Lਅਔਔਅ਒ ਔਏ ਔਈਅ E਄ਉਔਏ਒ Why is it so difficult to show that prothrombin complex concentrates are superior to fresh-frozen plasma for warfarin reversal? Giorgia Saccullo, Alexandra M. Bucko, Joost J. van Veen, Michael Makris Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Sheffield, United Kingdom

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because it is virtually impossible to match every risk factor. Among variables that are not always matched are: - the location and severity of the bleed; - the time between the bleed and the start of treatment with PCC/FFP; - the time between the bleed and the completion of treatment with PCC/FFP; - different doses and types of PCC, e.g. 3-factor vs 4-factor used; - different doses of FFP; - the dose of vitamin K used, the route by which it was given, and the timing in relation to the start of the bleed; - the use of other measures, such as endoscopy, to stop the bleeding; - variable follow up ranging from 24 hours2 to 3 months3. Ultimately the optimal study comparing PCC with FFP would be a randomised one with appropriate clinical endpoints as all variables will be matched. Such a study has been discussed for many years and was finally conducted in the USA where it was sanctioned by the FDA before approval of the PCC for use in the American market. Only equivalence to FFP had to be proven and since patients had to agree to enter a clinical trial some of the most sick patients were possibly excluded4,5. It is well recognised that there is definite morbidity and mortality after intracerebral or gastrointestinal bleeding in patients who are not on anticoagulants so as a minimum patients on anticoagulants with these types of bleeds would be expected to have the same morbidity and mortality. Studies reporting survival and morbidity rates lower than the ones in patients not on anticoagulants must be interpreted with caution as they are likely to have excluded the sickest patients from entry into the study. A further issue to consider is the effect of reanticoagulation once the acute bleed has been treated. There is great variation in the number of patients who are re-anticoagulated and in the anticoagulant used, the dose, and the timing. Starting the anticoagulant too early can lead to a potential re-bleed with additional morbidity and mortality, while failure to re-anticoagulate can leave the patient at risk of thrombosis. The issue of re-anticoagulation during follow up is rarely discussed in studies comparing PCC and FFP.

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Dear Sir, The agreed universal management of patients with haemophilia B (who have reduced levels of FIX) and intracranial bleeding is the immediate correction of coagulopathy and anything less indicates substandard care. Whenever FIX concentrate and fresh-frozen plasma (FFP) are both available, the preferred choice is always to use the concentrate, because correction of the coagulopathy is achieved much more quickly without the risk of fluid overload. Patients on warfarin can be considered to be similar to subjects with haemophilia B, except that they have reduced levels of factors II, VII and X in addition to FIX. So what logic is there behind the decision to manage these patients differently? Prothrombin complex concentrates (PCC) contain factors II, IX, X and variable amounts of factor VII. In our experience, those treating haemophilia will always use PCC in preference to FFP to treat patients with intracerebral bleeding on warfarin. Despite this, however, FFP continues to be used and there is considerable debate in the literature about whether PCCs are really superior to FFP, since most studies do not show benefit in terms of morbidity or mortality1. Here we discuss why it has been so hard to show the superiority of PCC over FFP in the emergency reversal of warfarin coagulopathy. The majority of reports comparing PCC and FFP use correction of the International Normalised Ratio (INR) rather than clinical end points. Invariably, when comparing PCC with FFP, a more rapid correction of the INR is observed with PCC; however, usually no clear clinical benefit is reported. It is important to remember that the magnitude of this INR reversal bears no relationship to the size of the bleed or the time since the bleed occurred. Excellent INR reversal with PCC will occur at any time, but clinical benefit will only be apparent for truly life-threatening bleeds treated shortly after they start. Treatment of less serious bleeds such as chronic subdurals can probably never show a clinical benefit for PCC over FFP. Similarly, treatment several hours after the start of the bleed will select survivors in both the PCC and FFP groups, and, again, will fail to show clinical PCC superiority. The studies comparing PCC with FFP have included parallel cohorts which were only partially matched

Blood Transfus 2017; 15: 277-8 DOI 10.2450/2016.0069-16 © SIMTI Servizi Srl

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Superiority of PCC would be expected to be most clearly shown in the reversal of the most severe bleeds where the rapidity of the reversal is critical. Despite this, most studies are carried out in patients where the rapidity of reversal is less critical. We believe that if PCC and FFP could be compared when administered for truly life-threatening bleeds within 2 hours of the start of the bleed the superiority of PCC would be clearer. As long as studies include all PCC/FFP treated patients irrespective of the severity of the bleed or the time since its onset, it is unlikely that any difference in morbidity or mortality between the two treatments will be seen.

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Sarode R, Matevosyan K, Bhagat R, et al. Rapid warfarin reversal: a 3-factor prothrombin complex concentrate and recombinant FVIIa cocktail for intracerebral hemorrhage. J Neurosurg 2012; 116: 491-7. Goldstein JN, Refaai MA, Milling TJ Jr, et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non inferiority, randomised trial. Lancet 2015; 385: 2077-87.

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Arrived: 15 March 2016 - Revision accepted: 13 April 2016 Correspondence: Michael Makris Sheffield Haemophilia and Thrombosis Centre Royal Hallamshire Hospital Glossop Road Sheffield S10 2JF, United Kingdom e-mail: [email protected]

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Parry-Jones AR, Di Napoli M, Goldstein JN, et al. Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage. Ann Neurol 2015; 78: 54-62. Carvalho MC, Rodrigues AG, Conceição LM, et al. Prothrombin complex concentrate (Octaplex): a Portuguese experience in 1152 patients. Blood Coag Fibrinolysis 2012; 23: 222-8. Imberti D, Magnacavallo A, Dentali F, et al. Emergency reversal of anticoagulation with vitamin K antagonists with 3-factor prothrombin complex concentrates in patients with major bleeding. J Throm Thrombolysis 2013; 36: 102-8.

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GS is a recipient of a NovoNordisk Access to Insight fellowship. MM has acted as consultant for CSL Behring and NovoNordisk. AMB and JJvV declare no conflicts of interest.

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Disclosure of conflicts of interest

Blood Transfus 2017; 15: 277-8 DOI 10.2450/2016.0069-16 278

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Why is it so difficult to show that prothrombin complex concentrates are superior to fresh-frozen plasma for warfarin reversal?

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