Thursday, October 26, 2017

FTFY: Prothrombin Complex Concentrate, That Is

logo-kcentra.pngThe last post on EMPharmD concerning fixed-dose Kcentra was way back in June, 2015 and discussed a newly published article by Klein et al. examining 1500 units of 4-factor prothrombin complex concentrate (4PCC) for warfarin reversal.(1)  Since that post, only one additional article has been published regarding fixed-dose 4PCC, and unfortunately, Abdoellakhan et al. only used 1000 units per dose as part of their protocol. As to be expected with the lower dosing, achievement of a goal INR < 1.5 was worse in the fixed-dose group compared to variable dosing group (68% vs 96%, p= 0.013).(2)


Although little has been published lately regarding fixed-dose 4PCC, there were a handful of posters presented at the last ASHP Midyear Clinical Meeting on fixed-dose PCC. Additionally, Gorlin et al. published survey results from 48 hospitals in the US, Europe, Canada, and South America on their VKA reversal protocols. Six institutions (18% of respondents) reported using a fixed-dose 4PCC protocol, with half of them dosing at 1500 units.(3) Currently, there are two trials listed on ClinicalTrials.gov evaluating fixed-dose protocols. One study is using 1500 units of 4PCC while the other is looking at activated-4PCC compared to standard 4PCC dosing. I know of at least two more ongoing studies examining fixed-dose PCC protocols and I’m sure there are several others out there.


If you don’t have a fixed-dose protocol in your hospital, you should consider implementing one. Why? Well, for starters, the ideal dose of Kcentra is unknown. Dose-finding studies were not completed as part of the FDA approval process for Kcentra and they aren’t due for submission until 2019.(4) You can rest assured that CSL Behring is going to wait as long as possible to submit those studies as they are likely to show that 5000 units of 4PCC is overkill. To put that amount of 4PCC in perspective, each unit (~250 ml) of FFP has approximately 200-250 units of FIX.(5) Therefore each 500 unit vial of Kcentra is equivalent to about 2 units of FFP, so 10 vials (i.e., the maximum dose) is about 20 units, or 5 liters, of FFP.


Additionally, by implementing a fixed-dose protocol you will save your hospital, and your patients, lots of money. Klein et al.’s study reported cost savings to the hospital of over $40,000 with only 36 patients; that’s over $1,000 per patient! When combined with equivalent efficacy (when used at the right doses), potentially less thrombotic complications with the lower dosing (6,7), and the dramatic cost savings, it becomes hard to argue against a fixed-dose protocol.

money gif.gif


I have implemented fixed-dose protocols in two health-systems so far and I want to help anyone else interested in implementing one at their hospital. With this post is a 19 page document with a review of the five most recent fixed-dose 4PCC studies and 1 systematic review that I have used as evidence to support the adoption of a fixed-dose Kcentra(R) protocol. The document can be found on the blog’s home page under the tab “Protocols and Additional Information.” I am including the document so any other healthcare professional who is interested in implementing a fixed-dose PCC protocol at their institution can use this to support their cause.

My protocol:
Proposed Kcentra® Dosing Protocol For Emergent Warfarin Reversal:
  • Kcentra® should be initiated prior to INR results to aid in rapid administration of therapy
  • All patients will receive 10 mg IV Vitamin K with Kcentra®
  • All patients will receive an initial fixed dose of 1500 units FIX (3 vials) of Kcentra® for severe life-threatening bleeding due to warfarin therapy
    • Non-life threatening bleeding recommended to be managed with FFP + Vit K
  • For the following patients, or at the discretion of the physician, consider increasing empiric dose to 2000 units FIX (4 vials):
    • TBW > 100kg
    • INR > 7.5-10 (if known prior to initiation of therapy)
  • For patients who have already received Kcentra® prior to INR results, and the baseline INR returns > 7.5-10, consider an additional 500 units FIX (1 vial) for a total of 2000 units FIX (4 vials)
  • Consider ordering a repeat PT/INR 10-60 minutes after Kcentra® infusion
  • If repeat INR is > 2, consider additional 500-1000 units FIX (1-2 vials) if patient has not had a positive clinical response to initial therapy
Avoid in patients with DIC, history of HIT, or recent history of thrombosis, MI or ischemic stroke


This protocol is slightly different than the standard 1500 units for everyone. First, for patients > 100 kg, the dose is increased to 2000 units. This recommendation was based on the post-hoc analysis by Klein et al which showed patients in the failure group had a median weight of 95 kg compared to 78.5 kg in the success group.(1) I choose 100 kg as the cutoff as it was a little “cleaner” and easier to remember than 95 kg. Additionally, as this was a post-hoc analysis (and only included 39 patients), my general takeaway is that larger patients require higher doses.  Secondly, for patients with a baseline INR > 7.5-10 (if known), the dose is increased to 2000 units. Again, in the post-hoc analysis by Klein, patients in the failure group were almost 10 times more likely to have their baseline INR > 10 (27.3% vs 3.6%). Additionally, based on Khorsand’s 2012 study (although only a 1000 units per dose), patients with a baseline INR of > 7.5 were less likely to reach post-PCC INR goal of < 2 compared to the standard dosing group (80% vs 91%).(8) Although most recommendations for post-PCC INR goals are < 1.3-1.5 (compared to < 2 in the Khorsand study), I still think you can extrapolate these results to 1500 unit regimens as the higher the INR, the more PCC is needed for adequate INR reversal.


