Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage

Around 20% of all intracerebral hemorrhage (ICH) patients are on vitamin K antagonists (VKA), with the incidence of VKA‐ICH increasing as the population grows older.1 The 3‐month case fatality of the condition is high at 50%.2, 3, 4 One‐third of ICH patients develop significant early hematoma expansion,5 and this risk is doubled in VKA‐ICH.6 Vitamin K takes several hours to initiate sufficient endogenous clotting factor production, so urgent treatments to rapidly replace vitamin K–dependent clotting factors (II, VII, IX, X) are widely used, with the aim of limiting further bleeding. Prothrombin complex concentrate (PCC), fresh frozen plasma (FFP), recombinant factor VIIa, or combinations of these are used, with practice varying between different centers and countries.7 Although there is a clear rationale for the use of these agents, none has been conclusively shown to improve outcome after VKA‐ICH. Evidence from patients with major VKA‐associated bleeding (predominantly gastrointestinal hemorrhage) demonstrates that relative to FFP, PCC normalizes the international normalized ratio (INR) more quickly, reduces the need for red blood cell transfusion, and does not lead to an increase in adverse events.8, 9 Although PCC is more expensive, it has practical advantages including more rapid administration, smaller infusion volume, and no need for ABO blood type match. This has led to PCC being recommended as a reasonable alternative to FFP in the USA10 and the first‐line treatment in the United Kingdom.11 The 2014 European consensus‐based ICH guidelines do not provide a recommendation, citing lack of evidence.12 Furthermore, different preparations of PCC have different concentrations of the vitamin K–dependent clotting factors, classified as 3‐factor or 4‐factor depending on the concentration of factor VII (FVII). Three‐factor PCCs are widely used in some countries, but may be less effective in correcting the INR than 4‐factor PCC.13 Although national and international guidelines recommend clotting factor replacement agents for the treatment of VKA‐ICH, there is currently no definite evidence of benefit and no international consensus. Our aim was to utilize the existing international variation in practice to test for an association between the choice of VKA reversal strategy and survival, adjusted for key prognostic factors, in a large population of patients with VKA‐ICH pooled from 16 registries in Europe, North and South America, and Australia.