Idarucizumab, the Sequel

There’s nothing hotter than idarucizumab, the reversal agent for dabigatran. It’s so hot, the New England Journal of Medicine once published a farcical 91 patient interim analysis of a planned 500 patient enrollment.  Now, two years later, we have the full cohort and it’s, well, more of the same, with all the flaws previewed in the previous iteration.

To recap, there are no viable reversal options for dabigatran besides this antibody fragment. And, in full sucker-born-every-minute fashion, Boehringer Ingelheim is both good cop and bad cop, selling us both the poison and the antidote.

There are 503 patients enrolled in this open-label study with two arms: Group A, with uncontrolled bleeding, or Group B, anticoagulated and requiring an urgent procedure. The primary outcome is, essentially, utterly unrelated to any of the context of enrollment – “maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab”, which is frankly already well-documented in the healthy-volunteer pharmacokinetic studies.

Theoretically, the interesting portion here is supposed to be the clinical relevance of the reversal effect – which is measured by secondary outcomes of subjective assessment of median time to cessation of bleeding in Group A or by periprocedural hemostasis in Group B. The most striking result in the interim result was a median time to cessation of bleeding of 11.4 hours – a concerningly high number calling into question the entire purpose of reversal. In this new publication, the median time to reversal is now reported as 2.5 hours. This also, oddly, differs from nearly identical cohort results presented to the American Heart Association – explicitly broken down as shown below:

Then, compare with this slide passed along by @bloodman from #ISTH2017 in Berlin:

Considering this was an easily critiqued result – and essentially the most clinically relevant – it’s not surprising the sponsor and their funded- and fee-supported collaborators solved the issue in the most expeditious fashion possible: exclude >55% of Group A from time-to-bleeding assessment.  Just toss out the patients who didn’t have cessation of bleeding within 24 hours, or – despite inclusion criteria of “signs and symptoms of (overt) uncontrolled bleeding” – the “bleeding location could not be identified”.

Most (93.4%) of patients in Group B were assessed as having normal hemostasis during their procedures, which occurred a median of 1.6 hours after completion of idarucizumab infusion. That said, many of the procedures were minimally invasive (catheter placement for dialysis, lumbar puncture, cutaneous abscess drainage) and likely favorably influenced both the fraction reported having normal hemostasis, as well as driving down the time to the intended procedure.

About 10% of the cohort had normal hemostasis at baseline as judged by the central laboratory, meaning they were likely not taking the dabigatran as reported or suspected – a smaller percentage than the interim analysis, where almost 25% were not. Whether this reflects better enrollment screening, or simply moving the goalposts again, cannot be reliably discerned from the results provided. Adverse events relating to the study drug, likewise, are difficult to parse without a true unexposed comparator.  Most of the cohort was elderly, with multiple comorbid conditions, in addition to their serious bleeding event or need for urgent procedural intervention. A handful of early thrombotic events and hypersensitivity-type reactions occurred, demonstrating there may yet be some consequential, but poorly quantified, risk to idarucizumab administration.

But, hand-wringing aside, we’re in the same place we were yesterday. Idarucizumab clearly and effectively removes dabigatran from circulation, unlike andexanet alfa and Factor-Xa inhibitors, and this ought to be occasionally clinically useful. I would certainly exhaust all potential supportive and expectant management options first, as well as try to definitively confirm dabigatran as the culprit for abnormal hemostasis. Ultimately, the best way to avoid idarucizumab? Don’t use dabigtran in the first place.

“Idarucizumab for Dabigatran Reversal — Full Cohort Analysis”

http://www.nejm.org/doi/full/10.1056/NEJMoa1707278

PCCs for Non-Warfarin ICH?

This quick post comes to you from the EMedHome weekly clinical pearl, which was forwarded along to me with a “Good stuff?” open-ended question.

The “good stuff” referred to a series of articles discussing the “CTA spot sign”, referring to a radiologic marker of ongoing extravasation of blood following an intracranial hemorrhage. As logically follows, ongoing bleeding into a closed space has been associated with relatively increased hematoma growth and poorer clinical outcomes.

