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PCC Products and Reversing Warfarin

William E. Dager, Pharm.D., FCSHP
March, 2007

Approaches to reversing the effects of warfarin can depend on presence or risk of bleeding in addition to the goals of reversal (partial or full), how fast, and for how long. In cases where emergent and full reversal is desired, agents such as prothrombin complex concentrates (PCC) or recombinant activated factor VII (rFVIIa) have been used. However, these products will only provide a temporary effect where their pharmacological effects can wear off (INR rebound) compared to the longer actions of warfarin or other vitamin K antagonists. For a biopsy in the setting of heart failure where fluids are a concern, this can be done as the single agent. If a longer duration of reversal is desired, then additional agents such as fresh frozen plasma (FFP) and vitamin K may be considered.

Of note when reversing anticoagulation is that a concern for thrombosis high enough to initiate anticoagulation already exists where administration of a prothrombotic agent has the potential to encourage new thrombosis formation.

Selecting a reversal agent(s) may also depend on product availability, costs, and experience with its use. The evidence of risk versus prolonged benefit in the setting of a major bleeding event on warfarin is unclear. The use of PCC (Proplex-T 25-50 IU/kg, chosen for its high factor VII content) was recently explored by Lankiewicz MW et al.¹ Fifty-eight warfarin patients (primary indication A Fibrillation = 38; and a majority with a CNS bleed = 36) of whom half also received FFP (which would potentially influence overall outcomes) were included in this open observational analysis. The INR had dropped from a mean of 11.7 (median 3.8) to < 2 in all but 2 patients within 1 hour. The mean and median INR at 24 hours was 1.5 (1.1-3.4). Their was no difference between those who did, or did not receive FFP. Four patients developed a thromboembolic complication (DVT x2; AMI x 2). An editorial by C Kessler in the same issue², however, points out critical issues of variability between products, thrombosis risks, and whether results from the use of one PCC product (each product will vary in the content of clotting factors and other coagulation modifiers) can be translated to others. The bases of the dose (i.e. factor IX content?) and effectiveness (and risk for thrombosis) of one product compared to another appears to be unclear. In addition are the perceived risks for thrombosis when other agents for establishing hemostasis such a DDAVP, FFP or aminocaproic acid are co-administered.

One analysis in 105 warfarin patients (40 had suspected or major bleeding) using Prothrombinex HT (most received a lower mean dose of ~13 IU/kg) either with (n=31) or without (n=31) FFP noted a variable response to correction of the INR, and apparently no benefit with FFP in those who received both.³ There are some limited data using Beriplex in 42 patients⁴; 10 patients (receiving concurrent IV Vit K⁵ with rapid reversal (~30 minutes). Yasaka did a dose ranging analysis in 42 patients using "PPSB-HT Nichiyaku" ⁶. Guidelines for the use of PCC as part of anticoagulation reversal however, have been published^{7, 8}.

Experience is also being gained with the use of rFVIIa to reverse the effects of warfarin with major bleeding or critical INR values. We recently published a review of the literature with a case series of 16 warfarin patients with major bleeding receiving low dose rFVIIa (1.2 mg), ⁹. Like PCC, the effects appear to be very rapid with complete reversal. Our series is now up to 24 patients with a mean INR of 3.5 (top over 16) reversing to 1.1 with a low dose of 1.2 mg (16 mcg/kg) rFVIIIa (one patient did not completely reverse). The effects were observed within 15 minutes, and, by pharmacy sending the 1.2 mg vial unconstituted, potential for drug wastage was reduced. We do have a gatekeeper system in place to evaluate the need for additional reversal therapies and the clinical situation prior to dispensing,. Most patients received both FFP and vitamin K to maintain the reversal, and in several cases rebound from FFP was observed shortly after the FFP infusion was completed prior to giving rFVIIa. Our choice of rFVIIa has been driven by being a level I trauma center with over 4000 admits/year and experience gained with using a reduced dose to establish hemostasis.

There are no studies comparing PCC and rFVIIa, nor are there good outcomes studies with either agent in this setting that I'm aware of. Rebound with ether product is possible (most likely sooner with rFVIIa) and may lead to developing a new thrombosis. Also, the costs of these product are important considerations. So the routine use of these products, rather than FFP or vit. K to reverse a critical INR value in the absence of major bleeding raises critical concerns.

References

1. Lankiewicz MW, Hays J, Friedman KD, Tinkoff G, Blatt PM. Urgent reversal of warfarin with prothrombin complex concentrate. J Thromb Haemost. 2006 May;4(5):967-70.
   
   
2. Kessler CM. Urgent reversal of warfarin with prothrombin complex concentrate: where are the evidence-based data? J Thromb Haemost. 2006 May;4(5):963-6.
   
   
3. Crawford JH, Augustson BM. Prothrombinex use for the reversal of warfarin: is fresh frozen plasma needed? Med J Aust. 2006 Apr 3;184(7):365-6.
   
   
4. Preston FE, Laidlaw ST, Sampson B, Kitchen S. Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients. Br J Haematol. 2002 Mar;116(3):619-24.
   
   
5. Evans G, Luddington R, Baglin T. Beriplex P/N reverses severe warfarin-induced overanticoagulation immediately and completely in patients presenting with major bleeding. Br J Haematol. 2001 Dec;115(4):998-1001.
   
   
6. Yasaka M, Sakata T, Naritomi H, Minematsu K. Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation. Thromb Res. 2005;115(6):455-9.
   
   
7. Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood EM; Warfarin Reversal Consensus Group. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust. 2004 Nov 1;181(9):492-7.
   
   
8. O'Shaughnessy DF, Atterbury C, Bolton Maggs P, et. al. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol. 2004 Jul;126(1):11-28.
   
   
9. Dager WE, King JH, Regalia RC, et. al. Reversal of elevated international normalized ratios and bleeding with low-dose recombinant activated factor VII in patients receiving warfarin. Pharmacotherapy. 2006 Aug;26(8):1091-8.

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