Category: Hematology

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

FFP Vs. PCCs for Warfarin Reversal – Special Advertising Supplement

It is generally well-known, the advantages of Prothrombin Concentrate Complexes over Fresh Frozen Plasma.  They are a smaller-volume infusion, more rapidly reverse the anticoagulant effect, and lack some of other disadvantages of hemostatic product use.  This study, therefore, a Phase 3b open-label trial of PCCs vs. FFP for anticoagulation reversal before urgent surgery, is essentially of questionable utility.  Is it emergency surgery?  Then use the immediate reversal agent.  Is it semi-elective?  Well, why not wait a bit?

So, why even run a trial for the use of PCCs in the non-emergent realm?  Well, it rapidly becomes clear how this study was conceived by review of the “Role of the funding source”:

This research was funded by CSL Behring. A steering committee of academic medical experts and representatives of the funder oversaw the design and conduct of the study. The funder participated in the selection of the board members. The funder was responsible for data collection, management, and analysis of the data according to a predefined statistical analysis plan. Preparation and review of the Article and the decision to submit for publication was done by a publication steering committee that included academic medical experts and representatives of the funder. Medical writing assistance was paid for by the funder. JNG and RS had full access to all the data in the study and took responsibility for the integrity and accuracy of the data analysis.

The goal: “indication creep” – an entirely obvious corporate landgrab, essentially sponsored, conducted, and written by CSL Behring to expand the use of PCCs beyond emergency reversal.  Indeed, it’s hard to even dignify this Lancet content with a summary.  The exclusion criteria were extensive.  The trial was modified after a letter from the FDA.  Some of the reported outcome numbers in the paper don’t match their ClinicalTrials.gov entry.  Almost all the differences in outcomes were subjective or surrogates for patient-oriented measures.  The authors conclusion:

“[T]hese data show that 4F-PCC is an effective and superior alternative to plasma in terms of haemostatic efficacy and rapid INR reduction for the rapid reversal of VKA therapy before urgent procedures.”

But, despite all these differences “favoring” PCCs, the surgical hemostasis was identical in practical terms – the difference in blood loss between cohorts was only 12 mL on average, only a handful of patients in each cohort required any sort of transfusion, and the total number of units transfused was nearly identical.  In fact, half of the FFP patients never had full INR reversal – with apparently no clinically important consequence.  Surgical cases went to the OR much faster with PCCs – so, as above, in an emergent or semi-emergent instance, PCCs are a great option.  Absent such a rush, however, ignore this Special Advertising Supplement masquerading as science in a supposedly reputable journal.

“Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial”
http://www.ncbi.nlm.nih.gov/pubmed/25728933

The Fixed-Ratio Massive Transfusion Answer

After years of wondering and wandering, we finally have the definitive answer for how best to resuscitate the severely-injured trauma patient – transfusion ratios best mimicking whole blood.  You know, just as we all expected, just as these authors hoped, and just what’s been reported from prior observational series and military combat experience.

More or less.

Regardless, this study – the Pragmatic, Randomized, Optimal Platelet and Plasma Ratios (PROPPR) trial – was a remarkable undertaking in logistics.  Each participating Level 1 trauma center incorporated sealed coolers into their ready blood supply, providing a random allocation of product ratio when the massive transfusion protocol was activated.  As transfusion continued, more coolers with the same ratio arrived.  As best as can be implemented, this reduces the immortality bias seen in other observational series – where survivors were survivors in part, basically, because they survived.

This trial randomized patients to 1:1:1 vs. 1:1:2 – that is, equal numbers of FFP, platelets and RBCs, or half as much FFP and platelets as RBCs.  Ultimately, it didn’t precisely test those same ratios, except as the initial resuscitation strategy.  Following the intervention period, the 1:1:2 arm caught up a bit with plasma and FFP – but the quantities transfused were not substantial.

Technically, this is a negative trial – the mortality advantage favoring the 1:1:1 cohort did not reach statistical significance at 24 hours or 30 days.  However, the authors powered the study expecting a 10% mortality advantage – and instead it was only 4.2% (95% CI -1.1 to 9.6) and 3.7% (95% CI -2.7 to 10.2) at each time point, respectively.  We are then left with the question whether this small difference reflects the underlying truth or chance.