However, the post also highlighted – more in an informational sense – an article highlighting potential use of prothrombin concentrate complexes for treatment of bleeding, regardless of anticoagulation status. We are all obviously familiar with their use in warfarin-related and factor Xa-associated ICH, but this article endeavors to promote a hypothesis for PCC use in the presence of any ICH with ongoing radiologically apparent bleeding.

The evidence produced to support their hypothesis? A retrospective 8 patient cohort of patients with ICH and CTA spot sign, half of whom received PCCs and half who did not. Given the obvious limitations regarding this level of evidence, along with problems of face validity, there is no reason to revisit their results. The EMedHome pearl seemed to suggest we ought to be aware of this therapy in case a specialist consultant requested it. Now, you are aware – expensive, unproven, and not indicated without a substantially greater level of evidence to support its use.

“Role of prothrombin complex concentrate (PCC) in Acute Intracerebral Hemorrhage with Positive CTA spot sign: An institutional experience at a regional and state designated stroke center”
https://www.ncbi.nlm.nih.gov/pubmed/27915393

Tranexamic Acid & The WOMAN Trial

Tranexamic acid is popular for the treatment of freckles and nosebleeds – oh, and major bleeding in the setting of trauma. But, originally, the drug was developed for use in controlling hemorrhage in obstetrics and gynecology. Finally, then, we have a trial examining its use for its intended purpose.

Comprising 20,060 patients with clinically significant post-partum hemorrhage across 193 hospitals in 21 countries, the WOMAN trial is – inconveniently – negative as originally designed. The initial study design called for 15,000 patients and a composite endpoint of hysterectomy or death within six weeks of childbirth. However, as the study progressed, it was clear the standard practice in the settings involved indicated the intervention was going to have no effect on hysterectomy rates, and the trial was then expanded to examine the effect on mortality.

So, then, with their expanded sample size, does TXA save lives, as reported profusely throughout the lay media?

Nope.

Mortality within 6 weeks was 2.3% in the TXA cohort and 2.6% with placebo a relative risk of 0.88 (0.74-1.05).

There is, however, some layered complexity in these outcomes. Broken down by cause of death, deaths due to bleeding were 1.5% in the TXA cohort compared with 1.9% with placebo, reaching “statistical significance” with a p-value of 0.045. Then, if you further unpack these results, it seems even within the TXA cohort there is probably a time-to-treatment effect similar to CRASH-2.  Mortality was 1.2% in those receiving their TXA within 3 hours compared with 1.7% treated with placebo. In those treated beyond 3 hours, there was no difference in outcomes – and much higher mortality, regardless (2.6% vs. 2.5%).

So, what should we take away from these data? Is TXA more than just a treatment for freckles, or are these authors and the lay media exaggerating secondary outcomes in the setting of an overall negative trial? As usual, the answer is a little bit of both. The magnitude of the treatment effect, considering the size of this trial, is very, very small. That said, death is a quite meaningful clinical outcome, TXA is fairly inexpensive, and no specific harms were detected in this trial. Therefore, in the settings in which this trial was conducted – Nigeria, Pakistan, Sudan, Albania, etc. – this is likely an important treatment for post-partum hemorrhage.

In more robust clinical settings where additional resources are typically available to support the resuscitation of women suffering bleeding complications from childbirth, the effect size on mortality is likely even much smaller. There may be clinically important effects regarding hysterectomy, hemostasis, and reduction in transfusion utilization, but I again suspect they will be very small and difficult to quantify without a similarly large trial. Then, as the NNT increases for clinically important outcomes, even the very rare harms of a treatment become relevant – and failure of this trial to detect harms may simply be a limit of its statistical power.

Ultimately, as the mortality benefit decreases, the range of acceptable practice variation for protocols incorporating TXA increases.  This is an important trial – but, as typically, not quite as breathlessly so.

“Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial”
http://thelancet.com/journals/lancet/article/PIIS0140-6736(17)30638-4/abstract

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