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
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…

  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].

Monday, June 1, 2015

It's 5 O'Clock in the ED Somewhere: An Intoxicating Review of Antidotal Ethanol you have a patient who consumed almost an entire gallon of antifreeze over a span of 24 hours. Even Animal House’s Blutowski would be concerned, given that an adult who inadvertently sips 10-30 mL of antifreeze should be referred to the emergency department for evaluation of potential toxicity [1]. Initial lab results reveal an ethylene glycol (EG) level of 76 mg/dL, arterial pH of 6.9, and a serum bicarbonate level of 7 mmol/L. The medical team requests treatment with fomepizole, however due to its recent stint on ASHP’s National Drug Shortage List [2], you're forced to create a good old-fashioned intravenous ethanol cocktail.

The use of ethanol as an antidote for methanol and EG poisonings was first documented in the 1940s and 1960s, respectively [3]. Toxicity occurs secondary to accumulation of toxic metabolites formed by the enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (Figure 1). Although clinical presentation may vary between individuals, acute EG intoxication often progresses through three distinct stages: central nervous system depression (0.5-12 hours post ingestion), followed by cardiopulmonary dysfunction (12-24 hours), and lastly renal dysfunction (24-72 hours) [4]. Profound metabolic acidosis arises from accumulation of glycolic acid and oxalic acid, which may trigger hyperventilation (Kussmaul breathing) as a compensatory mechanism. Furthermore, visual disturbances and blindness have been reported in patients with severe methanol poisoning.

Management generally consists of supportive care (e.g. intravenous fluids, correction of electrolyte abnormalities and acidemia, etc.), the use of antidotes to antagonize ADH and prevent the formation of toxic metabolites, and hemodialysis. Hemodialysis fosters the removal of parent compounds as well as their toxic metabolites and is considered a key element in the treatment of severe EG and methanol intoxication. This may allow for a shorter duration of antidotal therapy and a reduction in hospital length of stay [4].

When should antidotal therapy be initiated following EG or methanol ingestion? [3,5,6,7]
  1. Serum EG or methanol level >20 mg/dL
  2. Documented history of recent ingestion of toxic alcohol and osmole gap >10 mOsm/L
  3. Clinical suspicion of toxic alcohol poisoning with at least 2 of the following criteria: 
    •  Arterial pH <7.3  
    • Serum bicarbonate level <20 mmol/L
    • Serum osmole gap >10 mOsm/L
    • Calcium oxalate crystallization
Evidence regarding criteria for initiation of hemodialysis is more limited, and often based on clinical experience. Some criteria previously reported include an initial EG/methanol level >50 mg/dL, severe metabolic acidosis, renal failure, visual disturbances (methanol ingestion), and deterioration of vital signs or electrolyte imbalances unresponsive to conventional care [4].

Ethanol vs. Fomepizole
Since its approval in 2000, fomepizole has been touted as a safer, more practical antidote, which has subsequently led to a decreased usage of ethanol in the clinical setting. Nonetheless, practitioners should be aware of the evidence (albeit very limited) comparing these two antidotal agents given the recent shortage of fomepizole.
  • To date, no prospective randomized trials have directly compared the efficacy of ethanol to fomepizole
  • Neither ethanol nor fomepizole affect the toxic metabolites already present in the body
  • Fomepizole has a higher potency to inhibit ADH, with a slightly longer duration of action
  • An observational cohort study of 172 hospitalized patients found that the administration of ethanol was associated with a higher rate of adverse drug events (ADE) compared with fomepizole (57% versus 12%). Central nervous system depression was the most frequent ADE reported (48% ethanol vs. 2% fomepizole) [8].
  • Unlike ethanol, fomepizole does not require serum concentration monitoring
  • The acquisition cost of fomepizole is much greater than ethanol, however this may be negated by ICU costs should intravenous ethanol be required

Ethanol is a pharmacokinetic nightmare
A summary of in vitro experiments using human liver cells found the affinity of ethanol for alcohol dehydrogenase is 67 times that of ethylene glycol and 15.5 times that of methanol [9,10,11]. At least a 1:4 molar ratio of ethanol to EG/methanol is required for sufficient saturation of ADH to prevent further metabolism of EG and methanol to their toxic metabolites. To achieve this ratio, a goal serum ethanol concentration of 100-150 mg/dL should be targeted [12].

