A new gold standard treatment for the emergency correction of warfarin-induced coagulopathy

As a result of research undertaken by the University of Sheffield between 1995-2002, a new gold standard treatment for major bleeding when using warfarin has been established.

Brain bleeding image
Intracerebral bleeding in a patient on warfarin.

The treatment, using prothrombin complex concentrate (PCC) was shown to be far better than fresh frozen plasma (FFP), the standard alternative at the time, and two PCCs have now been licensed for this use in the UK. UK and international guidelines now recommend PCC over FFP.

Details of the impact:

Patients with venous or arterial thrombosis or with prosthetic metal heart valves are treated with warfarin anticoagulation. Approximately 600,000–1,200,000 patients are on warfarin in the UK at any time and 6,000-12,000 each year are likely to require emergency reversal of their anticoagulation due to life-threatening bleeding. At the time of our original research most patients with major bleeding on warfarin were treated with fresh frozen plasma (FFP), whilst now the vast majority are treated with prothrombin complex concentrate (PCC), based on our research findings.

Impact on national and international clinical guidelines

National and international guidelines now recommend the use of PCC for the management of life-threatening bleeding on warfarin.

A. The current UK guideline on the use of FFP published by the British Committee for Standards in Haematology (BCSH) states that for reversal of warfarin “FFP has only a partial effect, is not the optimal treatment, and should never be used for the reversal of Warfarin in the absence of severe bleeding”. The evidence supporting this statement in the guideline is our publication of 1997 (R1). (S1)

B. The current UK guideline on the management of patients on warfarin published by the BCSH recommends “All hospitals managing patients on warfarin should stock a licensed four factor prothrombin complex concentrate. Emergency anticoagulation reversal in patients with major bleeding should be with 25-50μ/kg for factor prothrombin complex concentrate....... Fresh frozen plasma produces suboptimal anticoagulation reversal and should only be used if prothrombin complex concentrate is not available.” This guideline lists our 1997 reference (R1) as showing “Complete and rapid correction of the coagulopathy is more rapidly achieved with PCC than FFP Makris et al 1997” (S2)

C. The use of PCC rather than FFP in patients on warfarin is also recommended by a 2013 guideline on the management of bleeding in patients on antithrombotic agents (S3). This is the BCSH guideline on anticoagulation reversal for all the different anticoagulant drugs.

D. In the UK, at the Dudley Group of Hospitals, the policy for reversal of warfarin in patients with intracranial or major bleeding recommends use of PCC and quotes our study R1 to support this recommendation (S4)

E. The French national guidelines on the management of major bleeding in patients on vitamin K antagonists, such as warfarin, recommend the use of PCC rather than FFP and quote our study R1 as demonstrating the superiority of PCC over FFP (S5)

F. The Italian national guidelines produced by the Italian Society for Transfusion Medicine and Immunohaematology working party also recommend the use of PCC over FFP for treatment of major bleeding on vitamin K antagonists and use all 3 of our studies R1, R2 and R3 to support this recommendation (S6).

Impacts on the economy and commerce

PCCs were introduced 40 years ago to treat haemophilia B. Initially we used them off-label in our research to treat warfarin related bleeding. PCCs are no longer used to treat haemophilia B.

In the last 7 years, however, two international pharmaceutical companies, Octapharma and CSL Behring, have brought concentrates to the market for use in emergency reversal of warfarin (Octaplex and Beriplex respectively). Beriplex, the product licensed in the UK in 2007, was the product first shown by us in 2002 (R3) to be safe and effective. CSL Behring referenced our publications (R1R3) in the clinical section of their license dossier submitted to the European Medicines Agency (S7).

In the Australian Public Assessment Report for Human Prothrombin Complex Concentrate it is stated that our publication R3 was included in the Beriplex license application as supportive evidence (S8).
Octapharma and CSL Behring have sold more than 20 million units of Octaplex/Beriplex in the UK in 2012 (S9).

In 2012 CSL Behring has sold in excess of 300 million units of Beriplex internationally (S7). In April 2013, the US Food and Drug Administration approved KCentra™, the first US FDA-approved 4-Factor prothrombin complex concentrate for urgent warfarin reversal in patients with acute bleeding, This is the US name for Beriplex and has enabled CSL Behring to access a new and very large market with the concentrate (S10).

Sources to corroborate the impact (indicative maximum of 10 references):

S1. O’Shaughnessy DF, Atterbury C, Bolton Maggs P, et al. Guidelines for the use of fresh frozen plasma, cryoprecipitate and cryosupernatant. British Journal in Haematology 2004; 126: 11-28.

S2. Keeling D, Baglin T, Tait C et al. Guidelines on oral anticoagulation with warfarin – fourth edition. British Journal of Haematology 2011; 154:311-324.

S3. Makris M, van Veen JJ, Tait CR, Mumford AD, Laffan M. Guideline on the management of bleeding in patients on antithrombotic agents. British Journal of Haematology 2013; 160:35-46.

S4. http://www.dwmh.nhs.uk/sections/publications/documents/FOI28824268083.pdf

S5. Pernod G, Godier A, Gozalo C et al. French clinical practise guidelines on the management of patients on vitamin K antagonists in at risk situations (overdose, risk of bleeding, and active bleeding). Thrombosis Research 2010; 126:e167-e174.

S6. Liumbruno G, Bennordello F, Lattanzio A, et al. Recommendations for the use of antithrombin concentrates and prothrombin complex concentrates. Blood Transfusion 2009; 7:325-334.

S7. Email from Head of Commercial Operations CSL Behring, on 11th June 2013 confirms use of Sheffield research findings in EMA application.

S8. http://www.tga.gov.au/pdf/auspar/auspar-beriplex.pdf

S9. Email from Director of Serious Hazards of Transfusion (SHOT) on 11th June 2013 confirms sales data.

S10. http://www.csl.com.au/docs/600/594/CSL_FINS_2013,1.pdf Page 3 of the CSL financial report corroborates availability of Beriplex in the US, under the name KCentra.

References to the research:

Authors working in Sheffield at the time are indicated in bold.

R1. Makris MGreaves MPhillips WSKitchen S, Rosendaal FR, Preston FE. (1997). Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thrombosis and Haemostasis. 77:477-480.

The key paper that changed the management of reversal of warfarin anticoagulation was carried out in Sheffield and published in 1997. PubMed ID: 9065997 [Scopus 275 citations]

R2. Watson HG, Baglin T, Laidlaw SLMakris MPreston FE. (2001). A comparison of the efficacy of response to oral and intravenous vitamin K in reversal of over-anticoagulation with warfarin. British Journal of Haematology. 115: 145-149.

Another publication from Sheffield, Aberdeen and Cambridge demonstrated that intravenous vitamin K was superior to oral vitamin K for the emergency reversal of warfarin. [Scopus 82 citations].

R3. Preston FELaidlaw SLSampson BKitchen S. (2002). Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients. British Journal of Haematology. 116:619-624.

A third publication demonstrated that a PCC called Beriplex used in haemophilia was highly effective for the emergency reversal of warfarin. [Scopus 125 citations].

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