Intracerebral haemorrhage (ICH) is less common than ischaemic stroke: ranging from 20 to 60 vs. 183 to 349 per 100 000 people per year for ICH and ischaemic stroke, respectively. However, ICH is associated with the highest reported death rate (up to 50% of cases), which ranges approximately between 0.2 and 0.4 cases per 1000 population per year [1-3]. Haematoma volume is the critical determinant of death as well as of functional outcome after ICH , and it appears to be the result of a dynamic process, with continuous bleeding or re-bleeding over several hours [4,5]. About 30% of ICH occurs in patients on antithrombotic treatment, but it has not been clearly demonstrated yet as to whether oral anticoagulant treatment (OAT) or antiplatelet treatment (APT) negatively affects the natural history of ICH, possibly leading to larger haematomas and more disabling strokes [6,7]. The relevance of this issue is evident when the increasing number of patients on antithrombotic treatment is compared with the rate of intracranial bleeding [8,9]. Therefore, the use of OAT or APT for the prevention of thromboembolic events [10,11] should take into account the outcome of possible haemorrhagic side-effects, particularly in elderly subjects [12-15].
It is possible that the use of OAT simply unmasks intracerebral bleeding that would otherwise remain asymptomatic . Actually, magnetic resonance imaging (MRI) studies indicate that micro-haemorrhages can be found even in normal individuals . Advancing age and cerebral amyloid angiopathy are important co-causal agents to lobar ICH in patients who receive OAT or not [18,19], suggesting that spontaneous intracerebral haemorrhage (SICH) and OAT-ICH may have the same underlying cause. Furthermore, the distribution of the cerebral locations where OAT-ICH occurs is similar to that of SICH [20,21]. Although most OAT-ICH cases occur when the prothrombin time-international normalized ratio (PT-INR) is within the therapeutic range, higher intensities of anticoagulation clearly increase the risk of OAT-ICH [20,22-24], suggesting that OAT may also directly cause ICH.
Although the incidence and dynamics of haematoma expansion in OAT-ICH still need to be established, it may be more common and occurs over a longer time frame than in SICH, because of persistent coagulopathy. Haematoma expansion up to day 7 was found in 16% (9/57) of patients who were not on OAT compared to 54% (7/13) of patients who were on OAT . Probably, in OAT-ICH the natural course of haematoma expansion is more prolonged, perhaps up to 24 or 48 h [25-27], raising the possibility that patients presenting within 24 h may benefit from effective haemostatic treatment.
The primary aim of OAT-ICH management is reversal of the anticoagulant effect to limit ongoing bleeding and haematoma expansion. Treatment options include vitamin K, fresh frozen plasma (FFP), prothrombin complex concentrates (PCC) and activated recombinant factor VII (rFVIIa) [28-31]. There are currently no standardized guidelines for reversal of the anticoagulant effect in patients with OAT-ICH. UK guidelines issued by the British Committee for Standards in Haematology recommend 5 mg of intravenous (i.v.) or oral vitamin K, and 50 U kg−1 of PCC or 15 mL kg−1 of FFP . The American Thoracic Society recommend 10 mg of i.v. vitamin K and PCC, without specifying the dose of PCC . In particular, no guidelines are given about resuming OAT after ICH. Considerations concerning whether and when to resume therapeutic anticoagulation in patients who have experienced OAT-ICH include whether intracranial bleeding has been fully arrested, the estimated ongoing risk of thromboembolism and the presumed pathophysiology of the ICH, which will determine the risk of haemorrhage recurrence [28,34-39].
Even if it takes at least 2-6 h for vitamin K to achieve an effective response and hence vitamin K alone is often inadequate to quickly normalize the PT-INR, the i.v. administration of 5-20 mg of vitamin K is necessary to achieve a sustained reversal of anticoagulation, because of the relatively short half-life of other procoagulant factors as compared to coumarin derivatives [32,33,40-42].
FFP contains all coagulation factors in a non-concentrated form; hence, to achieve effective haemostasis a large volume (up to 3500 mL) is required [28,43,44]. One mL of FFP per kg increases the plasma levels of coagulation factors by 1-2 IU dL−1 . Traditionally, 10-15 mL of plasma per kg body weight are administered, but they may have to be exceeded in massive bleeding . The large volume required and the rapid transfusion rate can lead to circulatory overload, particularly in cardiopathic patients. Moreover, FFP transfusion is associated with several adverse reactions, mainly transfusion-related acute lung injury and allergic reactions [47,48].
PCC contain coagulation factors VII, IX, X and prothrombin, and can be quickly given without compatibility testing and time for thawing. Small studies suggest that PCC correct a prolonged PT-INR more rapidly than FFP [43,49,50], but a retrospective study comparing vitamin K, FFP, PCC and no treatment in 151 patients with OAT-ICH found no difference in 90-day mortality . The main concern with PCC use focuses on the potential to induce thrombosis and disseminated intravascular coagulation [52-56].
rFVIIa administration is an appealing alternative to conventional factor replacement to reverse OAT anticoagulation. Almost any i.v. dose of rFVIIa can normalize the INR in an OAT patient within minutes , but the duration of INR normalization is short lasting and a function of the given amount. Doses of 5-20 μg kg−1 normalize the INR (<1.5) for 6-9 h, doses of 40-80 normalize the INR for 9-12 h and doses ≥120 μg kg−1 normalize the INR for 12-24 h . Published series indicate that a wide range of rFVIIa doses can rapidly normalize elevated INR values in patients with oral anticoagulant-related ICH [57,58]. In the majority of patients rFVIIa was given in addition to conventional therapy with FFP and vitamin K, and in these reports the dose of rFVIIa generally ranged from 60 to 90 μg kg−1. No thrombotic complications occurred, even in patients at very high risk .
Current clinical trials in OAT-ICH
An open, prospective, multicentre randomized pilot trial to evaluate efficacy and safety of rFVIIa against standard therapy is currently running in Italy. Totally, 32 patients have to be enrolled in Italian Emergency Departments and Stroke Units. To date, six patients have been randomized, and the trial is still recruiting participating centres. rFVIIa is administered as a single bolus of 80 μg kg−1 within 24 h from symptom onset and within 1 h from the diagnostic computed tomography (CT). The primary efficacy end-point is the change of the ICH volume as measured by CT head scans from prior to rFVIIa administration to 24 h after. The secondary efficacy end-points is the difference between groups on the modified Rankin Scale, the Barthel Index, the Extended Glasgow Scale and the National Institute of Health's Stroke Scale over the duration of the trial. Additional details about the trial are available at www.clinicaltrial.gov (NCT00222625 - rFVIIa in ICH in Patients Treated With Anticoagulants or Anti-Platelets - Phase II trial: Sponsored by the University of Perugia. Contact [email protected]).
Conflict of interest: None.
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