Abstract
Current guidelines recommend 4-factor prothrombin complex concentrate (4PCC) for emergent reversal of bleeding secondary to warfarin. While current research has demonstrated superiority of 4PCC over plasma, direct comparisons with 3-factor PCC (3PCC) are lacking. The purpose of this study is to compare the efficacy and safety of 3PCC and 4PCC. We conducted a retrospective analysis of patients who received PCC at one of four medical centers. All patients in the 3PCC group were treated at one center that utilizes a fixed, weight-based dosing protocol. After evaluation of all patients meeting inclusion criteria, propensity-score matching was used to adjust for differences in treatment characteristics. There was no difference in the primary outcome of INR ≤ 1.4 between 3PCC and 4PCC in both the unmatched (85.7 vs. 90.6 %; p = 0.37) and matched (84.2 vs. 92.1 %; p = 0.48) analyses. There was a significant difference in goal INR achieved favoring 4PCC (56.3 vs 90.0 %; p < 0.02) when baseline INR > 4.0. A total of three thrombotic events were documented, all in the 4PCC group. We found no difference in the rate of INR reversal in those treated with 3PCC and 4PCC. However, those with a baseline INR > 4.0 may experience more successful INR reversal with 4PCC.
Similar content being viewed by others
Abbreviations
- 3PCC:
-
3-Factor prothrombin complex concentrate
- 4PCC:
-
4-Factor prothrombin complex concentrate
- FFP:
-
Fresh frozen plasma
- INR:
-
International normalization ratio
- IQR:
-
Interquartile range
- PCC:
-
Prothrombin complex concentrate
References
Johnson JA (2012) Warfarin pharmacogenetics: a rising tide for its clinical value. Circulation 125:1964–1966. doi:10.1161/CIRCULATIONAHA.112.100628
Shehab N, Sperling LS, Kegler SR, Budnitz DS (2010) National estimates of emergency department visits for hemorrhage-related adverse events from clopidogrel plus aspirin and from warfarin. Arch Intern Med 170:1926–1933. doi:10.1001/archinternmed.2010.407
Schulman S, Beyth RJ, Kearon C, Levine MN, American College of Chest P (2008) Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133:257S–298S. doi:10.1378/chest.08-0674
Tazarourte K, Riou B, Tremey B, Samama CM, Vicaut E, Vigue B, Group Es (2014) Guideline-concordant administration of prothrombin complex concentrate and vitamin K is associated with decreased mortality in patients with severe bleeding under vitamin K antagonist treatment (EPAHK study). Crit Care 18:R81. doi:10.1186/cc13843
Kuramatsu JB, Gerner ST, Schellinger PD, Glahn J, Endres M, Sobesky J, Flechsenhar J, Neugebauer H, Juttler E, Grau A, Palm F, Rother J, Michels P, Hamann GF, Huwel J, Hagemann G, Barber B, Terborg C, Trostdorf F, Bazner H, Roth A, Wohrle J, Keller M, Schwarz M, Reimann G, Volkmann J, Mullges W, Kraft P, Classen J, Hobohm C, Horn M, Milewski A, Reichmann H, Schneider H, Schimmel E, Fink GR, Dohmen C, Stetefeld H, Witte O, Gunther A, Neumann-Haefelin T, Racs AE, Nueckel M, Erbguth F, Kloska SP, Dorfler A, Kohrmann M, Schwab S, Huttner HB (2015) Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage. JAMA 313:824–836. doi:10.1001/jama.2015.0846
Flibotte JJ, Hagan N, O’Donnell J, Greenberg SM, Rosand J (2004) Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology. 63:1059–1064
Bebulin VH(R) [package insert]. Baxter Healthcare Corporation D, IL; April 2011
KCentra(R) [package insert]. CSL Behring KoP, PA; April 2013
Sarode R, Milling TJ Jr, Refaai MA, Mangione A, Schneider A, Durn BL, Goldstein JN (2013) Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 128:1234–1243. doi:10.1161/CIRCULATIONAHA.113.002283
Chong CT, Lew TW, Kuperan P, Tan JJ, Tan HL, Kwek TK (2010) Rapid reversal of coagulopathy in warfarin-related intracranial haemorrhages with prothrombin complex concentrates. Anaesth Intens Care 38:474–480
Makris M, Van Veen JJ (2011) Three or four factor prothrombin complex concentrate for emergency anticoagulation reversal? Blood Transfus 9:117–119. doi:10.2450/2011.0111-10
Voils SA, Baird B (2012) Systematic review: 3-factor versus 4-factor prothrombin complex concentrate for warfarin reversal: does it matter? Thromb Res 130:833–840. doi:10.1016/j.thromres.2012.10.001
Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, Svensson PJ, Veenstra DL, Crowther M, Guyatt GH, American College of Chest P (2012) Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th edn: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 141:e152S-84S. doi:10.1378/chest.11-2295
Keeling D, Baglin T, Tait C, Watson H, Perry D, Baglin C, Kitchen S, Makris M (2011) British Committee for Standards in H. Guidelines on oral anticoagulation with warfarin—fourth edition. Br J Haematol 154:311–324. doi:10.1111/j.1365-2141.2011.08753.x
Mohrien KM (2014) Morgan Jones G, Boucher AB, Elijovich L. Evaluation of a fixed, weight-based dose of 3-factor prothrombin complex concentrate without adjunctive plasma following warfarin-associated intracranial hemorrhage. Neurocrit Care 21:67–72. doi:10.1007/s12028-014-9984-9
Austin PC (2011) Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies. Pharm Stat 10:150–161. doi:10.1002/pst.433
Leuven ESB (2003) PSMATCH2: Stata Module to Perform Full Mahalanobis and Propensity Score Matching, Common Support Graphing, and Covariate Imbalance Testing
