Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists

Summary

Prothrombin complex concentrates (PCCs) are recommended as the treatment of choice in warfarin-related coagulopathy. However, the risk of thromboembolic complications associated with their use is not well defined. We performed a meta-analysis to estimate the rate of thromboembolic complications in patients receiving vitamin K antagonists (VKAs) treated with PCCs for bleeding or before urgent surgery. Medline and Embase databases were searched. Two reviewers performed study selection and extracted data independently. Studies providing data on incidence of thromboembolic complications in VKA-treated patients were eligible for the study. Weighted mean proportion of the rate of thromboembolic complications and the mortality rate were calculated. Twenty-seven studies (1,032 patients) were included. Seven studies used 3-factor, and 20 4-factor PCCs. Twelve patients had a thromboembolic complication (weighted mean 1.4%; 95% CI 0.8–2.1), of which two were fatal. The incidence of thromboembolic events was 1.8% (95% CI 1.0–3.0) in patients treated with 4-factor PCCs, and 0.7% (95% CI 0.0–2.4) in patients treated with 3-factor PCCs. Total mortality rate was 10.6% (95% CI 5.9–16.6). In conclusion, our results suggest there is a low but quantifiable risk of thromboembolism in VKA-treated patients receiving PCCs for anticoagulation reversal. These findings should be confirmed in randomised, controlled trials.

Keywords

Prothrombin complex concentrates - PCC - coumarins - thromboembolic complications - haemorrhage