As these protocols have only been recently implemented, I don't have enough data yet to evaluate their efficacy compared to standard dose regimens (anecdotally, they seem equivalent so far). Hopefully within the next year or so we’ll have more answers regarding the efficacy compared to not only a standard dosing regimen but also a flat 1500 unit protocol.


You can use my protocol, you can use the more common 1500 units for everyone protocol (you can even use activated-4PCC). Either way, I believe fixed-dosing is the most cost-effective way to use 4PCC.


Scott Dietrich, PharmD
Emergency Medicine Clinical Pharmacist
University of Colorado Health – North

Peer reviewed by Craig Cocchio, PharmD, BCPS (@iEMPharmD) and Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)


Editor Commentary:
Fixed dose PCC is certainly on its way to becoming the standard, rather than the exception. In my own practice, there are clinical circumstances where 500 IU may be the best dose for a patient, particularly after discussing with the surgeons and EM physicians and putting the amount of FIX in PCC into context of FFP (as Scott outlined above).  
I think this is one of the best demonstrations of the benefits of the integration of social media/FOAM and traditional literature. Most of the initial buzz, and at minimum tweeting of the initial protocols of fixed dose PCC, pushed us to critically appraise what we knew about PCC dosing. It led to numerous stories of people in EDs everywhere that started a fixed dose protocol, and it seemed to have anecdotal success. This spread like wildfire around FOAM and now most EDs with EM pharmacists that I spoke with at ACCP indeed had these protocols. All of this accomplished in the 3 years since Kcentra was released. Take that 10 year knowledge-translation!


References: 

1. 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].
2. Abdoellakhan RA,  Miah IP, Khorsand N, Meijer K, Jellema K. Fixed versus variable dosing of prothrombin complex concentrate in Vitamin K antagonist-related intracranial hemorrhage: a retrospective analysis. Neurocritical Care. 2017;26(1):64-69. 
3. Gorlin J, Kinney S, Fung MK, Tinmouth A. Prothrombin complex concentrate for emergent reversal of warfarin: an international survey of hospital protocols. Vox Sang. 2017;112(6):595-597.
4. Zemark WR, Kelley E, Kovicic NL. Thrombotic complications following the administration of high-dose prothrombin complex concentrate for acute warfarin reversal. Am J Emerg Med. 2015 Dec [epub ahead of print]. 
5. Agus N, Yilmaz N, Colak A, Liv F. Levels of factor VIII and factor IX in fresh-frozen plasma produced from whole blood stored at 4°C overnight in Turkey. Blood Transfusion. 2012;10(2):191-193.
6. Dager WE. Using prothrombin complex concentrates to rapidly reverse oral anticoagulant effects. Ann Pharmacother. 2011;45(7-8):1016-1020. 
7. Sorensen B, Spahn DR, Innerhofer P, Spannagl M, Rossaint R. Clinical review: prothrombin complex concentrates- evaluation of safety and thrombogenicity. Crit Care 2011;15(1):201.  
8. Khorsand N, Veeger NJ, van Hest RM, Ypma PF, Heidt J, Meijer K. 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. Haematoligica. 2012;97(10):1501-1506.

Wednesday, October 11, 2017

Two Steps Forward, One Step Back: The Questionable Practice of Reversal of Anticoagulation to Facilitate rt-PA Administration for Stroke


In the process of caring for patients suffering from acute ischemic stroke (AIS), a cognitive bias shifts the focus of our typical approach to drug therapy selection. Rather than approach a problem and determine whether a drug is going to help, in the case of alteplase for AIS, we often look for reasons not to give this drug (contraindications) and fail to ask whether the given patient will benefit. Fewer still will ask, what is the patient oriented benefit? This shift in clinical reasoning is highlighted in this case report describing the reversal of heparin in order to facilitate alteplase administration.(1) This cognitive bias is further reflected in framing of the issue of whether or not we are treating enough patients with alteplase, as described by the authors quoting epidemiologic data. This bias can be remedied by reflecting on the evidence to support the use of alteplase for AIS.


