4-Factor Prothrombin Complex Concentrate for Warfarin Reversal - LECOM

4-Factor Prothrombin Complex Concentrate for Warfarin Reversal

Saturday, 01 March 2014

Phillip Rosel, Dhara Patel, Wendy Nguyen, Kevin Thu, PharmD Candidates; Marcus Campbell, PharmD, BC-ADM

Warfarin, a vitamin K antagonist (VKA), results in the hospitalization of 1% of all patients being treated each year, and can cause fatal-bleeding in 0.3% of those treated.1 Normally used to prevent or treat venous thrombosis, warfarin can cause major bleeding events due to its reduction of vitamin K-dependent clotting factors (VKDFs: Factors II, VII, IX, and X) and anticoagulant proteins C and S.2 Prolonged clotting times caused by the reduced levels of coagulation factors can be devastating in patients presenting with intracerebral hemorrhage or other acute bleeds that require prompt restoration of VKDFs. Vitamin K administration is not recommended as monotherapy for these patients because VKA reversal can take several hours.3 Administration of fresh frozen plasma (FFP) requires thawing and ABO blood typing, both of which can delay treatment. FFP has also been found to cause several transfusion-related adverse events. Clinicians need a reliable, safe, effective and timely VKA reversal agent to restore the body’s ability to slow the bleeding in an attempt to improve patient outcomes. Products of prothrombin complex concentrates (PCC) can be either 3 factor (3F-PCC) or 4 factor (4F-PCC). While 3F-PCCs contain a minimal amount of factor VII and are more effective at reversing anticoagulation at lower INRs, 4F-PCC could be a potential alternative treatment because it contains sufficient amounts of all 4 factors II, VII, IX, X and has the ability to reduce INR and stop bleeding more efficiently regardless of the initial INR.

A randomized, controlled study compared the safety and efficacy of 4F-PCC (Kcentra®; CSL Boehring) vs. FFP in VKA-treated patients who presented with a major bleed.3 The open-label, non-inferiority, prospective, multinational clinical trial consisted of 216 patients of similar baseline data and characteristics. To be included, patients were at least 18 years old, had an INR >2.0 within 3 hours of treatment, and experienced an acute major bleed (life-threatening or potentially life-threatening, associated with a fall in Hgb >2g/dL, or requiring blood transfusion). Patients were randomly assigned to receive either intravenous (IV) 4F-PCC or IV FFP; dosing was adjusted based on both baseline INR and body weight. Maximum infusion rate was 3 IU/kg/min for 4F-PCC, and 1 unit per 30 minutes for FFP. Vitamin K was given to all patients via slow IV infusion (dosing was adjusted according to 2008 ACCP guidelines or local clinical practice). Co-primary endpoints included hemostatic efficacy over 24 hours from the start of infusion and rapid INR reduction (<1.3) at 0.5 hours post-infusion. Secondary endpoints were time to INR correction and plasma levels of VKDFs and proteins C and S. Hemostatic efficacy was assessed by a blinded, independent endpoint adjudication board and classified as “excellent”, “good”, or “poor/none” based on hemoglobin, hematocrit, hemostatic treatments, adverse events and clinical outcomes. Hemostasis was considered effective if the rating was excellent or good over 24-hour period from the start of the infusion, and as non-effective if it was rated poor/none or patients required other hemostatic products besides the study treatment. The trial demonstrated non-inferiority of 4F-PCC to FFP, with effective hemostasis occurring in 72.4% in 4F-PCC versus 65.4% in FFP (difference 7.1% CI -5.8 – 19.9). Of the patients treated with 4F-PCC, 62.2% achieved rapid INR reduction compared to only 9.6% of those treated with FFP, showing the superiority of 4F-PCC (difference 52.6%; CI 39.4-65.9). Patients presenting with major musculoskeletal bleeding showed the highest rate of “good or excellent” hemostatic efficacy when treated with 4F-PCC compared to FFP (P=0.007).3

