the practical management of intracerebral hemorrhage associated with oral anticoagulant therapy

Reviews

The practical management of intracerebral hemorrhageassociated with oral anticoagulant therapy

Luca Masotti1�, Mario Di Napoli2, Daniel A. Godoy3, Daniela Rafanelli4,

Giancarlo Liumbruno5, Nicholas Koumpouros6, Giancarlo Landini7, Alessandro Pampana1,

Roberto Cappelli8, Daniela Poli9, and Domenico Prisco9

Oral anticoagulant-associated intracerebral hemorrhage is in-

creasing in incidence and is the most feared complication of

therapy with vitamin K1 antagonists. Anticoagulant-associated

intracerebral hemorrhage has a high risk of ongoing bleeding,

death, or disability. The most important aspect of clinical

management of anticoagulant-associated intracerebral hemor-

rhage is represented by urgent reversal of coagulopathy, de-

creasing as quickly as possible the international normalized

ratio to valuesr1.4, preferablyr1.2, together with life support

and surgical therapy, when indicated. Protocols for anticoagu-

lant-associated intracerebral hemorrhage emphasize the im-

mediate discontinuation of anticoagulant medication and the

immediate intravenous administration of vitamin K1 (mean

dose: 10–20 mg), and the use of prothrombin complex concen-

trates (variable doses calculated estimate circulating functional

prothrombin complex) or fresh-frozen plasma (15–30 ml/kg) or

recombinant activated factor VII (15–120lg/kg). Because of cost

and availability, there is limited randomized evidence compar-

ingdifferent reversal strategies thatsupportaspecific treatment

regimen. In this paper, we emphasize the growing importance

of anticoagulant-associated intracerebral hemorrhage and de-

scribe options for acute coagulopathy reversal in this setting.

Additionally, emphasis is placed on understanding current con-

sensus-based guidelines for coagulopathy reversal and the

challenges of determining best evidence for these treatments.

On the basis of the available knowledge, inappropriate adher-

ence to current consensus-based guidelines for coagulopathy

reversal may expose the physician to medico-legal implications.

Key words: adverse affects, factor VII, fresh-frozen plasma,

intracerebral hemorrhage, prothrombin complex concentrate,

treatment, vitamin K antagonists, warfarin

Introduction

Vitamin K antagonists (VKA) are a class of anticoagulants that

represent one of the main classes of drugs used in cardiovas-

cular medicine; 1–1�5% of the population in western countries

have been the subject of VKA or so-called oral anticoagulant

therapy (OAT) (1), with widespread use over the past two

decades (2, 3). However, clinical practitioners resist using OAT

(4, 5), especially in elderly patients, due to their difficult

management and the risk of severe bleeding complications

(6). Intracerebral hemorrhage (ICH) represents the most

serious and feared complication of VKA.

This review is focused on the therapeutic strategies used to

reverse coagulopathy in patients who develop acute nontrau-

matic ICH while on OAT.

Physicians should embrace new practices:

� reverse the coagulopathy as soon as possible to avoid further

hematoma growth

� treat the initial underlying cause of ICH independently to

the treatment of the coagulopathy

� treat small hemorrhage sizes aggressively and quickly be-

cause patients with a better prognosis could worsen with

hematoma expansion, and

� revert anticoagulation in patients with a therapeutic inter-

national normalized ratio (INR), and not necessarily with a

major level of INR (Table 1).

Basic principles in VKA therapy

The available VKA are represented by warfarin, acenocou-

marol, and phenprocoumon, which differ for the differentDOI: 10.1111/j.1747-4949.2011.00595.x

Conflict of Interest: None declared.

Correspondence: Luca Masotti�, UO Medicina Interna Ospedale di

Cecina, Via Montanara, Localita Ladronaia, 57023, Cecina (Li), Italy.

