Category: Hematology

Infections & Transfusions

We love our transfusions down in the Emergency Department.  We especially love them in our trauma patients – and, if anything, the move is to provide earlier, more aggressive volume replacement, and to use more FFP, cryoprecipitate, and platelet product to maintain optimal coagulation parameters.

The downside?  Besides cost, over-utilization of a limited resource, and the various adverse reactions that may occur – there’s a bit of an infection risk.

This JAMA meta-analysis pools together the results of 18 trials comparing “restrictive” vs. “liberal” transfusion strategies for PRBCs.  These trials ranged across medicine from cardiovascular settings, the critically ill, sickle cell disease, and other surgical settings.  In most trials, the restrictive transfusion setting ranged from a Hgb of 7 to 9 g/dL, while the liberal strategies were typically goals above 10 g/dL.  These authors simply looked at the pooled incidence of “serious infection”, which was typically reported as wound infection, bacteremia, pneumonia, or a broad definition of sepsis.

In the “restrictive” transfusion group, there was an overall pooled risk of infectious complication of 11.8% (95% CI, 7.0%-16.7%), compared with an infectious complication rate of 16.9% (95% CI, 8.9%-25.4%) in the “liberal” transfusion group.  The authors estimated a “number needed to harm” between 20 and 38, depending on the restrictive transfusion threshold.

This study does not, by itself, indicate transfusions ought to be withheld when indicated.  Rather, these authors primarily suggest, in order to fully describe the risks and benefits of any transfusion strategy, that infectious complications be included in data collection during trials.  This ought to be of even greater importance in the new surveillance of massive transfusion protocols – as PRBC products aren’t typically even the highest-risk for subsequent infectious complications.

“Health Care–Associated Infection After Red Blood Cell Transfusion”
http://www.ncbi.nlm.nih.gov/pubmed/24691607

4-Factor PCC, Skepticism and Surrogate Endpoints

A guest post by Rory Spiegel (@CaptainBasilEM) who blogs on nihilism and the art of doing nothing at emnerd.com.

Despite a lack of clinical data supporting their superiority, 4-factor PCCs have been universally accepted as the intervention of choice for the reversal of Warfarin induced bleeding. While PCCs have demonstrated rapid normalization of INR values, they have yet to show any added value over FFP in true clinically relevant endpoints. In the largest RCT to date, 4-factor PCC corrected INR values far faster than FFP but with a mortality rate that was almost double that of the FFP group. In a recent small RCT published in American Journal of Emergency Medicine, Karaca et al attempted to demonstrate that 4-factor PCCs provide more than just surrogate benefits when treating Warfarin induced gastrointestinal hemorrhage.


In this small unblinded trial, 40 patients with clinically suspected upper GI bleeds were randomized to have their coagulopathy reversed by either FFP or Cofact, a 4-factor PCC. The outcomes examined by the authors were INR values at 2 and 6 hours, time-to-endoscopy, and percentage of patients with active hemorrhage at time of endoscopy (based on the Forrest Classification). Patients were required to have their INR level reach 2.1 before undergoing definitive endoscopic interventions. As is typical in FFP vs PCC trials, the dose of FFP used was bordering on a straw man dose at 10-15 cc/kg.

To what should be no one’s surprise, 4-factor PCC reduced INR levels significantly faster than FFP, and thus patients in the PCC group underwent endoscopy earlier than their FFP counterparts. Patients in the PCC group received their endoscopy on average at 8 hours after admission, while the FFP group underwent endoscopy closer to the 12 hour mark. Endoscopy revealed more patients with active hemorrhage (Forrest Classification 1a or 1b) in the FFP group (7 patients vs 0) and sclerotherapy was performed in 10 patients in the FFP group, with 1 in the PCC group. Furthermore 3 patients in the FFP group required further therapy due to rebleeding, while no events of rebleeding occurred in the PCC group.

These superiorities in surrogate and pseudo-surrogate endpoints did not translate into the patient oriented endpoint of mortality, which was equivalent (one patient in each group). As far as the dreaded complication of “thrombolic events” that has been associated with PCC use it is somewhat unclear. One patient in the PCC group experienced a fatal IVC thrombosis but authors claim this condition was a presenting malady rather than an adverse event due to the administration of PCC.

Once again PCC has found success upon examination of soft endpoints. In an unblinded trial with surrogate and subjective endpoints, it is unclear if the PCC group’s performance was due to the medication’s efficacy or simply random chance and a small cohort. Until superiority in concrete clinically relevant outcomes is demonstrated, we should be wary of the crown of supremacy PCCs currently flaunt.

