis was masked.  The primary outcome is was functional outcome on the modified Rankin Scale, analyzed via ordinal shift analysis.

The authors do not present the number of patients screened for potential enrollment during the study period, but, ultimately, 190 participants were included from 41 centers.  The authors state patients were well-balanced on most demographics, although median ICH volumes were a little higher in the platelet-transfusion group, with 34% of patients having ICH >30mL versus only 21% in the standard-care group.  There were four patients in the platelet-transfusion group who did not receive transfusion, and two in the standard-care that did.

In the end, outcomes were universally dismal.  Only 15 patients in the entire study survived with minimal disability or better.  The vast majority of patients were at least moderately disabled or dead at follow-up.  And, while the confidence intervals for many of their comparisons cross unity, none of the trends favored platelet transfusion.  Generally speaking, there were more deaths, fewer patients with minimal disability, and additional adverse events in the transfusion group.

I tend to feel this is a small enough cohort the heterogeneity between individual patients is enough to effect the overall results – including the apparent harms relating to platelet-transfusion.  However, there is certainly no signal of benefit, and lacking a compelling indication to utilize a scarce resource, I believe this is enough to suggest this practice should be routinely avoided.

“Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30392-0/abstract

The Great Reveal of Andexanet Alfa

The brave new world of “bleeding that doesn’t stop” is a little closer to ending today.  However, this is definitely just the smallest of baby steps in that direction – and hardly as straightforward and simple as the authors’ conclusion:

“Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects.”

This is ANNEXA-A and ANNEXA-R, two healthy-volunteer studies evaluating the utility of Andexanet Alfa for reversal of Factor Xa inhibitors.  Andexanet is a recombinant Xa decoy protein with a higher afinity for the Xa inhibitors than endogenous Factor Xa, having the net effect of restoring thrombin production.  In these studies, the 40-odd participants in each were housed at the study site for 8 days, loaded with either apixaban or rivaroxaban, and then assigned in a 3:1 or 2:1 ratio to receive either Andexanet or placebo.  Then, the participants were assigned to single-bolus dosing or bolus plus infusion.

The general gist of the outcomes is best visualized by the following graphic:

Andexanet, as expected, rapidly binds circulating Factor Xa.  However, there are two quite obvious, clinically important considerations.  First, reversal is very short-acting if only the bolus is given.  Then, it seems clear while the Factor Xa inhibitor is bound, it cannot be eliminated – and there is a rebound phenomenon to near-baseline levels once the infusion is stopped.  It appears this may be a very tricky drug to use in certain clinical scenarios, considering the duration of required reversal – especially if full and permanent effects are desired.

And, as noted before, this is just baby steps.  This handful of healthy volunteers did not have any specific adverse events related to the infusion, but the small numbers prevent any reliable conclusions regarding safety.  This is also just a pharmacokinetic study without clinical outcomes, and we don’t truly know its real-world effectiveness based on this publication.

It is quite an interesting innovation, but it still lands somewhere between “promising” and “minimally useful” – and almost certainly expensive.

“Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity”
http://www.nejm.org/doi/full/10.1056/NEJMoa1510991

Don’t Hospitalize Warfarin & Minor TBI

There have been a few retrospective, observational studies evaluating the outcomes of anticoagulated patients with minor head injury.  The incidence reported by such series ranges from 6% in observation with mandatory repeat CT, to 0.6% with discretionary CT.

