Category: Hematology

Toss Up: A Little Bleeding, or A Lot of Platelets

Platelets are the good little minions of hemostasis. In their absence, invasive procedures develop additional risk, ranging from minimal to clinically important, and the mitigation strategy ranges from avoidance, the alternative procedural techniques, to prophylactic platelet transfusions. Platelets, like any blood product, are associated significant risks, not limited to acute lung injury, transfusion-related circulatory overload, allergic reactions, and more.

This prospective, randomized trial evaluated whether, in patients with thrombocytopenia, a platelet transfusion was necessary before central venous catheter placement. Enrolled patients included those undergoing in-hospital, ultrasound-guided CVC placement, primarily “regular” CVCs, placed into the internal jugular and subclavian veins. Patients randomized to transfusion received one unit of platelet concentrate roughly one hour prior to the procedure. The primary outcome was CVC-related bleeding, graded on a scale of 0 to 4, where Grade 3 and 4 bleeding was associated with significant intervention.

In those receiving a platelet transfusion prior to CVC placement, grade 3 and 4 bleeding was seen in 4 of 188 (2.1%) of patients, compared with 9 of 185 (4.9%) of those who did not receive a transfusion. There were also excesses of Grade 1 and 2 bleeding in those who did not receive a transfusion prior to the procedure. Secondary subgroup analyses were underpowered to determine if any specific subgroups were at higher risk, but it is reasonable to suggest the risk may increase as the initial platelet count decreases, while internal jugular placement was the safest site.

The cost of this initial protection was, obviously, quite a number of platelet transfusions. Owing to observed bleeding complications, the mean number of units of platelets transfused following CVC placement was much higher in the group not having received a prophylactic transfusion. However, when the initial prophylaxis is taken into account, the transfusion cohort received more than double the platelets within 24 hours of the procedure. Red blood cell transfusion was not different between groups, and other observed length-of-stay and mortality outcomes are probably not reliably different.

The trial is presented as “negative”, as the differences in serious bleeding fail to meet the pre-specified endpoint for non-inferiority. The authors, however, make an appropriately nuanced interpretation regarding the sliding scale of risk for bleeding, and suggest lower platelet counts, and those likely to require a platelet transfusion in the near future for other clinical indications, represent the most judicious population in which to consider prophylactic transfusion.

“Platelet Transfusion before CVC Placement in Patients with Thrombocytopenia”

https://www.nejm.org/doi/full/10.1056/NEJMoa2214322

Let’s Sell Andexxa

Have you heard the Good News (from Portola) about andexanet?

It’s an ever-changing landscape of anticoagulants and reversal agents in the Emergency Department – though, it’s not so much as a whirlwind as it is a creeping ooze. The latest developments have all been covered ad nauseum over the past few years – dabigatran, idarucizumab, factor Xa inhibitors, and coagulation factor Xa (recombinant) inactivated-zhzo (andexanet alfa). This final product, trade name Andexxa, has generally been held in a dim view over the past year by many, including yours truly, Rebel EM, the Skeptic’s Guide to Emergency Medicine, EmCrit, first10EM, the American Society of Hematology, and both the European Medicines Agency and the Food and Drug Administration’s own clinical reviewers.

There is, however, a competing viewpoint in which Andexxa is Tier 1 therapy for treatment of major bleeding in the context of of direct Xa inhibitor use – such as this recent “Recommendations of a Multidisciplinary Expert Panel” piece in Annals of Emergency Medicine. What aspect of their review differs so greatly in their affinity for Andexxa?

The expert panel meeting was convened with funds from unrestricted educational grants from Portola Pharmaceuticals and Boehringer Ingelheim to the American College of Emergency Physicians.