Do the secondary aspects of these data validate the difference?  The expected advantage of 1:1:1 resuscitation is the warding off of evil spirits associated with transfusion-related coagulopathy – and we see in this study the primary driver of differences in mortality was related to deaths secondary to exsanguination.  Likewise, a greater number in the 1:1:1 group achieved satisfactory hemostasis.  So, using a Bayesian approach to interpreting the statistical tests for mortality, it is reasonable to adopt approaches based initial 1:1:1 resuscitation when massive transfusion is necessary, despite the limitations of the evidence.

One oddity worth noting in these data were the relatively small differences in sepsis and ARDS in the 1:1:1 group.  Increased use of FFP and, in particular, platelets are associated with these transfusion-related complications – and it has always been of particular interest whether a 1:1:1 ratio is safe, for precisely these reasons.  The inclusion of platelets in the 1:1:1 randomization may also be a matter for debate; few patients had any indication for platelets following the intervention, and further work could consider the relative utility of aggressive use of platelets.

Overall, however, this is best evidence to date the 1:1:1 ratio is a worthy initial target.

“Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1 vs a 1:1:2 Ratio and Mortality in Patients With Severe Trauma”
http://www.ncbi.nlm.nih.gov/pubmed/25647203

4-Factor Works for Factor Xa Inhibitors

The newest study regarding the reversal of the novel oral anticoagulants also concerns the newest of their family – edoxaban, joining a market already occupied by rivaroxaban and apixiban.  Yes, it’s just another “me too” drug trying to shoehorn its way into the massive warfarin-replacement market – but, at least, this is useful evidence.

4-Factor prothrombin concentrate complexes have been established as a treatment option in the setting of hemorrhagic complications during anticoagulation with the Factor Xa inhibitors.  However, the initial studies of PCCs primarily concerned themselves with laboratory markers of reversal, and any live bleeding studies were in animals (rabbits!).  For this study, however, the authors & Daiichi Sankyo paid 110 healthy volunteers to take edoxaban, then undergo punch biopsy, and then receive either placebo or 4-factor PCC in either 10 IU/kg, 25 IU/kg, or 50 IU/kg doses.

And, pleasantly, it works – in a dose dependent fashion, even, with 50 IU/kg providing the most effective reversal.  So, this essentially confirms what we thought we knew about PCCs based on surrogate markers and animal studies.  These volunteers only suffered a minor dermatologic procedure – and are not critically ill patients with other associated coagulopathies – but it still provides reasonable insight.

How this reversal strategy will fit versus andexanet alfa, a NOAC-specific reversal agent, remains to be seen – particularly with regards to cost and pro-thrombotic adverse effects.

“Edoxaban Effects on Bleeding Following Punch Biopsy and Reversal by a 4-Factor Prothrombin Complex Concentrate”
http://circ.ahajournals.org/content/early/2014/11/16/CIRCULATIONAHA.114.013445.abstract

No Good Ever Comes of Dabigatran

Is anyone actually still using this drug?  If so, why?  There has been nothing but an endless progression of bad news associated with this medication – from Boehringer Ingelheim settling a massive lawsuit, the authors from RE-LY admitting they “missed” additional adverse events for a second time, and, now, further evidence describing flawed real-world effectiveness contrary to its supposed demonstrated efficacy.

The RE-LY trial showed non-inferiority for dabigatran at stroke prevention in non-valvular atrial fibrillation, but appeared to place patients at significantly lower risk of bleeding compared with warfarin.  One of the critiques of RE-LY, however, is the patients were not appropriately representative of the general population at-risk for atrial fibrillation.  By omitting chronic kidney disease and enrolling a generally white population in Europe, the generalizability of their findings is ultimately impaired.

And, thus, we see the fruits of such critiques.  This is a retrospective cohort of Medicare beneficiaries prescribed either dabigatran or warfarin for atrial fibrillation.  Based on propensity matched samples of 1,302 dabigatran users and 8,102 warfarin users, major bleeding of the dabigatran cohort exceeded that of the warfarin cohort – 9.0% (95% CI 7.8 – 10.2) versus 5.9% (95% CI 5.1 – 6.6).  Risks were increased in the elderly, blacks, those with chronic kidney disease, and those on concomitant anti-platelet therapy.

So, we have a lesson – one of effectiveness versus efficacy, or one that’s an indictment of the original RE-LY study protocol.  Medications should not be expected to perform the same in general use as they do in clinical trials – even those with tens of thousands of patients, such as RE-LY.  Independent, confirmatory study ought be mandatory to ensure the safety of the public.