E-mail: [email protected] Medicine, Cecina Hospital, Cecina, Italy2Neurological Service, San Camillo de’ Lellis General Hospital, Rieti, Italy3Neurointensive Care Unit, Sanatorio Pasteur, Catamarca, Argentina4Transfusion Medicine, Pistoia Hospital, Pistoia, Italy5Transfusion Medicine and Clinical Pathology, San Giovanni Calibita

Fatebenefratelli Hospital, Rome, Italy6Neurosurgery, S.S. Filippo e Nicola Hospital, Avezzano, Italy7Internal Medicine, Santa Maria Nuova Florence Hospital, Florence, Italy8Thrombosis Center, University of Siena, Siena, Italy9Department of Medical and Surgical Critical Care, University of Florence,

Thrombosis Center, Florence, Italy

& 2011 The Authors.International Journal of Stroke & 2011 World Stroke Organization Vol 6, June 2011, 228–240228

mailto:[email protected]

plasma half-life. VKA drugs act on the liver by inhibiting g-

carboxylation of glutamate residues on the N-terminal regions

of vitamin K-dependent coagulation factors (factor II, VII, IX,

and X) (6) (Fig. 1).

The main indicators for OATare represented by prophylaxis

in patients with cardioembolic sources, primary or secondary

prophylaxis of venous thromboembolism, and thromboem-

bolic prophylaxis in patients with prothrombotic syndromes

(7–9). The efficacy and safety of OAT depends on the quality

control monitoring of the therapy. The bleeding complications

increase with increasing INR values. The risk of bleeding

doubles with each increment of one unit in the INR value.

INR44�5 represents the most significant risk factor for

bleeding in patients with OAT increasing bleeding risk by

about six times (7, 10) (Fig. 2).

Bleeds secondary to OAT are classified as either major or

minor (11). Bleeds are classified ‘major’ if it:

� occurs in critical organs, the brain, retro-peritoneum,

peritoneum, chest, spinal cord, joints, gastro-intestinal tract

� results in a hemorrhagic shock, a decrease of 2 g/dl in

hemoglobin levels, requires surgical or invasive maneuvers, or

� results in death.

The remaining bleeds are classified as ‘minor’ bleeds (11).

Bleeding complications can be reduced, and the accurate

selection of patients’ absolute and relative contraindications

for OAT, patient monitoring in an anticoagulation clinic

Intrinsic pathway

FXII FXIIa

FXI FXIa

FIX FIXa

FVIII FVIIIa FX FXa

Prothrombin (FII) Thrombin (FIIa)

FV FVa

Fibrin monomerFibrinogen

Fibrin multimer

Crosslinked fibrin

Extrinsic pathway

Tissue injury

FVIIa FVII

Fig. 1 Sites of action (red) of oral anticoagulants in the clotting cascade.

Table 1 The NIKE principles in the reversal of anticoagulant-associated intracerebral hemorrhage

N 5 Normalize Normalize INR (and other coagulation parameters) as soon as possible

I 5 Immediate All patients should have immediate coagulopathy reversal, even if hemorrhage is small and clinical condition is good

K 5 Vitamin K1 Initial correction must include longer-acting agents (e.g. vitamin K1) to avoid rebound INR elevation later.

E 5 Elevation of INR Level of INR elevation does not influence timing of reversal. All levels of INR elevation (modest o2�0, therapeutic 2�0–3�0,

supratherapeutic 43�0) require urgent correction

INR, international normalized ratio.

0

2

4

6

8

10

1.9-2.0 2.4-2.7 3.1-3.4 3.7-4.3 4.9-5.7 6.6-8.0Estimated International Normalized Risk (INR) values

Od

ds

Rat

io f

or

intr

acra

nia

lb

leed

ing

ris

k

Fig. 2 Risk of intracerebral hemorrhage in outpatients according to INR levels. INR, international normalized ratio.

& 2011 The Authors.International Journal of Stroke & 2011 World Stroke Organization Vol 6, June 2011, 228–240 229

L. Masotti et al. Reviews

(specifically designed for monitoring OAT patients), together

with the self OAT monitoring (6), have contributed (12).

The risk factors for bleeds in patients with OAT are as

follows:

� advanced age

� severe liver and kidney diseases

� severe thrombocytopenia

� history of previous bleeding

� anemia

� dementia, and

� risk of falls (6).

Some genetic polymorphisms for enzymes involved in the

metabolism of VKA drugs, such as hepatic cytochrome P450

(CYP2C9�2 and CYP2C9�3) and enzyme vitamin K epoxide

reductase complex sub unit 1 (VKORC1), represent adjunctive

risk factors, identifying patients who require small doses of

VKA to reach the therapeutic range (13, 14).