And, to no great surprise, the convened panel reflects the funding source:

Dr. Baugh has worked as a consultant for Janssen Pharmaceuticals and previously received research funding from Janssen Pharmaceuticals and Boehringer Ingelheim as a coinvestigator. Dr. Cornutt has received speaker’s fees from Boehringer Ingelheim. Dr. Wilson has worked as a consultant for Janssen Pharmaceuticals, Boehringer Ingelheim, BMS/Pfizer Pharmaceuticals, and Portola Pharmaceuticals, and has also received research funding from them. Dr. Mahan has served on the speaker’s bureau and as a consultant for Boehringer Ingelheim, Janssen Pharma, Portola Pharma, and BMS/Pfizer and as a consultant to Daiichi-Sankyo, WebMD/Medscape, and Pharmacy Times/American Journal of Managed Care. Dr. Pollack is a scientific consultant to Boehringer Ingelheim, Janssen Pharma, Portola Pharma, and BMS/Pfizer; he also received research support from Boehringer Ingelheim, Janssen Pharma, Portola Pharma, Daiichi-Sankyo, CSL Behring, and AstraZeneca. Dr. Milling’s salary is supported by a grant from the National Heart, Lung, and Blood Institute. He serves on the executive committee for the ANNEXA-4 and ANNEXA-I trials, the steering committee for the LEX-209 trial, and the publications committee for the Kcentra trials. He has received consulting fees or research funding from CSL Behring, Portola, Boehringer Ingelheim, Genentech, and Octapharma. He received speaker’s fees from Janssen. Dr. Peacock has received research grants from Abbott, Boehringer Ingelheim, Braincheck, CSL Behring, Daiichi-Sankyo, Immunarray, Janssen, Ortho Clinical Diagnostics, Portola, Relypsa, and Roche. He has served as a consultant to Abbott, AstraZeneca, Bayer, Beckman, Boehringer-Ingelheim, Ischemia Care, Dx, Immunarray, Instrument Labs, Janssen, Nabriva, Ortho Clinical Diagnostics, Relypsa, Roche, Quidel, and Siemens. He has provided expert testimony on behalf of Johnson & Johnson and has stock and ownership interests in AseptiScope Inc, Brainbox Inc, Comprehensive Research Associates LLC, Emergencies in Medicine LLC, and Ischemia DX LLC. Dr. Rosovsky has served as an advisor or consultant to Janssen, BMS, and Portola and has received institutional research support from Janssen and BMS. Dr. Sarode has served as a consultant for CSL Behring and Octapharma and advisor to Portola Pharmaceuticals. Dr. Spyropoulos is a scientific consultant to Janssen, Bayer, Boehringer Ingelheim, Portola, and the ATLAS Group; he also has received research support from Janssen and Boehringer Ingelheim. Dr. Woods is a scientific consultant to Boehringer Ingelheim. Dr. Williams serves as a consultant to Janssen Pharmaceuticals, Boehringer Ingelheim, and Portola Pharmaceuticals.

This work is effectively an advertorial, masquerading as serious academic literature, and part of a well-executed marketing and promotional campaign by the manufacturers of these drugs – particularly Portola, which is having difficulty getting Andexxa on formulary due its cost and controversial clinical data. This publication in Annals is just one of many sponsored products:

The further afield these pseudo-guidelines permeate, the more likely the product – the $25k or $50k a dose Andexxa – is incorporated into hospital formularies and local practice. These also have implications for risk-management assessments, in which the costs – passed along to the patient or payor – are far outweighed by the potential liability of a decision to make the drug unavailable for treatment.

It should be clear from all the non-conflicted opinion the role of Andexxa is yet to be clearly established, with true RCT evidence unfortunately years away. To state otherwise – and to make Tier 1 recommendations – is simply misleading.

“Anticoagulant Reversal Strategies in the Emergency Department Setting: Recommendations of a Multidisciplinary Expert Panel”
https://www.annemergmed.com/article/S0196-0644(19)31181-3/fulltext

Pulmonary Embolism in Syncope, Forever

For about the zillionth time – the Prandoni observations of 16% prevalence of pulmonary embolism in syncope are not not generalizable.

This is the BASEL IX study (BAsel Syncope EvaLuation Study) whose primary purpose is to gather observational data regarding the outcomes of patients with syncope. These authors pulled a chunk of their data to address the question of whether PE was highly prevalent among those with syncope, as well as to describe the timing of such any downstream “missed” diagnoses.

The data presented comes from 1,895 patients enrolled in the main study, 1,397 of whom were eligible via being clinically stable enough to provide informed consent, and in whom a D-dimer result was available. Patients underwent clinical assessment by treating physicians without influence by the study.