“Risk of Bleeding With Dabigatran in Atrial Fibrillation”

http://archinte.jamanetwork.com/article.aspx?articleid=1921753

Addendum:
Walid Gellad on Twitter points out this study in Circulation, published last week to much lesser fanfare, which uses a larger Medicare sample to come to the opposite conclusion – that dabigatran is better than, and safer than, warfarin.  Which is correct?  A subject for continued debate, to be certain.  The correct answer is probably somewhere in between – dabigatran is safer for some, but more dangerous for others.  However, given the lack of reversal – wouldn’t a Factor Xa inhibitor be a better choice, regardless?

Blood is Good for the Injured Brain – Or is it?

A guest post by Dr. Andrew Kirkpatrick (@AskEMdoc), an Emergency Medicine resident at the University of Texas Medical School at Houston.

Hypoxia, of course, is lethal to vulnerable cells.  Erythropoeitin, in many small trials, has been shown to be neuroprotective after injury.  So, given these apparently obvious beneficial and synergistic treatments, the authors of this study set out to answer the question: What happens when a patient with Traumatic Brain Injury (TBI) is given blood and erythropoietin?
This is a randomized control trial with a factorial (2×2) design that tested Erythropoietin (Epo) versus Placebo and Transfusion Threshold of 7.0g/dL versus 10g/dL to determine if either of the above interventions conferred the benefit of improved neurologic recovery in TBI.  A total of 200 individuals with TBI were randomized into one of four groups using a block randomization strategy, sorting individuals into groups with and without transfusion thresholds or Epo administration.  Both the treatment team and the follow up personnel were blinded to Epo administration, but only follow up personnel could be blinded to transfusion threshold group.  Then, to make this study even further convoluted, the Epo dose and frequency was changed mid-stream due to safety concerns, dividing the Epo arm into the Epo1 and Epo 2 groups.   They also changed the study from a superiority trial to futility, and unusually selected 0.15 as their one-tailed alpha – a choice severely restricting their ability to reject the null hypothesis.
Determination of primary outcome data was completed utilizing the Glasgow Outcome Scale (GOS) using a variety of strategies, including in person and phone follow up.   For all comparisons – both transfusion thresholds and Epo – no statistically significant difference was detected.  Given their small sample, they may simply have been unable to produce a difference – as Epo seemed to potentially have some beneficial effect, though transfusion certainly showed no such signal.  Risk of death, infection, ARDS, and Cardiovascular complications including VTE were evaluated for as well, and both Epo groups and the 10g/dL transfusion group had significant increased risk of adverse events.  And, regarding resource utilization, the transfusion threshold group obviously consumed more blood products.
The study had several limitations including change in Epo protocol with 1/3 of the patients already enrolled, inability to blind clinicians to transfusion threshold, the aforementioned statistical limitations, and generalizability limitations owing to its enrollment at only two trauma centers.  Overall the results were unable to demonstrate benefit to either strategy – but were able to demonstrate definite harms.  Until further evidence is presented, it is prudent to continue conserving blood products and abstaining from giving ineffective, expensive medication.
“Effect of Erythropoietin and Transfusion Threshold on Neurological Recovery After Traumatic Brain Injury A Randomized Clinical Trial”

http://www.ncbi.nlm.nih.gov/pubmed/25058216

The Scandal of Dabigatran – A Summary

We’ve been desperate for a more elegant solution to anticoagulation than rat poison for seemingly an eternity.  Now, we have them: direct thrombin and factor Xa inhibitors.  The studies supporting their use seem favorable.

But, as the old story goes – and as previously reported on this blog many times – Boehringer Ingelheim has been selectively reporting only the most favorable aspects of their flagship drug, dabigatran.  Increased cardiovascular events have been downplayed through study design not powered to detect a difference.  Issues with fixed dose therapy – and lack of a range of options for patients with renal impairment – rear their ugly head in multiple case reports.

Then, the most damning – the recent legal action reveals Boehringer Ingelheim, after selling dabigatran as not requiring monitoring nor having a reliable assay to monitor its effects, was hiding information on both counts.  There is, in fact, substantial individual-patient variability in dabigatran efficacy and bleeding risk, and the HEMOCLOT test is, in fact, a reliable method of measuring activity.  Review of internal documents shows employees were aware many patients might benefit from routine monitoring of levels – but this would eliminate one of its selling points (and cost savings) over warfarin.  These e-mails also specifically address the potential damaging effect on sales if said information were released in the scientific literature.

Clearly, yet another case where first-mover status into a lucrative market trumped patient-safety concerns.  If you wonder where the rampant skepticism regarding conflict-of-interest comes from on this blog – this is a beautifully flagrant example.

