Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial.
BACKGROUND
Haematoma expansion is a major cause of mortality in intracranial haemorrhage related to vitamin K antagonists (VKA-ICH). Normalisation of the international normalised ratio (INR) is recommended, but optimum haemostatic management is controversial. We assessed the safety and efficacy of fresh frozen plasma (FFP) versus prothrombin complex concentrate (PCC) in patients with VKA-ICH.


METHODS
We did an investigator-initiated, multicentre, prospective, randomised, open-label, blinded-endpoint trial. Patients aged at least 18 years with VKA-ICH who presented within 12 h after symptom onset with an INR of at least 2·0 were randomly assigned (1:1) by numbered sealed envelopes to 20 mL/kg of intravenous FFP or 30 IU/kg of intravenous four-factor PCC within 1 h after initial cerebral CT scan. The primary endpoint was the proportion of patients with INR 1·2 or lower within 3 h of treatment initiation. Masking of treatment was not possible, but the primary analysis was observer masked. Analyses were done using a treated-as-randomised approach. This trial is registered with EudraCT, number 2008-005653-37, and ClinicalTrials.gov, number NCT00928915.


RESULTS
Between Aug 7, 2009, and Jan 9, 2015, 54 patients were randomly assigned (26 to FFP and 28 to PCC) and 50 received study drug (23 FFP and 27 PCC). The trial was terminated on Feb 6, 2015, after inclusion of 50 patients after a safety analysis because of safety concerns. Two (9%) of 23 patients in the FFP group versus 18 (67%) of 27 in the PCC group reached the primary endpoint (adjusted odds ratio 30·6, 95% CI 4·7-197·9; p=0·0003). 13 patients died: eight (35%) of 23 in the FFP group (five from haematoma expansion, all occurring within 48 h after symptom onset) and five (19%) of 27 in the PCC group (none from haematoma expansion), the first of which occurred on day 5 after start of treatment. Three thromboembolic events occurred within 3 days (one in the FFP group and two in the PCC group), and six after day 12 (one and five). 43 serious adverse events (20 in the FFP group and 23 in the PCC group) occurred in 26 patients. Six serious adverse events were judged to be FFP related (four cases of haematoma expansion, one anaphylactic reaction, and one ischaemic stroke) and two PCC related (ischaemic stroke and pulmonary embolism).


CONCLUSIONS
In patients with VKA-related intracranial hemorrhage, four-factor PCC might be superior to FFP with respect to normalising the INR, and faster INR normalisation seemed to be associated with smaller haematoma expansion. Although an effect of PCC on clinical outcomes remains to be shown, our data favour the use of PCC over FFP in intracranial haemorrhage related to VKA.


BACKGROUND
Octapharma.
Department of Neurology, Klinikum Frankfurt Höchst, Frankfurt, Germany; Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany. Electronic address: thorsten_steiner@med.uni-heidelberg.de.
Thorsten
T
Steiner
Department of Neurology and Stroke, Hertie Institute for Clinical Brain Research, Tübingen University Hospital, Germany.
Sven
S
Poli
Department of Neurology, Mannheim UMM, Heidelberg University, Heidelberg, Germany.
Martin
M
Griebe
Coordination Center for Clinical Trials, Heidelberg University Hospital, Heidelberg, Germany.
Johannes
J
Hüsing
Coordination Center for Clinical Trials, Heidelberg University Hospital, Heidelberg, Germany.
Jacek
J
Hajda
Coordination Center for Clinical Trials, Heidelberg University Hospital, Heidelberg, Germany.
Anja
A
Freiberger
Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.
Martin
M
Bendszus
Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
Julian
J
Bösel
Department of Neurology, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, Denmark.
Hanne
H
Christensen
Department of Neurology, Cologne University Hospital, Cologne, Germany.
Christian
C
Dohmen
Department of Neurology, Mannheim UMM, Heidelberg University, Heidelberg, Germany.
Michael
M
Hennerici
Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.
Jennifer
J
Kollmer
Department of Neurology, Cologne University Hospital, Cologne, Germany.
Henning
H
Stetefeld
Department of Neurology, Halle University Hospital, Halle, Germany.
Katja E
KE
Wartenberg
Department of Neurology, Essen University Hospital, Essen, Germany.
Christian
C
Weimar
Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
Werner
W
Hacke
Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany; Department of Stroke Medicine, Imperial College London, London, UK.
Roland
R
Veltkamp
D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000009:adverse effects*; D001779:Blood Coagulation Factors / Q000008:administration & dosage / Q000494:pharmacology*; D016913:Blood Component Transfusion / Q000009:adverse effects / Q000379:methods*; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D020300:Intracranial Hemorrhages / Q000139:chemically induced*; D008297:Male; D017063:Outcome Assessment, Health Care; D010949:Plasma; D016037:Single-Blind Method; D014812:Vitamin K / Q000037:antagonists & inhibitors*
D000925:Anticoagulants; D001779:Blood Coagulation Factors; D014812:Vitamin K; C025667:prothrombin complex concentrates