Overall, only 14% underwent imaging for PE, with PE ultimately found in 1.4% of the cohort at initial presentation. About half the remaining patients who did not undergo imaging had normal D-dimer results and were retrospectively calculated to have low pre-test probability. By logical conclusion, however, that means half the remaining cohort was either non-low pretest or had elevated D-dimer – but still did not undergo imaging.

The follow-up period was up to two years in 83% of this cohort, and only 12 events occurred in follow-up, all in the non-low/elevated D-dimer group not undergoing initial imaging evaluation. Eight of these were PEs and 4 were cardiovascular deaths. The good news: the earliest subsequent PE diagnosis was 55 days, and earliest death was almost a year later.

So, no, again, no – no need to pursue PE in syncope unless otherwise clinically indicated, even if the patient may be at incidentally elevated risk.

“Prevalence of Pulmonary Embolism in Patients With Syncope”
http://www.onlinejacc.org/content/74/6/744.full

Choosing Wisely Hepatology, Eh?

The Choosing Wisely campaign is quite popular in theory, if not in practice – ranging widely across the specialties from Pediatric Hospital Medicine to our own, beloved, Emergency Medicine.

This list is from the Canadian Association for the Study of the Liver, and two of their five recommendations are somewhat relevant to EM. Without further ado:

Statement 1: Don’t order serum ammonia to diagnose or manage hepatic encephalopathy

This was their most highly ranked recommendation when members were surveyed at their annual meeting. They cite multiple confounders regarding ammonia levels, factors affecting accuracy of the measurement, and state “elevated ammonia levels do not add any diagnostic, staging, or prognostic value.” The diagnosis, they feel, ought to be made based on clinical history and response to therapy alone.

Statement 2: Don’t routinely transfuse fresh frozen plasma, vitamin K, or platelets to reverse abnormal tests of coagulation in patients with cirrhosis prior to abdominal paracentesis, endoscopic variceal band ligation, or any other minor invasive procedures

This is another one of my favorite pet topics – transfusion intended to “restore normal hemostasis” in a dysfunctional, but somewhat already rebalanced coagulation system. As they say, “Routine tests of coagulation do not reflect bleeding risk in patients with cirrhosis and bleeding complications of these procedures are rare.” In fact, I’ve seen several articles approaching even liver resection in the context of elevated coagulation parameters absent any major bleeding complications – so this ought certainly apply to minor procedures, including those in the Emergency Department.

No doubt the uptake of these recommendations will be highly variable among hospitals and specialty groups, but lists like these are great tools with which to start the conversation.

“Choosing Wisely Canada-Top Five List in Hepatology”
https://www.ncbi.nlm.nih.gov/pubmed/30596626

Disutility, Thy Name is ANEXXA-4

About two and a half years ago, we were introduced to andexanet alfa (Andexxa), a modified recombinant form of factor Xa designed as a reversal option for factor Xa inhibitors. The mechanism of action is simple: andexanet mimics native factor Xa, providing the various Xa inhibitors (rivaroxaban, apixaban, edoxiban, betrixiban, and enoxaparin) an alternative target. When sufficient Xa inhibitor is bound to andexanet, the native version is freed to return to its normal work in hemostasis.

The problem, however, is the reversal is not durable. The half-life of andexanet is approximately 1 hour, after which point the factor Xa inhibitor levels rise and hemostasis is again impaired. This necessitates a bolus and an infusion. A bolus and infusion that costs ~$3,000 per 100mg vial – and requires 900mg for a “low dose” protocol or 1,800mg for a “high dose” protocol. And, it all vanishes to dust when the infusion completes.

The first NEJM publication regarding andexanet featured just the first 67 patients from ANNEXA-4, an open-label, single-arm descriptive study of patients given andexanet for major bleeding. Now, presented at the International Stroke Conference 2019 in Honolulu, we have the results from the full 352 patient cohort – and they’re every bit as uninspiring as the preview.

Nearly all patients were receiving rivaroxaban (half-life 7 to 13 hours) or apixaban (half-life 12 hours), with a handful on enoxaparin. As in the preview, the bolus of andexanet effectively dropped circulating levels of the factor Xa inhibitor down to negligible amounts. Again, as seen before, after cessation of the bolus, factor Xa levels returned to a level consistent with their terminal half-lives. Case in point: “At 4, 8, and 12 hours after andexanet infusion, the median value for anti–factor Xa activity was reduced from baseline by 32%, 34%, and 38%, respectively, for apixaban and by 42%, 48%, and 62%, respectively, for rivaroxaban.” This is just normal metabolism, not andexanet magic.