This series from Singapore reports: 0.3%.
In this series, all patients taking warfarin and having minor head trauma underwent protocolized initial CT and hospitalization for observation.  Repeat CT was performed, however, only at the discretion of the treating physicians.  Of the 295 patients hospitalized, only 11 underwent repeat CT, and only 1 abnormality was identified.  That one patient underwent neurosurgical intervention.  Of the remainder, no patients returned within two weeks of the initial incident with a further episode of delayed bleeding.  Thus, 0.3%.
Is it the difference between mandatory and discretionary repeat CT resulting in the wide range of reported incidence of delayed hemorrhage?  But, if there aren’t any symptomatic changes, are the extra hemorrhages detected clinically important?
Interestingly enough, they also reported three deaths from nosocomial pneumonia.  So, yes, the risk of delayed hemorrhage is non-zero – but likely lower than the risks associated with hospitalization.
“Outcomes of warfarinized patients with minor head injury and normal initial computer tomographic scan”

Let’s Reverse: Dabigatran

‘Round EMLoN headquarters, we’re big fans of a few medications.  Oseltamivir.  Ticagrelor.  Alteplase.  And, finally, dabigatran.  After all, a blog needs content – and controversy begets content.  Dabigatran, if you need any reminder, is an irreversible direct thrombin inhibitor, whose sponsored trial results continue to receive “updates” for additional “newly discovered” adverse events.  It was also subject to a $650M legal settlement related to its under-emphasized risks to patients.

This pair of articles, presumably, addresses one critical issue with dabigatran – lack of effective reversal options.  The first, published in the Lancet, relates to controlled pharmacokinetics of the monoclonal antibody fragment binding dabigatran, idarucizumab.  Healthy volunteers, all men, were loaded with four days of dabigatran, and the four cohorts of 12 participants each were assigned to receive various doses of idarucizumab.  By every measure of coagulation function, the two highest-dose cohorts effectively reversed dabigatran.  However, given the small number of participants, it is impossible to claim idarucizumab is safe, even in the setting of only a handful of adverse events.  Entertainingly, almost half the research participants complained of at least two subjective adverse symptoms during the dabigatran load.

The second article, in the NEJM, is bizarrely an interim analysis of the first 90 patients enrolled of a planned 300 patient phase III study of idarucizumab.  The appropriateness of reporting a fraction of enrollment from a sponsored phase III study, let alone in the NEJM, is unfathomable.  Regardless, the study enrolled patients requiring urgent reversal for life-threatening bleeding or urgent surgery.  As in the Lancet publication, administration of idarucizumab reversed coagulation parameters almost instantly.  There was, however, a small rebound in anticoagulation and dabigatran activity approximately 12 hours after the initial dose, suggesting a limit to the durability of the reversal in some patients.

Clinically, outcomes are a little difficult to evaluate without a specific control or comparison group.  The patients generally did poorly – 18 of 90 died – but, probably as expected in an elderly, anticoagulated cohort confronted by acute medical issues.  In the patients with life-threatening bleeding, time to resolution was 11.4 hours following administration of idarucizumab – not dissimilar to the use of prothrombin-concentrate complexes for warfarin or Factor Xa inhibitors.  Of course, nearly a quarter of patients were enrolled despite what turned out to be normal initial coagulation profiles – inflating any measure of apparent reversal or bleeding time cessation.  And, again, in such a small sample, without a control population, no obvious statement on safety may be made, even in the setting of just a handful of thromboembolic events.

In short, Boehringer Ingelheim, having scattered the nails in the street, is almost ready to sell you new tires.  Certainly, whatever the adverse effects of idarucizumab, it is better than uncontrolled bleeding – and will doubtless be a welcome addition to many formularies.  The costs, however, will be quite unwelcome – and without a method to readily detect dabigatran activity in the clinical setting, this expensive antidote will likely be uselessly given to many patients without the possibility of benefit, as seen in a quarter of patients here.

Finally, as a bit of an aside, the accompanying editorial is penned by a physician who receives consulting fees from both Boehringer Ingelheim and Portola specifically for his work on the antidotes for dabigatran and the Factor Xa inhibitors.  Is it really so difficult to identify qualified editorialists without the most egregious possible COI?

“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”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60732-2/abstract

“Idarucizumab for Dabigatran Reversal”
http://www.nejm.org/doi/full/10.1056/NEJMoa1502000