4F-PCC patients had higher plasma levels of coagulation factors (p<0.05), and an acceptable safety profile compared with FFP patients (9.7% vs 21.1% patients with related non-serious adverse events, and 1.9% vs 3.7% patients with related serious adverse events, respectively). The study was not powered to show a significant difference between treatment groups for safety outcomes.3

Clinical trial data has proven 4F-PCC to be a safe and effective alternative to FFP in the treatment of severe bleeds in patients currently treated with warfarin.  In April 2013, The FDA approved the first 4F-PCC product (Kcentra®; CSL Boehring) for use in the United States for the urgent reversal of warfarin therapy in adult patients with acute major bleeding. In December, the indication was expanded to include urgent reversal of warfarin in adult patients needing an urgent surgery or other invasive procedure.

The most recent guidelines published by the American College of Chest Physicians recommend the use of a 4F-PCC along with slow IV injection of Vitamin K to rapidly reverse warfarin-associated major bleeding events, rather than the use of FFP.4 Due to the greater volume requirements and increased risk for fluid overload in patients treated with FFP, patients who are at risk for fluid overload such as those suffering from heart failure, renal failure, or cirrhosis are likely to respond more positively to treatment with 4F-PCC.3,7 A limitation to more widespread use of 4F-PCC is the significant cost difference as compared to FFP. A single course of 4F-PCC in a 175 pound patient with an INR=5 exceeds $5000.5,6

New data shows the use of 4F-PCC may be effective in reversing the effects of rivaroxaban,8 a factor Xa inhibitor indicated for the treatment of deep vein thrombosis and pulmonary embolism, and the prevention of stroke.More studies are required to test the safety and efficacy of 4F-PCC in the reversal of rivaroxaban before making any off-label recommendations. As the only commercially available 4F-PCC in the U.S., and considering its clinical advantages such as quick onset and acceptable safety profile, Kcentra is a viable option for patients with major acute bleeds requiring rapid reversal.


  1. Makris M, van Veen JJ. Three or four-factor prothrombin complex concentrate for emergency anticoagulation reversal?. Blood Transfus. 2011 April; 9(2): 117–119. doi: 10.2450/2011.0111-10.
  2. Warfarin. Lexi-Drugs Online [Internet]. Hudson (OH): Lexi-Comp, Inc. 1978-2014 [cited 2013 December 8]. Available from: hhttps://online.lexi.com.lecomlrc.lecom.edu/lco/action/doc/retrieve/docid/patch_f/7879#f_adverse-reactions.
  3. Sarode A, Milling TJ, Refaai MA, et al. Efficacy and safety of a Four-Factor Prothrombin Complex Concentrate (4F-PCC) in patients on vitamin K antagonists presenting with major bleeding: A randomized, plasma-controlled, phase IIIb study. [published online ahead of print August 9, 2013]. Circulation. doi: 10.1161/CIRCULATIONAHA.113.002283
  4. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141:e152S-184S. doi: 10.1378/chest.11-2295.
  5. CSL Behring LLC. Kcentra quick reference guide. https://www.kcentra.com/docs/Kcentra_Quick_Reference_Guide.pdf. Accessed December 5, 2013.
  6. PL Detail-Document, Clotting Factors for Reversing Anticoagulants. Pharmacist’s Letter/Prescriber’s Letter. October 2013. https://pharmacistsletter.therapeuticresearch.com/pl/ArticleDD.aspx?nidchk=1&cs=STUDENT&s=PL&pt=6&fpt=31&dd=291012&pb=PL&searchid=44245507.
  7. Coyle JD, Matzke GR. Disorders of Sodium and Water Homeostasis. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: Mc-Graw-Hill; 2011. p. 873-890.
  8. Eerenberg ES, Kamphuisen PW, Sijpkens, MK, et al. Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate. Circulation. 2011;124:1573-1579. doi:10.1161/CIRCULATIONAHA.111.029017.
  9. Rivaroxaban. Lexi-Drugs Online [Internet]. Hudson (OH): Lexi-Comp, Inc. 1978-2014 [cited 2010 Dec 5]. Available from: https://online.lexi.com.lecomlrc.lecom.edu/lco/action/doc/retrieve/docid/patch_f/1275239.