Death occurred in 14% of patients within 30 days, and there were thrombotic events in 10%. Hemostasis at 12 hours, their primary outcome, was 82% “in 204 of 249 patients who could be evaluated”. Specifically, they excluded a third of their population because they were effectively enrolled in error, as they met bleeding criteria but not Factor Xa inhibitor level criteria. This is similar to the idarucizumab open-label demonstration, in which many patients who were not actually coagulopathic were treated with anticoagulation reversal. This represents tremendous waste and cost.

Finally, the nail in the coffin, this admission in the abstract and the text: “Overall, there was no significant relationship between hemostatic efficacy and a reduction in anti–factor Xa activity during andexanet treatment.” The primary outcome wasn’t even correlated with their intervention!

As you can tell from the tone of this post, I am profoundly unimpressed with the value demonstrated here. There’s no evidence this is clinically useful, nor a potentially preferred strategy to use of prothrombin concentrate complexes to replete missing factor. The company and the FDA effectively admit the same:

The most important limitation of this trial is that it did not include a randomized comparison with a control group. At the time of study initiation, it was determined that a randomized, controlled trial would have logistic and ethical challenges, given the perceived risks of placebo assignment in this highly vulnerable population. However, continued use of unapproved agents, despite a lack of rigorous clinical data, has changed the equipoise for a trial. Thus, under the guidance of the FDA and as a condition of accelerated approval in the United States, the sponsor is conducting a randomized trial (ClinicalTrials.gov number, NCT03661528) that is expected to begin later this year.

I’m sure more will be made to unpack even further unfavorable details as time passes – and, until further reliable evidence can be presented, I’d pass on andexanet, as well.

“Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors”

https://www.nejm.org/doi/full/10.1056/NEJMoa1814051


Anything But Crystalloid

The balanced transfusion ratio has been in vogue for many years in military settings (read: whole blood), but, until recently, less popular with civilians. There are probably still kinks to be worked out with respect to improving the value of resource consumption in massive transfusion, but, at the least, it appears roughly equivalent ratios of plasma to blood cells are beneficial.

So, given the opportunity, why not initiate this sort of balanced resuscitation in the prehospital setting?

This somewhat messy and heterogenous trial does precisely that – randomizing 523 unstable trauma patients to either standard resuscitation or transfusion of 2 units of FFP, followed by standard resuscitation. The randomization took place in clusters at the aeromedical transport base level, and included bases whose initial protocol included PRBC transfusions for eligible patients. In these instances, the FFP was transfused first, and then the PRBCs. Additionally, 111 of the enrolled aeromedical transports were transfers from an outlying hospital. This meant the pre-enrollment resuscitation could be virtually any permutation of potential volume replacement. While the two groups were roughly balanced as far as etiologies of trauma, injury severity, and other baseline features, the initiation of FFP prior to standard resuscitation did skew the numbers with respect towards prehospital PRBCs, as they had to wait until the intervention transfusion was complete.

Overall, 24-hour mortality was 22% in the “standard care” group and 14% in the plasma group. Only a handful of potentially transfusion-related adverse events occurred, and this early survival advantage proved durable through the length of follow-up. There is enough in the pre-specified subgroup analysis to fuel any number of editorials, other retrospective analyses, and homegrown inclusion or exclusion criteria for prehospital FFP – but, overall, this grossly consistent with our priors for a survival advantage associated with balanced transfusions.

Now, what we really need, is a plasma product with a better shelf-life ….

“Prehospital Plasma during Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock”

If It Bleeds, It Can Get TXA?

When trauma bleeds: TXA! When women bleed: TXA! When the nose bleeds: TXA! When your freckles need lightening: TXA!

But, what about inside the brain?

This is TICH-2, an international, randomized, placebo-controlled trial testing tranexamic acid versus placebo for patients with primary intracerebral hemorrhage. The intervention arm received 1g of IV TXA as a bolus, followed by 1g over the subsequent 8 hours. The primary outcome was functional status at day 90 measured – inappropriately so, of course – as shift on the modified Rankin Scale. We’ve critiqued the ordinal shift several times as, effectively, statistically magnifying unimportant differences as a crutch for trials struggling to find a difference using a traditional, dichotomous endpoint.

