Monday, June 8, 2015

Prothrombin Complex Concentrate: Is Less More with Fixed Doses?

Four-factor prothrombin complex concentrate (4FPCC) has been available in the United States for the past two years. We first broke news of its approval by the FDA in the branded form of Kcentra on this blog, and now that we have had clinical experience with it in its use for warfarin-associated bleeding (as well as its off-label use for management of target specific oral anticoagulants as we await the highly anticipated pipeline antidotes of these agents), we can speak to its various accolades and challenges. Indeed, on this very blog, we have covered several aspects related to the clinical application of this product – everything from the trial leading to the approval of the product by the FDA, clinical outcomes relevant for measuring efficacy, and practical issues associated with caveats related to administration of the product, including rate of administration.


And here we are again, revisiting 4FPCC, to discuss one additional nuance that we felt ought to be addressed in light of recent literature. The question here is related to the actual amount that we are administering to our patients for warfarin-associated bleeding. As many clinicians are already aware, the product labeling is very specific as it relates to the amount of 4FPCC necessary for reversal of warfarin-induced coagulopathy, and approved dosing (based on the labeling of Kcentra) is based on INR at presentation and patient weight and is as follows:

Initial INR
2 to < 4
4 to < 6
> 6
Dose
25 units/kg up to a maximum of 2500 units
35 units/kg up to a maximum of 3500 units
50 units/kg up to a maximum of 5000 units
Administer with vitamin K IV x 1 over 30 minutes

As the product has been extensively utilized in both Europe and Canada for several decades prior to its approval in the United States, a debate has ensued as to whether fixed doses or tailored regimens based on initial INR and patient weight can yield superior results. A variety of fixed dose regimens of PCC have been evaluated (1-4), with some even incorporating various fixed doses based on the indication for reversal. However, many folks have advocated for such an individualized dosing regimen for PCC in the management of bleeding secondary to oral anticoagulants (5-6), as standard fixed doses evaluated as a comparator have typically ranged from 500 to 1000 IU of PCC, which are relatively low and may potentially contribute to the perceived greater rate of success with regimens tailored based on initial INR and patient weight, with outcomes traditionally defined as achievement in reduction of INR and/or cessation of bleeding. Indeed, some clinicians have caught on to this observation that a higher dosing regimen may yield better outcomes for bleeding patients and have altered their institutional protocol to reflect this observation (7).

Even among discussions with some of my colleagues regarding this topic, the most common concern that arose was that several of these studies were conducted outside of the United States, making it difficult to apply the results of these studies to the branded product of 4FPCC that is currently available here. To me, it did not make much of a difference; in my mind, the results should be replicable, regardless of the “brand” of 4FPCC. To some, however, until there was some evidence to demonstrate this, the results could not necessarily apply to our patients.

So the question now becomes whether higher fixed doses of 4FPCC can yield similar and potentially more cost-effective results. In fact, investigators of one study, which was published electronically ahead of print (8), aimed to answer this very question. They utilized a fixed dose of 1500 IU of 4FPCC (and yes, the investigators did use the brand Kcentra) for emergent warfarin reversal to preclude the delay in anticipating INR results prior to administration of the product while allowing for rapid administration and potentially yielding lower costs associated with administration of such therapy. In their retrospective review of 39 patients who received such a fixed dose over an 11-month period at a single institution, a median dose of 1659 IU (approximately 20.4 IU/kg [based on varying units of the amount of factor contained per vial]) was administered with nearly 93% of patients also receiving concomitant intravenous vitamin K per the institutional protocol. Nearly three-quarters of all patients had an intracranial hemorrhage at presentation as the indication for 4FPCC. The median INR at presentation was 3.3, and INR measured at a median time of 51 minutes following administration of 4FPCC was 1.4. Nearly all patients had INR reduced to a target value of less than 2, and 71.8% of patients achieved an INR less than 1.5. There was no evidence of thromboembolic events within seven days of treatment, and 76.9% of patients survived to hospital discharge. The authors do note several limitations in their study, not unlike many of those previously conducted, particularly the small number of patients and clinical indicators for hemostasis (or lack thereof), and they do advocate for future evaluations that may overcome some of these limitations.

Nonetheless, this may have important implications in clinical practice. Utilizing potentially less of a product, one that already has a black mark in the budget of many institutional pharmacies and hospital formularies, that can lead to similar results in management of warfarin-induced coagulopathy is certainly a potential game-changer. In addition, having the essential information that a patient presents with a life-threatening bleeding event secondary to warfarin may be enough in and of itself without waiting what may seem like an endless amount of time for an INR and other laboratory values while simultaneously managing other sick patients in the emergency department or other critical areas of the hospital.

Does this tale sound familiar? Well, it was not too long ago where a similar discussion developed over number of years for another product. Dare I mention its name? Yes: Recombinant factor VIIa. And we all know now the fate of that drug in clinical practice; let us just say that it was not pretty.

Who knows what the future holds with 4FPCC? The reversal landscape may be very different within the next two to five years as the pipeline antidotes for target specific oral anticoagulants reach the market and make it into widespread clinical practice, leaving 4FPCC high and dry with potentially decreased off-label use for at least these agents. But then again, warfarin is around to stay...and I have no doubt that the manufacturers of 4FPCC will certainly ensure that sufficient amount of their product will as well.

However, it may be worthwhile approaching the formulary managers at your institution, preferably before the next time you begin to pop off the tops of the ten vials of Kcentra that you may require for reconstitution for your bleeding warfarin patient with an INR of 7 who is over 150 kg – especially since you may not have needed to wait for that INR result to begin with prior to administration of the product itself.


And so the 4FPCC saga continues…

References:
  1. Hirri HM, Green PJ. Audit of warfarin reversal using a new Octaplex reduced dose protocol. Tranfus Apher Sci 2014; 51:141-145.
  2. Junagade P, Grace P, Gover P. Fixed dose prothrombin complex concentrate for the reversal of oral anticoagulation therapy. Hematology 2007; 12:439-440.
  3. Khorsand N, Veeger NJ, van Hest RM, et al. An observational, prospective, two-cohort comparison of a fixed versus variable dosing strategy of prothrombin complex concentrate to counteract vitamin K antagonists in 240 bleeding emergencies. Haematologica 2012; 97:1501-1506.
  4. Varga C, Al-Touri S, Papadoukakis S, et al. The effectiveness and safety of fixed low-dose prothrombin complex concentrates in patients requiring urgent reversal of warfarin. Transfusion 2013; 53:1451-1458.
  5. van Aart, Eijkhout HW, Kamphouis JS, et al. Individualized dosing regimen for prothrombin complex concentrate more effective than standard treatment in the reversal of oral anticoagulant therapy: An open, prospective randomized controlled trial. Thromb Res 2006; 118:313-320.
  6. Khorsand N, Veeger NJ, Muller M, et al. Fixed versus variable dose of prothrombin complex concentrate for counteracting vitamin K antagonist therapy. Transfus Med 2011; 21:116-123.
  7. Wozniak M, Kruit A, Padmore R, et al. Prothombin complex concentrate for the urgent reversal of warfarin: Assessment of a standard dosing protocol. Transfus Apher Sci 2012; 46:309-314.
  8. Klein L, Peters J, Miner J, et al. Evaluation of fixed dose four-factor prothrombin complex concentrate for emergent warfarin reversal. Am J Emerg Med 2015 [Epub ahead of print].