The only supporting evidence for alteplase in AIS comes to us from the NINDS-2 (NINDS 1 & 2, two studies published in one manuscript) and ECASS-3.(2,3) In these studies, the benefits observed were improvement in functional neurologic outcomes at 90 days.  These improvements are not to be confused with a return to baseline function or a curative intervention. Furthermore, NINDS-1 failed to demonstrate superiority of alteplase in improving NIHSS by at least 4 points or neurologic recovery at 24 hours. If you continued to line up the studies where alteplase failed to show improvement in primary outcomes or was stopped early due to futility you have a list including: ECASS-1, ECASS-2, ATLANTIS-A, ATLANTIS-B.(4-7) Not to mention the curious results of the uncontrolled, analysis of registry data ITS-3 study.(8)  However, pause to consider the risk versus benefit: reduction in disability versus intracranial hemorrhage (fatal or not).  Furthermore, these potential harms are the best case scenario given the strict inclusion and exclusion criteria from these studies. In practice, each time we venture outside, we increase the risk of harm without proven increase in potential benefit.(9,10,11,12,13)


When faced with almost certain peril, Dr Ian Malcolm asked “[you] scientists were so preoccupied with whether or not they could, they didn’t stop to think if they should.”(14)  While this quote refers to the genetic engineering and creation of dinosaurs in a fictional story, it cuts through to the core of the issue described in this case. Stroke care has been rapidly advanced in recent years and the patient population exposed to alteplase continues to increase. While we continue to see the strict inclusion and exclusion criteria for this drug slip away, we must remember to stop and think although we can treat this patient with alteplase, should we?


I read with great interest the case report presented by Drs. Fontaine and Smith where a patient was treated with protamine sulfate to reverse unfractionated heparin in order to administer alteplase for AIS following a percutaneous coronary intervention (PCI). It is worth noting that the prasugrel, aspirin and tirofiban that were administered during PCI were not attempted to be reversed. An analysis of 965 patients treated with alteplase found that dual antiplatelet therapy was associated with a significantly increased risk of symptomatic intracranial hemorrhage.(15) In this case, the patient experienced what the authors’ described as a favorable outcome with a modified rankin score of 3 at three months follow up. This outcome would not be included in the primary endpoints of favorable neurologic outcome in either the NINDS-2 or ECASS-3, as scores of 2 or greater were considered “unfavorable” in these trials. While a modified rankin score improvement from 5 to 3 at three months is a positive finding, one should not attribute this outcome to alteplase without acknowledging the improvements made in the totality of stroke rehabilitation care.


This trend in reversing anticoagulant therapy in order to administer alteplase for acute ischemic stroke is troubling given the lack of evidence to support safety and efficacy. Given the minute clinical patient oriented outcome benefits with alteplase for AIS, using reversal strategies to facilitate thrombolytic therapy should not be conducted outside of research settings.


Craig Cocchio, Pharm.D., BCPS
Emergency Medicine Clinical Pharmacist
CHRISTUS Trinity Mother Frances Health System


Kyle DeWitt, Pharm.D., BCPS
Emergency Medicine Clinical Pharmacist
The University of Vermont Medical Center


Scott Deitrich, Pharm.D., BCPS
Emergency Medicine Clinical Pharmacist
Poudre Valley Hospital




  1. Fontaine, G. V. and Smith, S. M. Alteplase for acute ischemic stroke after heparin reversal with protamine – a case report and review. Pharmacotherapy. Accepted Author Manuscript
  2. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke.N Engl J Med. 1995 Dec 14;333(24):1581-7
  3. Hacke W, Kaste M, Bluhmki E, et al.Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008 Sep 25;359(13):1317-29
  4. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Höxter G, Mahagne MH, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995 Oct 4;274(13):1017-25.
  5. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators.Lancet. 1998 Oct 17;352(9136):1245-51
  6. Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g) : results of a double-blind, placebo-controlled, multicenter study. Thromblytic therapy in acute ischemic stroke study investigators. Stroke 2000 Apr;31(4):811-6
  7. Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke.JAMA. 1999 Dec 1;282(21):2019-26.
  8. IST-3 collaborative group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial.Lancet. 2012 Jun 23;379(9834):2352-63.
  9. Graham GD. Tissue plasminogen activator for acute ischemic stroke in clinical practice: a meta-analysis of safety data. Stroke. 2003 Dec; 34(12):2847-50.
  10. Albers GW, Bates VE, Clark WM, et al. Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. JAMA. March 1 2000;283(9):1145–1150.
  11. Lopez-Yunez AM, Bruno A, Williams LS, et al. Protocol violations in community-based rTPA stroke treatment are associated with symptomatic intracerebral hemorrhage. Stroke. January 2001;32(1):12–16.
  12. Tsivgoulis G, Frey JL, Flaster M, et al. Pre-tissue plasminogen activator blood pressure levels and risk of symptomatic intracerebral hemorrhage. Stroke. November 2009;40(11):3631–3634.
  13. Bravata DM, Kim N, Concato J, Krumholz HM, Brass LM. Thrombolysis for acute stroke in routine clinical practice. Arch Intern Med. 2002;162:1994–2001.
  14. Cucchiara B, Kasner SE, Tanne D, et al. Factors associated with intracerebral hemorrhage after thrombolytic therapy for ischemic stroke: pooled analysis of placebo data from the Stroke-Acute Ischemic NXY Treatment (SAINT) I and SAINT II Trials. Stroke. 2009 Sep;40(9):3067-72.

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