Friday, September 14, 2012

FEIBA and PCCs


I was recently asked what I thought about FEIBA as a reversal agent for warfarin or dabigatran related bleeds.  At first, I was as excited about FEIBA as the individuals who asked me my opinion of the drug for this use. A prothombin complex concentrate that had active factor VII? In effect, a four factor PCC product available in the US? A small study suggesting it effectively lowers supratherapeutic INRs?[1] Sign me up!

But then I started to wonder why save for a small study published back in 20091, everything that I’ve either read or hear of focuses on either rFVIIa or 3 factor PCC for warfarin or dabigatran reversal…  Has FEIBA been blown over?

Short answer: no it hasn’t.

Long answer: Thrombosis risk.

FEIBA is an acronym for factor eight inhibitor bypassing activity. FEIBA belongs to a class of PCCs referred to as four factor active prothrombin complex concentrate. It’s considered active since it contains activated factor VII and a mix of active and inactive (mostly) factors II, IX and X.[2] Interestingly, its hemostatic effects are associated with its factor X and prothrombin content, not factor VIIa.[3] Three factor PCCs on the other hand (in the US, most of us are familiar with BebulinVH or ProfilnineSD), are inactive PCCs.  They’re composed of factor II, IX and X, all inactive.[4]

At this point, I thought that of course FEIBA is going to work better than 3 factor PCC! Why would I want to give an inactivate PCC to a patient that has warfarin or dabigatran on board that will continue to prevent their activation?

The safety experience with FEIBA sheds light on part of the problem. True, between 4 and 9 thrombotic events occur per every 100,000 FEIBA infusions in the hemophilia population.[5] Using FEIBA for its labeled use is relatively safe. However, using it as a warfarin or dabigatran reversal agent is not its intended purpose. It wasn’t created for this indication, nor appropriately assessed for appropriate dosing, efficacy and safety. Not to say there isn’t a role for drugs like FEIBA or other PCCs off-label; but we must understand as best as possible the risks and benefits.

Thrombotic complications like VTE, DIC, MI, PE, etc., are of concern when administering PCCs.[6] Patients at risk of excessive thrombin generation and thrombosis from PCCs are those who are of 1) advanced age, and 2) have athleroscloerotic disease.[7] Equally, there are inherent risks involved with the product itself: prothrombin content is the major determinant of excessive thrombin generation in PCCs.[8] FEIBA, has a high content of prothrombin as well as thrombin. In addition, the balance between procoagulant and anticoagulant activity plays a large role in thrombosis related to FEIBA and PCCs.  Going back to the comparison between 3 factor PCC and FEIBA once again, other 3 factor and 4 factor PCCs contain either heparin or a combination of Protein C, Protein S and Protein Z to balance procoagulation and anticoagulation.[6,9] FEIBA does not contain an anticoagulant.

Lets put it all together.

In a patient with a supratherapeutic INR from warfarin and ICH, their ability to activate factors II, VII, IX and X are severely impaired.  Importantly, warfarin reduces Protein C, S and Z concentrations as well as these active coagulation factors.  Ultimately, administering FEIBA will certainly replace the inactive factors, but place the patient at high risk of thrombosis because, as mentioned above, it contains no anticoagulant and its prothrombin content.  Off label use is likely to increase incidence of thrombotic events, similar to what has been observed with rFVIIa.[10,11,12] Not forgetting the reason the patient required anticoagulation in the first place for some previous thrombotic event, and the patient is likely elderly and has athlerosclerotic disease (all increasing risk of thrombosis).  In the case of a similar patient with ICH on dabigatran, FEIBA will replace some active factor II, but the same risks of thrombosis as with any other patient on warfarin still exist.  Certainly three factor PCCs could pose a similar risk, albeit presumably lower (we need data). But the risk/benefit seems to favor three factor vs FEIBA to me.

So what do I think of FEIBA? Since that was the whole question.

I think when matched up with the other 3 factor PCCs, FEIBA seems to pose a higher risk of thrombosis.  FEIBA will stop bleeding but at the cost of giving the patient an MI, VTE or causing DIC.  Of all the products, Bebulin should have the best efficacy/safety balance since it contains inactive factor II and heparin.  Remember though, these products are being used not for their intended purposes; square pegs and round holes.

1. Wojcik C, Schymik ML, Cure EG. Activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for the reversal of warfarin-induced coagulopathy. Int J Emerg Med (2009) 2:217–225
2. Gallistl S, Cvirn G, Leschnik B, Muntean W. Respective roles of factors II, VII, IX, and X in the procoagulant activity of FEIBA. Blood Coagulation and Fibrinolysis 2002, 13:653–655
3. Turecek PL, Váradi K, Gritsch H, Schwarz HP. FEIBA: mode of action. Haemophilia 2004;10(Suppl 2):3–9
4. Patanwala AE, Acquisto NM, Erstad BL Prothrombin Complex Concentrate for Critical Bleeding. Ann Pharmacother 2011;45:990-9
5.Aledort LM. Factor VIII inhibitor bypassing activity (FEIBA) – addressing safety issues. Haemophilia (2008), 14, 39–43
6.Sørensen et al. Clinical review: Prothrombin complex concentrates - evaluation of safety and thrombogenicity. Critical Care 2011, 15:201-10
7. Cromwell C, Aledort LM. FEIBA: A Prohemostatic Agent. Semin Thromb Hemost 2012;38:265–267
8. S. Gallistl et al. Roles of FII, FVII, FIX and FX in activity of FEIBA. Blood Coagulation and Fibrinolysis 2002;13(7):653-55
9. Key NS, Negrier C. Coagulation factor concentrates: past, present, and future. Lancet 2007; 370: 439–48
10. O’Connell KA, Wood JJ, Wise RP, Lozier JN, Braun MM. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 2006; 295: 293–8
11. Yank V, Tuohy V, Logan AC, et al. Effectiveness of off-label use of recombinant factor VIIa. Ann Intern Med. 2011;154:529-540
12. Levi M, Levy JH, Andersen HF, Truloff D. Safety of Recombinant Activated Factor VII in Randomized Clinical Trials. N Engl J Med 2010;363:1791-800

Also…
I.          Zareh M, Davis A, Henderson S. Reversal of Warfarin-Induced Hemorrhage in the Emergency Department. West J Emerg Med. 2011;12(4):386–392
II.         van Ryn et al. Effect of dabigatran on coagulation assays and reversal strategies. Thromb Haemost 2010; 103: 1116–1127
III.       Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011 Oct 4;124(14):1573-9. Epub 2011 Sep 6.
IV.        Hellstern P. Production and composition of prothrombin complex concentrates: correlation between composition and therapeutic efficiency. Thromb Res. 1999;95(4 suppl 1):S7-S12.
V.         Lusher JM. Thrombogenicity associated with factor IX complex concentrates. Semin Hematol. 1991;28(3 suppl 6):3-5.
VI.        Kohler M. Thrombogenicity of prothrombin complex concentrates. Thromb Res. 1999;95(4 suppl 1):S13-S17.