When administered orally, ethanol is rapidly absorbed from the stomach within 5-10 minutes and reaches peak effect in 30-90 minutes; however, these parameters are highly variable and depend on the concentration of ethanol and the size/duration from last meal, chronic alcohol ingestion, nutritional status, and several other factors [13]. While intravenous ethanol has the advantage of complete absorption and may provide slightly easier titration, IV treatment requires ICU admission and frequent monitoring of serum ethanol levels (every 1-2 hours) [14].

Regardless of route of administration, the effect of ethanol on the CYP system may lead to unwanted drug interactions and pharmacokinetic tolerance after several days of administration [15].

Preparation and dosing
Commercial preparations of ethanol in 5% dextrose are no longer available for IV administration. A 10% sterile ethanol USP solution can be extemporaneously prepared by adding 55 mL or 110 mL of absolute ethanol to 500 mL or 1000 mL of D5W, respectively.

If any delay in preparing ethanol for IV use is expected, then oral ethanol should be initiated immediately. In addition to antidotal therapy, thiamine and pyridoxine should be administered daily to stimulate the conversion of glyoxylate to nontoxic metabolites.

Loading dose
Maintenance dose
Adjustment for HD
Common ADEs
(20% ethanol [40 proof] in juice given orally or via NG tube)

4 mL/kg

0.4-0.7 mL/kg/hour

Chronic drinker:
0.8 mL/kg/hour

0.22 mL/kg/hour

Chronic drinker:
0.33 mL/kg/hour

status changes, hypoglycemia, liver toxicity, pancreatitis

(10% solution in D5W) Central line preferred to reduce venous irritation

8 mL/kg over 20-60 min

 0.8-1.3 mL/kg/hour

Chronic drinker:
1.5 mL/kg/hour

2.5 mL/kg/hour

Chronic drinker:
3.5 mL/kg/hour

Loading dose
Maintenance dose
Adjustment for HD
Common ADEs

Fomepizole (IV)

15 mg/kg

10 mg/kg q12h x 4 doses, then 15 mg/kg q12h until resolution of toxicity and EG level <20 mg/dL

Administer dose at initiation of HD is last dose given >6 hours ago

Increase dosing frequency to q4h

Alternative regimen: 1-1.5 mg/kg/hour continuous infusion

Headache (14%), nausea (11%), dizziness (6%), increased drowsiness (6%)

How long should antidotal therapy be administered?
Antidotal therapy should continue until serum EG/methanol level is <20 mg/dL and clinical manifestations of toxicity are resolved (e.g. resolution of metabolic acidosis and osmole gap, etc.). The half-lives of EG and methanol are dependent on both the presence of ADH blockade and hemodialysis.

EG follows zero-order kinetics with a half-life of 3-9 hours in the absence of treatment. This is extended to approximately 17 hours in the setting of ADH blockade [16,17,18]. Alternatively, methanol does not undergo significant renal elimination and is cleared more slowly than EG with a half-life of 30-54 hours in the setting of ADH blockade [19,20,21]. When hemodialysis is combined with antidotal therapy, half-lives of EG and methanol are both dramatically reduced to approximately 2.5-3.5 hours [21,22].

The bottom line…
  • Fomepizole is currently on ASHP’s national drug shortage list (a limited supply is available from Mylan for drop shipment only)
  • Ethanol is an effective alternative for the management of toxic EG or methanol ingestion but is associated with a greater number of adverse effects (e.g. altered mental status, hypoglycemia, hepatic toxicity) when compared with fomepizole
  • Ethanol dosing must be adjusted for patients with chronic alcohol consumption and in those receiving  hemodialysis
  • Serum ethanol levels should be monitored every 1-2 hours with a target concentration of 100-150 mg/dL
  • Continue antidotal ethanol until serum EG level is <20 mg/dL and clinical manifestations of toxicity are resolved