However, regardless, their efforts are for naught: their primary endpoint still failed to reach statistical significance. Across five years and 2,325 randomized participants, nearly all patient-oriented outcomes showed no difference: 29% of TXA patients were mRS ≥2 at 90 days, compared with 29% of placebo. The numbers of deaths by day 90 were virtually identical, as were measures of quality of life, functional status, and days at home. Adjusted analyses and various subgroups generated odds ratios whose confidence intervals almost broke free of unity, but not quite.

The major quirk – over two-thirds of the trial was randomized greater than 3 hours from onset. The trauma literature focuses on early anti-fibrinolytic treatment, and it is reasonable to suggest the delay in treatment was too great to demonstrate a benefit. Then, even though no patient-oriented benefit was observed, hematoma expansion was attenuated in the TXA cohort. This is not the first time an ICH trial has seen benefits with regard to hematoma expansion absent patient-oriented outcome improvements, but it still seems a valid surrogate for, at least, a small effect size for which this trial may (or not) be underpowered to detect.

My takeaway is this trial hasn’t done much to move the needle with regard to evaluating TXA in ICH. It does show, at least, as administered in this trial, it is unlikely to have substantial benefit. However, TXA is inexpensive and seems to demonstrate a reasonable margin of safety. It is still reasonable to consider its use in as timely a fashion as possible, with the expectation the true NNT may be ~50 to 200, while awaiting further data from other trials currently underway.

“Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial”
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31033-X/fulltext

TACO Time!

One of the best acronyms in medicine: TACO. Of no solace to those afflicted by it, transfusion-related circulatory overload is one of the least-explicitly recognized complications of blood product transfusion. The consent for blood products typically focuses on the rare transmissibility of viruses and occurrence of autoimmune reactions, yet TACO is far more frequent.

This report from an ongoing transfusion surveillance study catalogued 20,845 patients receiving transfusions of 128,263 blood components. The incidence of TACO was one case per 100 transfused patients. Then, these authors identified 200 patients suffering TACO, and compared their baseline characteristics to 405 patients receiving similar transfusion intensity, but who did not develop TACO. Clinically relevant risk factors for developing TACO identified in their analysis were, essentially:

  • Congestive heart failure
  • End-stage or acute renal disease
  • End-stage liver disease
  • Need for emergency surgery

… or, basically, the population for whom a propensity for circulatory overload would be expected. It appears, generally speaking, clinicians were aware of the increased risks in these specific patients, as a greater percentage received diuretic treatment prior to transfusion as well. 30-day mortality in those suffering TACO was approximately 20%, roughly double that of those matched controls.

More good reasons to adhere to as many restrictive transfusion guidelines as feasible.

“Contemporary Risk Factors and Outcomes of Transfusion-Associated Circulatory Overload”

https://www.ncbi.nlm.nih.gov/pubmed/29300236

What Does the ACC Say About OAC Reversal?

Just in case you were curious ….

Conventional tests useful for ruling out clinically relevant levels contributing to bleeding risk:

  • Dabigatran – a normal Thrombin Time or sensitive activated partial thromboplastin time (aPTT).
  • Factor Xa-inhibitors – None.

If you have access to Anti-Xa specialized assays, they can be used to measure the level of activity for the Factor Xa-inhibitors.

Managing OAC-associated bleeding:

  • Warfarin – 4-factor prothrombin concentrate complexes (PCCs) at weight-based dosing between 25 units/kg and 50 units/kg based on INR.
  • Dabigatran – Idarucizumab.
  • Factor Xa-inhibitors – 4-factor PCCs at 50 units/kg.

The authors also suggest use of PCCs as second line for idarucizumab, but this is likely to be fruitless and the evidence is very weak. Hemodialysis is also an option for removal of circulating dabigatran in a narrow set of clinical scenarios.

The authors also mention andexanet alfa and ciraparantag as potentially useful adjuncts at some point in the future, but no specific clinical role has yet been defined.

“2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants”
http://www.onlinejacc.org/content/early/2017/11/10/j.jacc.2017.09.1085

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