“Dabigatran: how the drug company withheld important analyses”
http://www.bmj.com/content/349/bmj.g4670 (free fulltext)

Previous EM Lit of Note Posts:
“Rivaroxaban Can Be Reversed, But Not Dabigatran” – Sept 2011
“Scattering Tacks In The Road” – Jan 2012
“Dabigatran — Uncharted Waters and Potential Harms” (Annals of Internal Medicine) – May 2012
“Dabigatran – It’s Everywhere!” – Sept 2012
“Not-So Routine Surgery on Dabigatran” – Sept 2012
“Dabigatran: Hidden Danger in the Home” – Nov 2012
“Dabigatran & CES1 SNP rs2244613” – Mar 2013

A Prehospital Transfusion Confusion

Which is to say – endorsing conclusions founded on sparse data is worse than simply admitting the limitations of our knowledge.

Clearly, if a patient requires blood, the more, the sooner, the better with severe injury.  However, starting that transfusion outside a setting fully capable of assessing injury severity and physiology can mean wasted or inappropriate product use.

These authors attempt to show patients receiving blood in the pre-trauma center setting have markedly decreased mortality and traumatic coagulopathy.  However, they do so using a retrospective database of patients from 2003 to 2010, of which only 50 patients received pre-trauma center transfusion, compared with 1,365 who did not.  Additionally, there were diverse differences in ISS, base deficit, and total crystalloid and product transfusion.  They subsequently attempt to control for this using logistic regression and by deriving a propensity-matched cohort – which then compares 35 patients with pre-hospital transfusion with 78 patients without, but still has diverse significant differences in initial physiology and total product transfusion.

So, because of all these intrinsic differences, all their reported odds ratios are adjusted after “controlling for confounders”.  After all the statistical wrangling, “covariate-adjusted” 30 day survival was ~95% in the cohort with pre-trauma center transfusion, and ~88% in others.  The propensity-matched results showed similar odds ratios.  Unadjusted mortality in the cohorts is not presented.

Who knows what this really shows?  The data used is retrospective, heterogenous and collected over the course of 8 years, their sample of pre-trauma center transfusions is tiny, and all their reported odds ratios required huge statistical adjustments.  Pre-trauma center transfusions are probably helpful, if used judiciously, but this is not the study that shows it.

“Pretrauma Center Red Blood Cell Transfusion Is Associated With Reduced Mortality and Coagulopathy in Severely Injured Patients With Blunt Trauma”

Predicting Past Massive Transfusion Practices

Traumatic resuscitation is evolving – and reasonably so – to an aggressive, early-intervention strategy.  The current evidence seems to suggest patients benefit from early, whole blood volume replacement in the setting of hemorrhage.

But, in order to aggressively intervene early, it’s necessary to predict such need equally early in the initial trauma assessment process.  Therefore, a variety of prediction decision-instruments have been derived, such as this one from Japan.  These authors looked retrospectively at 119 severely injured trauma patients, developed odds ratios for massive transfusion via logistic regression, and then created a scoring system with a cut-off predicting massive transfusion.  They then subsequently validated this score on another retrospective cohort of 113 patients from the same institution.  Their score contains, essentially, the expected elements – age, lactic acid level, systolic blood pressure, FAST exam findings, and pelvic fracture type – and a score of 15 or higher was 97.4% sensitive and 96.2% specific for massive transfusion.

However, what this rule predicts is not the population that needs massive transfusion – but, because both steps were performed retrospectively, it simply describes the consistency in the authors’ general practice at this single institution.  At the authors’ institution, the patients that looked like the ones described by the rule – elderly, hypotensive, positive FAST, etc. – are the ones that received massive transfusion.  Therefore, when they look back to derive a decision instrument – they’ll find it simply reflects their general practice.  Subsequently, to validate the instrument – again, if their practices haven’t changed, the decision rule will simply accurately reflect the continued practice pattern from which it was derived.  The authors do not mention whether they had a formal early massive transfusion protocol or practice in place, but, if so, this would further skew the decision instrument to reflect the guidelines guiding practice, rather than actual patient need.  Finally, for one last hit to external generalizability, a “massive transfusion” was defined as 10 units of PRBCs – which, in Japan, are about 1/3rd the volume of those in the United States.

Despite its reportedly excellent performance, this rule cannot be relied upon until prospective, external study validates its use.

“Predicting the need for massive transfusion in trauma patients: The Traumatic Bleeding Severity Score”
http://www.ncbi.nlm.nih.gov/pubmed/24747455