• References

• 1 Hanley JP. Warfarin reversal. J Clin Pathol 2004; 57: 1132-1139.
• 2 Pindur G, Morsdorf S. The use of prothrombin complex concentrates in the treatment of hemorrhages induced by oral anticoagulation. Thromb Res 1999; 95: S57-61.
• 3 Taberner DA, Thomson JM, Poller L. Comparison of prothrombin complex concentrate and vitamin K1 in oral anticoagulant reversal. Br Med J 1976; 2: 83-85.
• 4 Samama CM. Prothrombin complex concentrates: a brief review. Eur J Anaesthesiol 2008; 25: 784-789.
• 5 FEIBA VH Prescribing Information.. Westlake Village, CA: Baxter Healthcare Corporation; April 2005
• 6 Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: A prevalent adverse effect resulting in regulatory action. Arch Intern Med 2007; 167: 1414-1419.
• 7 Libby EN, Garcia DA. A survey of oral vitamin K use by anticoagulation clinics. Arch Intern Med 2002; 162: 1893-1896.
• 8 Leissinger CA, Blatt PM, Hoots WK. et al. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol 2008; 83: 137-143.
• 9 Coimbra R, Hoyt DB, Anjaria DJ. et al. Reversal of anticoagulation in trauma: a North-American survey on clinical practices among trauma surgeons. J Trauma 2005; 59: 375-382.
• 10 Dentali F, Ageno W, Crowther M. Treatment of coumarin-associated coagulopathy: a systematic review and proposed treatment algorithms. J Thromb Haemost 2006; 4: 1853-1863.
• 11 Blauhut B. Indications for prothrombin complex concentrates in massive transfusions. Thromb Res 1999; 95: S63-69.
• 12 Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol 2000; 53: 1119-1129.
• 13 McGinn T, Wyer PC, Newman TB. et al Evidence-Based Medicine Teaching Tips Working Group. Tips for learners of evidence-based medicine: 3. Measures of observer variability (kappa statistic). CMAJ 2004; 171: 1369-1373.
• 14 Hayden GF, Kramer MS, Horwitz RI. The case-control study. A practical review for the clinician. J Am Med A 1982; 247: 326-331.
• 15 Bland JM, Kerry SM. Statistics notes. Weighted comparison of means. Br Med J 1998; 316: 129.
• 16 Higgins JP, Thompson SG, Deeks JJ. et al. Measuring inconsistency in metaanalyses. Br Med J 2003; 327: 557-560.
• 17 Imberti D, Barillari G, Biasioli C. et al. Prothrombin complex concentrates for urgent anticoagulation reversal in patients with intracranial haemorrhage. Pathophysiol Haemost Thromb 2008; 36: 259-265.
• 18 Bruce D, Nokes TJC. Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital. Crit Care 2008; 12: R105.
• 19 Yasaka M, Sakata T, Naritomi H. et al. Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation. Thromb Res 2005; 115: 455-459.
• 20 van Aart L, Eijkhout HW, Kamphuis 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.
• 21 Nitu EC, Perry DJ, Lee CA. Clinical experience with the use of clotting factor concentrates in oral anticoagulation reversal. Clin Lab Haematol 1998; 20: 363-367.
• 22 Riess HB, Meier-Hellmann A, Motsch J. et al. Prothrombin complex concentrate (Octaplex) in patients requiring immediate reversal of oral anticoagulation. Thromb Res 2007; 121: 9-16.
• 23 Preston FE, Laidlaw ST, Sampson B. et al. Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients. Br J Haematol 2002; 116: 619-624.
• 24 Schick KS, Fertmann JM, Jauch KW. et al. Prothrombin complex concentrate in surgical patients: retrospective evaluation of vitamin K antagonist reversal and treatment of severe bleeding. Crit Care 2009; 13: R191.
• 25 Safaoui MN, Aazami R, Hotz H. et al. A promising new alternative for the rapid reversal of warfarin coagulopathy in traumatic intracranial hemorrhage. Am J Surg 2009; 197: 785-790.
• 26 Lubetsky A, Hoffman R, Zimlichman R. et al. Efficacy and safety of a prothrombin complex concentrate (Octaplex) for rapid reversal of oral anticoagulation. Thromb Res 2004; 113: 371-378.
• 27 Evans SJ, Biss TT, Wells RH. et al. Beriplex P/N reverses severe warfarin-induced overcoagualation immediately and completely in patients with major bleeding. Br J Haematol 2001; 115: 998-1001.
• 28 Pabinger I, Brenner B, Kalina U. et al Beriplex P/N Anticoagulation Reversal Study Group. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost 2008; 6: 622-631.
• 29 Junagade P, Grace R, Gover P. Fixed dose prothrombin complex xoncentrate for the reversal of oral anticoagulation therapy. Hematology 2007; 12: 439-440.
• 30 Lankiewicz MW, Hays J, Friedman KD. et al. Urgent reversal of warfarin with prothrombin complex concentrate. J Thromb Haemost 2006; 4: 967-970.
• 31 Cartmill M, Dolan G, Byrne JL. et al. Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies. Br J Neurosurg 2000; 14: 458-461.
• 32 Lorenz R, Kienast J, Otto U. et al. Successful emergency reversal of phenprocoumon anticoagulation with prothrombin complex concentrate: a prospective clinical study. Blood Coagul Fibrinolysis 2007; 18: 565-570.
• 33 Lavenne-Pardonge E, Itegwa MA, Kalaai M. et al. Emergency reversal of oral anticoagulation through PPSB-SD: the fastest procedure in Belgium. Acta Anaesthesiologica Belgica 2006; 57: 121-125.
• 34 Siddiq F, Jalil A, McDaniel C. et al. Effectiveness of Factor IX complex concentrate in reversing warfarin associated coagulopathy for intracerebral hemorrhage. Neurocrit Care 2008; 8: 36-41.
• 35 Fredriksson K, Norrving B, Stromblad LG. Emergency Reversal of Anticoagulation After Intracerebral Hemorrhage. Stroke 1992; 23: 972-977.
• 36 Boulis NM, Bobek MP, Schmaier A. et al. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery 1999; 45: 1113-1118.
• 37 Kalina M, Tinkoff G, Gbadebo A. et al. A protocol for the rapid normalization of INR in trauma patients with intracranial hemorrhage on prescribed warfarin therapy. Am Surg 2008; 74: 858-861.
• 38 Makris M, Greaves M, Phillips WS. et al. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost 1997; 77: 477-480.
• 39 Tiraferri E, Galletti M, Argento A. Emergency use of prothrombin complex concentrates in oral anticoagulant therapy rapid reversal. Haematologica 2004; 89: 177.
• 40 Carvalho M, Carneiro J, Monteiro C. et al. Prothrombin complex xoncentrate for reversal of oral anticoagulation therapy in urgent situations. Experience of a single center. J Thromb Haemost. 2007 5. 02 Abstract P-M-174.
• 41 Sharples R. The safety and efficacy of beriplex P/N for rapid warfarin reversal in major hemorrhage – a prospective evaluation of a regional protocol. Br J Haematol. 2003 Abstract P1115.
• 42 Vigué B, Ract C, Tremey B. et al. Ultra-rapid management of oral anticoagulant therapy-related surgical intracranial hemorrage. Intensive Care Med 2007; 33: 721-725.
• 43 Demeyere R, Gillardin S, Arnout J. et al. Comparison of fresh frozen plasma and prothrombin complex concentrate for the reversal of oral anticoagulants in patients undergoing cardiopulmonary bypass surgery: a randomised study. Vox Sang 2010; 99: 251-260.
• 44 Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003; 139: 893-900.
• 45 Ansell J, Hirsh J, Hylek E. et al American College of Chest Physicians. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 160S-198S.
• 46 van der Meer FJ, Rosendaal FR, Vandenbroucke JP. et al. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Arch Intern Med 1993; 153: 1557-1562.
• 47 Ageno W, Garcia D, Aguilar MI. et al. Prevention and treatment of bleeding complications in patients receiving vitamin K antagonists, part 2: Treatment. Am J Hematol 2009; 84: 584-588.
• 48 Mayer SA, Brun NC, Begtrup K. et al FAST Trial Investigators. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2008; 358: 2127-2137.
• 49 Levi M, Levy JH, Andersen HF. et al. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2010; 363: 1791-1800.
• 50 Stroup DF, Berlin JA, Morton SC. et al. Metaanalysis of observational studies in epidemiology: a proposal for reporting. Metaanalysis Of Observational Studies in Epidemiology (MOOSE) group. J Am Med A 2000; 283: 2008-2012.
• 51 Steiner T, Griebe M, Ivandic B. et al. Multicenter, prospective randomized trial on the use of prothrombin complex and fresh frozen plasma to normalize the INR in patients with coumadin related intracerebral hemorrhage related to vitamin K antagonists – The INCH-trial. Cerebrovasc Dis 2009; 27: 185.