“Use and effectiveness of PCC vs FFP in gastrointestinal hemorrhage due to warfarin usage in the emergency department”
www.ajemjournal.com/article/S0735-6757%2814%2900107-7/abstract

All NSAIDs are Created Equally . . . Right?

A guest post by Anand Swaminathan (@EMSwami) of EM Lyceum and Essentials of EM fame.

It’s been more than 10 years since Merck made headlines regarding the increased risk of atherothrombotic events with it’s drug rofecoxib (Vioxx) and 3 years since the almost $1 billion settlement regarding the drug. Over this time period, physicians have questioned the use of all non-steroidal anti-inflammatory drugs (NSAIDs) in patients with increased risk of coronary artery disease. Rofecoxib and its brethren were developed in the 1990’s as alternatives to the traditional NSAIDs (tNSAIDs). These newer drugs only inhibited COX-2 and theoretically would lead to less gastrointestinal bleeding since inhibition of COX-1 is believed to lead to this side effect. Based on this pathophysiologic theory and strong marketing, the drugs became widely prescribed. Unfortunately for our patients, saving the gut may compromise the heart. Or is it actually that all NSAIDs, regardless of which COX they inhibit, raises the risk?

This research group performed a meta-analysis of a large number of trials looking at both NSAIDs vs. placebo (280 trials) and one NSAID vs. another NSAID (474 trials). All of the studies look at length of use of at least four weeks but many had longer treatment durations. So, what did they find? When compared to placebo, coxibs (COX-2 inhibitors), diclofenac and ibuprofen all increased the risk of major coronary events but naproxen did not:
Coxibs RR (CI)
Diclofenac RR (CI)
Ibuprofen RR (CI)
Naproxen RR (CI)
Major Vascular Events
1.37 (1.14 – 1.66)
1.41 (1.12 – 1.78)
1.44 (0.89 – 2.33)
0.93 (0.69-1.27)
Major Coronary Events
1.76 (1.31-2.37)
1.70 1.19-2.41)
2.22 (1.10 – 4.48)
0.84 (0.52 – 1.35)
Gastrointestinal Complications
1.81 (1.17-2.81)
1.89 (1.16-3.09)
3.97 (2.22-7.10)
4.22 (2.71-6.56)

Additionally, it didn’t matter which coxib they looked at: all of them increased major coronary events. The coxibs did, however, do what they were supposed to do; the risk of gastrointestinal bleeding was lower in comparison to tNSAIDs like ibuprofen and naproxen.

Does this change what we should do? Can we give NSAIDs to older patients without fearing a major coronary event or death from an MI? The numbers here are small but important. For every 1000 patients allocated to a coxib, three more had major vascular events and one of these events would be fatal. That’s an absolute increase of 0.1% in comparison to placebo. Small increased risk but avoidable. Why not give naproxen instead? In fact, NSAIDs like ibuprofen interfere with the binding of aspirin negating its cardioprotective effects if the two are taken together. Naproxen doesn’t have this issue.
The relative safety in terms of major vascular events associated with naproxen versus ibuprofen was recently written about by the FDA and reported by the Associated Press here –

http://hosted.ap.org/dynamic/stories/U/US_PAIN_RELIEVERS_SAFETY?SITE=AP&SECTION=HOME&TEMPLATE=DEFAULT

I think the bottom line here isn’t much of a surprise. If you can, avoid NSAIDs in patients with cardiac risk factors. Ibuprofen isn’t a safe alternative. If you need to give an NSAID for whatever reason, use naproxen and use short courses of therapy.
“Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomized trials”

More Bleeding Nightmares

Do you like managing bleeding on aspirin?  How about aspirin plus clopidogrel?  What would you say to aspirin + clopidogrel + vorapaxar?

Vorapaxar, a selective antagonist for protease-activated receptor 1, is the next proposed layer of anti-thrombotic prevention for high-risk cardiovascular patients.  Just this week, back from the dead, it received a favorable review from an FDA panel tasked with examining its application for approval.

The subject of both TRACER and TRA 2°P-TIMI 50, vorapaxar may soon bless your Emergency Department with a roughly 60% increase (2% vs. 3.5%) the risk of GUSTO moderate or severe bleeding.  What’s most fascinating about this drug is, technically, both trials were negative for the primary endpoint, and TRACER was stopped early after interim safety review.  However, a pre-specified and pre-allocated subgroup from TRA 2°P-TIMI 50 for patients with recent MI – and no history of stroke – showed benefit.