Practical scores may help in identifying the bleeds risk of

each patient on OAT.

The Outpatients Bleeding Risk Index considers four inde-

pendent predictors of bleeding:

� age 465 years

� prior stroke

� prior gastrointestinal bleeding, and

� any of four comorbidities (recent myocardial infarction,

anemia, diabetes, or renal insufficiency) (15).

The most recent HEMORR2HAGES score, which includes

genetic polymorphisms, is shown in Fig. 3a and b (16).

However, the current clinical usefulness of this one is poor

and routine use might not significantly change the choice of

OAT in elderly patients (17).

Optimal anticoagulation with VKA is clinically challenging

because of various patient food and drug interactions. Fluc-

tuations in dietary vitamin K intake can have a significant

effect on the degree of anticoagulation in patients treated with

VKA. The interactions with many drugs (azole antibiotics,

macrolides, quinolones, nonsteroidal anti-inflammatory

drugs, including selective cyclooxygenase-2 inhibitors, selec-

tive serotonin reuptake inhibitors, omeprazole, lipid-lowering

agents, amiodarone, and fluorouracil) suggest that coadmi-

nistration with VKA should be avoided or at least closely

monitored (18). In addition, an increase of patient use of

various dietary herbal products and supplements can

lead to undesired outcomes on anticoagulant levels of

warfarin (19), increasing bleeds risk (20). Case reports have

described an association between their use and ICH due to a

possible antiplatelet effect and VKA potentiate (21, 22).

Because this information is not from human research trials,

it is prudent to avoid the use of herbal agents in patients

who are taking VKA medications and patients and health

care providers should be vigilant of potential herb–drug

interactions (23).

VKA and intracerebral hemorrhagic risk

The OAT-associated ICH (OAT-ICH) represents major bleed-

ing, resulting in a life-threatening condition, sometimes fatal.

The risk of OAT-ICH is of 0�2–0�6% per year of treatment (24,

25). The individual patient cumulative risk of bleeding is

directly related to the length of OAT. Higher frequencies of

bleeding are reported early in the course of therapy; the

frequency of major bleeding decreased from 3�0% during

the first month of outpatient OAT therapy to 0�8%/months

during the rest of the first year of therapy and to 0�3%/months

thereafter (26). Approximately 70% of OAT-ICH are intracer-

ebral, whereas 30% are in the subarachnoid space. The

OAT-ICH represent about 15% of all ICH, with incidence

estimated in the general population of about 1�8/100 000 in-

habitants/year and 8000–10 000 new cases expected every year

in the United States (25, 27, 28). As the use of VKA has

» Points

• 1 Liver disease

Renal disease• 1

• 1Alcoholism

• 1Cancer

• 1 Age > 75 yeras

• Platelets count < 75000/mm 3 1

• Concomitant antiplatelets treatment 1

• 1Previous bleeding

• Uncontrolled arterial blood hypertension 1

• Haemotocrit < 30% 1

• CYP2C9*2 or CYP2C9*3 presence 1

• High risk of falls or cognitiveimpairment 1

• 1Previous stroke

(a) (b)

Fig. 3 (a) The HEMORR2HAGES score. (b) Annual risk of hemorrhage according to HAEMORR2HAGES score.


Reviews L. Masotti et al.

increased, so has the incidence of OAT-ICH. In fact, VKA may

be associated with as many as 17% of ICH cases, up from

5% 20 years ago (29). The most important OAT-ICH incidence

increase has been seen in patients aged more than 80 years,

ranging from 2�5% in 1988 to 45�9% in 1999 (29). The

risk of ICH increases significantly when OAT is combined

with other antithrombotic therapy (acetyl salicylic acid, ticlo-

pidine, clopidogrel, unfractioned, or low-molecular-weight

heparin) (6).

Although in many cases OAT-ICH occurs in patients with a

VKA overdose demonstrated by an outrange INR value, ICH

can also occur in conditions of INR values within the

therapeutic range. A recent case–control study shows that

only 6% of patients with OAT-ICH were excessively antic-

oagulated before the bleed, demonstrating that OAT use is

associated with an increasing risk of ICH despite appropriate

INR monitoring (30). Figure 4 shows an example of ICH in a

patient with INR in the normal range.