1.       Caravati EM, Erdman AR, Christianson G, et al. Ethylene glycol exposure: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol. 2005;43(5):327-45.
2. Accessed electronically 22 May 2015.
3.       Barceloux DG, Krenzelok EP, Olson K, et al. American Academy of Clinical Toxicology Practice Guidelines on the treatment of ethylene glycol poisoning. Ad Hoc Committee. J Toxicol Clin Toxicol. 1999;37:537–560.
4.       Rietjens SJ, de Lange DW, Meulenbelt J. Ethylene glycol or methanol intoxication: which antidote should be used, fomepizole or ethanol? Neth J Med. 2014;72(2):73-9.
5.       Brent J. Fomepizole for ethylene glycol and methanol poisoning. N Engl J Med. 2009;360:2216-23.
6.       Barceloux DG, Bond GR, Krenzelok EP, et al. American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning. J Toxicol Clin Toxicol. 2002;40:415-46.
7.       Megarbane B. Treatment of patients with ethylene glycol or methanol poisoning: focus on fomepizole. Open Access Emerg Med. 2010;2:67-75.
8.       Lepik KJ, Levy AR, Sobolev BG, et al. Adverse drug events associated with the antidotes for methanol and ethylene glycol poisoning: a comparison of ethanol and fomepizole. Ann Emerg Med. 2009;53:439–450.
9.       Li TK, Theorell H. Human liver alcohol dehydrogenase: inhibition by pyrazole and pyrazole analogs. Acta Chem Scand. 1969;23:892–902.
10.   Pietruszko R. Human liver alcohol dehydrogenase inhibition of methanol activity by pyrazole, 4-methylpyrazole, 4-hydroxymethylpyrazole and 4-carboxypyrazole. Biochem Pharmacol. 1975;24:1603–1607.
11.   Pietruszko R, Voigtlander K, Lester D. Alcohol dehydrogenase from human and horse liver—substance specificity with diols. Biochem Pharmacol. 1978;27:1296–1297.
12.   Jacobsen D, McMartin KE. Methanol and ethylene glycol poisonings: mechanism of toxicity, clinical course, diagnosis and treatment. Med Toxicol. 1986;1:309–334.
13.   Zakhari S. Overview: how is alcohol metabolized by the body? Alcohol Res Health. 2006;29:245–254.
14.   Julkunen RJ, Tannenbaum L, Baradna E, et al. First pass metabolism of ethanol: an important determinant of blood levels after alcohol consumption. Alcohol. 1985;2:437–441.
15.   Howland M. Antidotes in Depth. In: Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. eds. Goldfrank's Toxicologic Emergencies, 10e. New York, NY: McGraw-Hill; 2015.
16.   Boyer EW, Mejia M, Woolf A, Shannon M. Severe ethylene glycol ingestion treated without hemodialysis. Pediatrics. 2001;107;172–173.
17.   Cheng JT, Beysolow TD, Kaul B, et al. Clearance of ethylene glycol by kidneys and hemodialysis. J Toxicol Clin Toxicol. 1987;25:95–108.
18.   Sivilotti MLA, Burns MJ, McMartin KE, Brent J. Toxicokinetics of ethylene glycol during fomepizole therapy: implications for management. Ann Emerg Med. 2000;36:114–124.
19.   Brent J, McMartin K, Phillips S, et al. Fomepizole for the treatment of methanol poisoning. N Engl J Med. 2001;344:424–429.
20.   Kraut JA, Jurtz  I. Toxic alcohol ingestions: clinical features, diagnosis, and management. Clin J Am Soc Nephrol. 2008;3:208–225.
21.   Palatnick W, Redman LW, Sitar DS, et al. Methanol half life during ethanol administration: implications for management of methanol poisoning. Ann Emerg Med. 1995;26:202–207.
22.   Eder AF, McGrath CM, Dowdy YG, et al. Ethylene glycol poisoning: toxicokinetic and analytical factors affecting laboratory diagnosis. Clin Chem. 1998;44:168-77.