Of course, as is standard for these sorts of cardiovascular trials, it showed benefit primarily in the questionable combined endpoints – and, likewise, was only safe in the narrowest slicing and dicing of favorable endpoints and bleeding outcomes.

It should be of no surprise to anyone most authors are being substantially enriched by multiple drug companies.  I’m certain whatever foot-in-the-door Merck receives will be enough to extract the necessary healthcare dollars from the system for minimal benefit – a net NNT for mortality of ~450.

Oh, and as the great Tom Deloughery (@bloodman) writes:

“Hmmm – a competitive platelet inhibitor with a T1/2 of ~300hrs!  So, sounds like it will inhibit any platelets you give for the next 12 days … I guess Dr. Radecki will be holding direct pressure for a long time!”

“Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial”
http://www.ncbi.nlm.nih.gov/pubmed/22932716

4-Factor PCC is Here! Yay?

The self-described “EM Nerd” Rory Spiegel from Newark Beth Israel writes in to point out a fascinating discovery – previously undiscovered clinical trial results for Kcentra, the newly available 4-Factor Prothrombin Complex Concentrate, embedded in the product labeling.

4-factor PCCs are well-known from their use in Europe – capable of rapid reversal of factor-dependent coagulopathy at the expense of increased thrombotic complications.  Within the package labeling, however, two new Phase III trials are described – open-label, randomized, non-inferiority comparisons.  The trials, for what they’re worth, show no significant outcome difference compared with FFP – but, yet again, no clinically relevant threshold for non-inferiority is established to drive sample size calculations.  I’d like to comment more, but they only provide detailed adverse event information on one of the two trials.  Perhaps we’ll see these published and peer-reviewed imminently.

It should also be noted the extensive exclusion criteria used to enroll patients in these studies – a far longer list than the few contraindications listed on the package label.  These criteria may be noted on the ClinicalTrials.gov site.

Lovely to see we’ve now another costly reinvention of the wheel that will almost certainly be overutilized at the behest of Bering’s marketing army.

“Efficacy and Safety Study of BERIPLEX® P/N Compared With Plasma in Patients With Acute Major Bleeding Caused by Anticoagulant Therapy”
http://clinicaltrials.gov/ct2/show/NCT00708435

“The Sign of Four…”
http://emnerd.tumblr.com/post/50947148065/the-sign-of-four

“CSL Behring 1.14.1.3 Draft Labeling Text”
http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM350239.pdf

Prophylactic Platelet Transfusions Needed?

Every so often, we’re referred a patient from the hematology clinic for prophylactic platelet transfusion when their infusion center is full.  As these authors state, it is common practice to routinely prophylactically transfuse platelets in the presence of severe thrombocytopenia.

And, the abstract conclusion here is:  “The results of our study support the need for the continued use of prophylaxis with platelet transfusion and show the benefit of such prophylaxis for reducing bleeding, as compared with no prophylaxis.”

This conclusion is the dubious interpretation of a combined endpoint of uncertain clinical significance.  Their primary endpoint was the summation of WHO 2, 3 and 4 bleeding.  Nearly all their bleeding was WHO 2 – essentially, troublesome, but self-limited bleeding not requiring transfusion.  With regards to major bleeding, the per-protocol rates were 5/258 in the no-prophylaxis group and 1/230 in the prophylaxis group – falling short of statistical significance, but reasonably clinically significant.

There was a 0.2 unit PRBCs per patient difference in transfusion between the prophylaxis group and the no prophylaxis group.  There was, obviously, a 1.3 unit platelets per patient difference between groups.  Hospitalization days were similar.  No patient died from bleeding.  One patient in the prophylaxis group suffered a transfusion-related anaphylactic event.

So, yes – platelet transfusions reduce bleeding.  I’m just not certain these authors have demonstrated the net benefit – given 66 patients receiving prophylactic transfusions, 1 fewer non-fatal important bleeding event.  Clinically insignificant net PRBC difference, significantly higher usage of platelet transfusions.  I think there is plenty of room to debate cost and benefit – particularly considering interesting hypothesis-generating subgroup variation.

The authors declared multiple conflicts-of-interest, although it’s not clear to me if any of them would be relevant to the current study.

“A No-Prophylaxis Platelet-Transfusion Strategy for Hematologic Cancers”
http://www.nejm.org/doi/full/10.1056/NEJMoa1212772