Triggering factors for an OAT-ICH in well-anticoagulated

patients are:

� uncontrolled arterial hypertension

� head trauma

� rupture of an unknown intracranial aneurysm or an arter-

ial-venous malformation

� leukoaraiosis

� amyloid microangiopathy

� primary or metastatic cerebral tumors, and

� unmonitored concomitant occasional therapy leading to an

increase of INR (31).

Cerebral microbleeds (MB) are known to be indicative of

bleeding-prone microangiopathy and potential risk factors for

ICH (32, 33) with a close positional association between

• CT scan after 3 hours• NIHSS 22• Glasgow Coma Scale 7/15• INR 0.7

• The patient is transfered to NeurosurgicalDepartment for haemorrhage evacuation

• Brain CT scan at hospital arrival of a female, 76-years old, about 60 kg of weight, in OAT for atrialfibrillation (suggested INR therapeutic range 2.0-3.0, target 2.5)

• INR at hospital arrival 3.2• NIHSS 6• Clasgow Coma Scale 12/15• Treatment with PCC (Uman Complex®, Kedrion,

Castelvecchio Pascoli, Lucca, Italy)at dosage of 1500 UI in five minutes followed byraFVII (Novoseven®, NovoNordisk) at dosage of1.2mg in five minutes and vitamin K1 (Konakion®,Roche) at dosage of 20 mg in 250 cc of salinesolution in thirty minutes

(a) (b)

• Brain CT scan after 25 days• Brain CT scan after neurosurgicalhaemorrhage evacuation

(d)(c)

Fig. 4 Example of spontaneous intracerebral hemorrhage in patient on oral anticoagulant therapy. CT, computed tomography; INR, international normalized

ratio; PCC, prothrombin complex concentrate.



recurrent ICH and prior MB (34). Excessive MB in OAT

patients with ICH compared with other groups suggests that

MB increase the risk of OAT-ICH (35) and underlying MB are

independently associated with a higher incidence of OAT-ICH.

However, the risks and benefits of VKA medication in patients

with MB are not well defined (33).

Thirty-day acute mortality for OAT-ICH is high, ranging

from 12% to 60% (25, 36), and it is nearly doubled when

compared with nonanticoagulated patients (37). However,

hematoma volume and lower level of consciousness measured

by the Glasgow Coma Scale but not INR levels are major

determinants of a poor outcome in patients with OAT-ICH

(38, 39). Hematoma enlargement is a major determinant of a

poor prognosis in OAT-ICH. The OAT-ICH is associated with

a greater baseline median ICH volume, more hemorrhage

expansion, and greater mortality than spontaneous ICH (40).

Experimental ICH animal models demonstrate that hema-

toma volume increases drastically between two- and 24 h,

hematoma volume increases steadily with increasing of INR

values, and mortality is critically associated with hematoma

volume (41). Although, in OAT-ICH patients, initial hema-

toma volume seems not to be significantly different compared

with non-OAT-ICH until INR r3�0, it is larger in OAT-ICH

with INR higher than 3�0 (42–44). It has been demonstrated

that VKA-treated patients continue to bleed more often and

for a longer duration compared with non-OAT-ICH (37).

Approximately 50% of OAT-ICH patients present a secondary

volume expansion compared with 17% of non-OAT-ICH

patients (37).

The time factor represents the most important variable in

the OAT-ICH patient prognosis (45). Patients with suspected

or confirmed OAT-ICH should be treated as a medical

emergency. OAT reversal should start as soon as possible after

symptom onset to prevent hematoma expansion (27). OAT

reversal, together with surgical treatment, and support thera-

pies such as reduction of blood hypertension and hemostatic

therapy represent the possible effective options to restrict

secondary hematoma expansion in OAT-ICH (46).

Practical management of OAT-ICH

Post OAT-ICH, it is possible and important to make an urgent

OAT reversal. Key measures to reverse OAT in patients with

OAT-ICH can be achieved through the immediate disconti-

nuation of OAT and three different pathways:

� direct competition by administering vitamin K1

� replacement of native coagulation factors by using fresh-

frozen plasma (FFP) or a prothrombin complex concentrate

(PCC), and

� by-passing the central part of the coagulation cascade

through the use of recombinant activated factor VII (rFVIIa)

(6, 47).

The goal of these therapeutic measures is to decrease the

INR values to levels r1�4, preferably r1�2 (6, 8, 25, 48–53).

