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
While I agree that the data don't necessarily support abandoning FFP or 3PCC for FDA-approved indications, off-label use for dabigatran toxicity is supported by the toxicology literature; currently we use novoseven + 3PCC… having it all in one product is more useful, IMHO.
http://www.ncbi.nlm.nih.gov/pubmed/21887485/
Cheers!
Hm, I have to disagree that PCCs or rVII are indicated for dabigatran-related bleeding. I've read hundreds of articles and case reports, and the "limited and mixed data" referred to by that article is hardly inspiring. You're almost certainly harming as many folks with thrombotic complications as you are (only possibly) helping by partially attenuating the bleeding, at extraordinary cost.
I disagree about harm, and need to point out the difficulty with doing tox-related research that isn't case reports/series – namely, it's unethical (amongst many other things) to intentionally poison a patient. The use of HIE, intralipid, methylene blue all come from animal studies and large case series/metaanalyses/experience.
I'm referring to significant life-threatening bleeding (e.g. ICH); otherwise, the halflife means it's not a big issue. The argument that it's dialyzable is of questionable basis, as most of the nephrologists I've spoken with about this are not clamoring to dialyze an already bleeding patient (need to add heparin to the dialyzer circuit).
Until pradaxa gets pulled, PCC + aVII are the best bet, IMHO, in specific bleeding problems such as ICH.
Of course experimentation in toxicology is limited by ethics, but even the case reports and healthy-volunteer studies of PCCs in dabigatran reversal aren't terribly promising. If you have closed-space bleeding, such as ICH, I think you're much better off with dialysis as an adjunct to neurosurgery. I know some hospitals that have established an rVIIa + PCC protocol for dabigatran, but I think it's a mistake.
Toxicology literature may not have many RCTs, but PCC has been studied prospectively in healthy volunteers who were anticoagulated with dabigatran then given that reserval agent – with essentially no difference compared to placebo. When only the weakest literature supports efficacy while the strongest data says no benefit, I think it's a pretty big jump to say a drug works.