Al-Majzoub O, Rybak E, Reardon DP, Krause P, Connors JM (2015) Evaluation of warfarin reversal with 4-factor prothrombin complex concentrate compared to 3-factor prothrombin complex concentrate at a Tertiary Academic Medical Center. J Emerg Med. doi:10.1016/j.jemermed.2015.07.024
Goldstein JN, Thomas SH, Frontiero V, Joseph A, Engel C, Snider R, Smith EE, Greenberg SM, Rosand J (2006) Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke 37:151–155. doi:10.1161/01.STR.0000195047.21562.23
Huttner HB, Schellinger PD, Hartmann M, Kohrmann M, Juettler E, Wikner J, Mueller S, Meyding-Lamade U, Strobl R, Mansmann U, Schwab S, Steiner T (2006) Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke 37:1465–1470. doi:10.1161/01.STR.0000221786.81354.d6
European Stroke Initiative Writing C, Writing Committee for the EEC, Steiner T, Kaste M, Forsting M, Mendelow D, Kwiecinski H, Szikora I, Juvela S, Marchel A, Chapot R, Cognard C, Unterberg A, Hacke W (2006) Recommendations for the management of intracranial haemorrhage—part I: spontaneous intracerebral haemorrhage. The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI Executive Committee. Cerebrovasc Dis 22:294–316. doi:10.1159/000094831
Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood EM (2004) Warfarin Reversal Consensus G. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust 181:492–497
Cang WWS, Derry K, von Drygalski A, Lane J (2014) A comparison of INR reversal between 4-factor and 3-factor prothrombin complex concentrates. Crit Care Med 42:A1465
Voils SA, Holder M, Premraj S, Catlin J, Hinton M, Allen B (2014) Safety and effectiveness of 3- vs 4-factor PCC in patients requiring emergent Warfarin reversal. Crit Care Med 42:A1466
Tran H, Collecutt M, Whitehead S, Salem HH (2011) Prothrombin complex concentrates used alone in urgent reversal of warfarin anticoagulation. Internal Med J 41:337–343. doi:10.1111/j.1445-5994.2010.02237.x
Imberti D, Barillari G, Biasioli C, Bianchi M, Contino L, Duce R, D’Inca M, Gnani MC, Mari E, Ageno W (2011) Emergency reversal of anticoagulation with a three-factor prothrombin complex concentrate in patients with intracranial haemorrhage. Blood Transfus 9:148–155. doi:10.2450/2011.0065-10
van Aart L, Eijkhout HW, Kamphuis JS, Dam M, Schattenkerk ME, Schouten TJ, Ploeger B, Strengers PF (2006) 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 118:313–320. doi:10.1016/j.thromres.2005.08.005
Khorsand N, Veeger NJ, Muller M, Overdiek JW, Huisman W, van Hest RM, Meijer K (2011) Fixed versus variable dose of prothrombin complex concentrate for counteracting vitamin K antagonist therapy. Transfus Med 21:116–123. doi:10.1111/j.1365-3148.2010.01050.x
Holland L, Warkentin TE, Refaai M, Crowther MA, Johnston MA, Sarode R (2009) Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion 49:1171–1177. doi:10.1111/j.1537-2995.2008.02080.x
Switzer JA, Rocker J, Mohorn P, Waller JL, Hughes D, Bruno A, Nichols FT, Hess DC, Natarajan K, Fagan SC (2012) Clinical experience with three-factor prothrombin complex concentrate to reverse warfarin anticoagulation in intracranial hemorrhage. Stroke 43:2500–2502. doi:10.1161/STROKEAHA.112.661454
Huynh TK, Costello JL, Rebuck JA (2014) Optimizing the dose of three-factor prothrombin complex concentrate in traumatic brain injury patients on warfarin therapy. Pharmacotherapy. 34:260–264. doi:10.1002/phar.1384
Jr EL (2001) Hemostatic Problems in Surgical Patients. In: Colman RWHJ, Marder VJ, Clowes AW, George JN (eds) Hemostasis and Thrombosis, 4th edn. Lippincott Williams & Wilkins, Philadelphia, p 1033
Bolton-Maggs PHBPD, Chalmers EA (2004) The rare coagulation disorders—review with guidelines for management from the United Kingdon Haemophilia Centre Doctors’ Organisation. Haemophilia 10:593–628
Yuan S, Ferrell C, Chandler WL (2007) Comparing the prothrombin time INR versus the APTT to evaluate the coagulopathy of acute trauma. Thromb Res 120:29–37. doi:10.1016/j.thromres.2006.07.002
Gulati G, Hevelow M, George M, Behling E, Siegel J (2011) International normalized ratio versus plasma levels of coagulation factors in patients on vitamin K antagonist therapy. Arch Pathol Lab Med 135:490–494. doi:10.1043/2009-0474-OA.1
Dentali F, Marchesi C, Giorgi Pierfranceschi M, Crowther M, Garcia D, Hylek E, Witt DM, Clark NP, Squizzato A, Imberti D, Ageno W (2011) Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost 106:429–438. doi:10.1160/TH11-01-0052
Acknowledgments
No funding was obtained for the conduction of this study. The results of this study have not been presented previously.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
All authors of this study have no direct or indirect conflict of interest to disclose.
Rights and permissions
About this article
Cite this article
Jones, G.M., Erdman, M.J., Smetana, K.S. et al. 3-Factor Versus 4-Factor Prothrombin Complex Concentrate for Warfarin Reversal in Severe Bleeding: A Multicenter, Retrospective, Propensity-Matched Pilot Study. J Thromb Thrombolysis 42, 19–26 (2016). https://doi.org/10.1007/s11239-015-1330-3
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11239-015-1330-3