The different pharmacological and blood product options

have specific characteristics related to ease of administration,

timing and duration of effect, and cost, which may potentially

influence the choice of their use. The specific options for OAT

reversal should be used complementary to general therapeutic

measures for ICH and life support (51).

Vitamin K1

The administration of vitamin K1 (phytomenadione) is the

first point of any warfarin reversal strategy. However, it has a

slow action onset, making it a poor choice as a single agent. To

effectively reverse the effect of warfarin, vitamin K1 usually

takes at least two- to six-hours, and frequently 12–24 h (6, 8,

25, 49, 50). The effect of vitamin K1 is more rapid when given

intravenously (IV) (53, 54). Vitamin K1 is inexpensive, but

anaphylaxis (three per 10 000 doses) from an IVadministration

has reduced its use (27, 54). Because of the short half-life and

duration of action of other OATreversal measures, vitamin K1

should be administered in all patients in order to avoid a

rebound in coagulopathy (10–20 mg in 250 ml of normal saline

in about 30 mins, infusion rate being 1 mg/min), with the aim

of inducing de novo hepatic synthesis of vitamin K-dependent

coagulation factors and of achieving the stabilization of OAT

reversal (6, 8, 25, 48–53). Subcutaneous and oral administra-

tions represent alternative routes because they do not carry the

same anaphylaxis risk as the IV route; however, the onset of

action is not as rapid or reliable, especially when neurological

status is compromised. Therefore, in OAT-ICH, the IV route is

preferred (6, 8, 25, 48–53).

PCC

Prothrombin complex concentrates represent a generic term

for several products that are derived from plasma and contain

factors II, VII, IX, and X in different concentrations. PCC is

considered the first therapeutic choice in OAT-ICH (6, 8, 25,

48–53, 55). Originally designed as factor IX concentrates, there

are at least 10 different PCC products that are available in

different parts of the world and contain varying levels of factors

II and X, and low levels of factor VII (56, 57). The most

widespread types of PCC generally contain three or four

vitamin K-dependent factors. Generally, PCC with three

factors do not contain factor VII. It has been suggested that

PCC containing three vitamin K-dependent coagulation fac-

tors could be less effective in reversal OAT, and thus, in some

situations, the addition of rFVIIa may be warranted (58).

However, in a prospective study, considering about 90 patients

with spontaneous and traumatic ICH, Imberti et al. (36)

reached the goal to obtain an INRr1�5 30 mins postadminis-

tration of a PCC containing three factors (factors II, IX, and X)

in 75% of patients, and maintained this benefit until 96 h after

administration in 98% of patients, with a very low 30-day

mortality (about 12%). A meta-analysis (n 5 460 patients) has

demonstrated the effectiveness of the PCC in determining the

rapid OAT reversal, the superiority of the PCC over the FFP



and/or vitamin K1, reducing the times of OAT reversal, with-

out cases of disseminated intravascular coagulation and low

thrombotic risk (1�5%) (59).

The PCC are available as a concentrate, which can be

reconstituted to a total volume of about 50–150 ml and

delivered in 10–30 mins depending on the volume and rate

of infusion. The PCC infusion dose is dependent on body

weight; it is related to INR and is based on a dose of factor IX

necessary to reversal (56). For each international unit of

PCC per kg of body weight, the plasma concentration of factor

IX increases by 1% (60). Table 2 summarizes the recommended

dose of PCC to be infused in patients with OAT-ICH. Optimal

PCC dosing (INR-based vs. a standardized fixed dose) remains

somewhat controversial, although individualized dosing

may ensure INR correction more rapidly. PCC can correct

the INR within minutes (36). Thus, they are very good agents

for acute OATreversal because of the small volume, the range of

coagulation factors provided, and the rapid onset of action.

However, PCC are significantly more expensive than vitamin

K1 and FFP (6, 8, 25, 48–53, 55). When using PCC prepara-

tions with low amounts of factor VII, coadministration of

one- to two-units of FFP or rFVIIa may also be considered

(8, 50, 55).

FFP

Fresh-frozen plasma is the most common agent utilized in

OAT-ICH, especially in the United States, where 60% of

consumed FFP is used for OAT reversal (61). The FFP is a

blood product that contains all the coagulation factors. How-

ever, the actual levels of vitamin K-dependent clotting factors

in each unit of FFP are not standardized and may vary widely.

Table 3 shows the average content of individual coagulation

factors present in a single unit of FFP as reported by Blood

Transfusion Task Force of British Committee for Standards in

Haematology (62). Anyway, the ordinary FFP unit is inevitably

subject to the biological variability associated with a single

donor (63). Furthermore, the infusion of FFP has some risks.

In particular, it may be necessary to use large volumes of

plasma to correct the coagulation defect. Initial doses of 15 ml/

kg of FFP are suggested (6, 8, 25, 49, 50, 62), although there is

evidence that a dose of 30 ml/kg produces more complete

correction of coagulation factor levels (60, 64–67). Although

the required volume of FFP somewhat depends on the initial

INR, the target INR is the more relevant issue. According to a

recent study, the difference in the predicted FFP transfusion

volume between an INR goal of 1�3 and 1�7 is two-liters of

plasma at all initial INRs. This represents a significant patient

overload volume with potentially dangerous effects in the

elderly and cardio pulmonary disease patients (66). Further-

more, in these patients, the infusion rate should not be too

quick and this can lead to delays in OAT reversal. The FFP

Table 2 How to choose the dose of PCC or FFP for urgent warfarin

reversal: calculated or fixed dose

INR value Estimated functional PC

Calculated dose

First step: Convert INR to % of estimated circulating functional

prothrombin complex (PC)

Z5 5%

4�0–4�9 10%

2�6–3�2 15%

2�2–2�5 20%

1�9–2�1 25%

1�7–1�8 30%

1�4–1�6 40%

1�0–1�3 100%

Second step

Calculate the dose:

IU of PCC or ml of FFP needed to be infused 5 (Target in % of PC to be

reached–current estimated % of PC)� kg of body weight

Example:

Present INR 4�5 corresponding to estimated functional PC 10%

Target INR 1�4 corresponding to estimated functional PC 40%

Body Weight 70 kg

IU needed to be infused 5 (40–10)� 70 5 2100 IU of PCC or 2800 ml

of FFP

INR value PCC dose (IUkg) FFP dose (ml/kg)

Fixed dose

1�5–2�0 20 15

2�0–4�0 30–40 15–30

Z4�0 50 15–30

Example:

Present INR 4�5Body weight 70 kg

IU needed to be infused 5 3500 IU of PCC or 1050–2100 ml of FFP

Adapted from Aguilar et al. (25).INR, international normalized ratio;

PCC, prothrombin complex concentrate; FFP,fresh-frozen plasma.

Table 3 Average composition of 250–300 ml of fresh-frozen plasma

after thawing at 41C

Levels after

thawing (41C)

Levels

after 24 h

Levels after

five days

Fibrinogen 260–270 mg/dl 220–230 mg/dl 220–230 mg/dl

Factor II 80 IU 80 IU 80 IU

Factor V 80 IU 75 IU 65 IU

Factor VII 90 IU 80 IU 70 IU

Factor VIII 90 IU 50 IU 40 IU

Factor IX 100 IU / /

Factor X 85 IU 85 IU 80 IU

Factor XI 100 IU / /

Factor XII 80 IU / /

Factor XIII 100 IU / /

Antithrombin 100 IU / /

Von Willebrand

factor

80 IU / /

Adapted from British Committee for Standards in Hematology, Blood

Transfusion Task Force (62).



requires compatibility testing and thawing before administra-

tion; there is an inherent delay in initiating FFP transfusion

(62, 67). Thanks to the introduction of several preventive

measures, the residual risk for the three major viral infections

(i.e., hepatitis B virus, hepatitis C virus, HIV/AIDS) is cur-

rently very low (68). Anyway, other equally life-threatening

risks of FFP transfusion are far more common, such as severe

allergic reactions (69), transfusion-associated circulatory over-

load (70), and transfusion-related acute lung injury (71).

Because of these considerations, FFP should be used in the

OAT- ICH if PCC is not available (60).

rFVIIa

Recombinant activated factor VII is an approved medication

for the treatment of hemophilia.

Randomized clinical trials (RCT) have evaluated the benefit

of avoiding enlargement of hematoma in the acute phase of

spontaneous noncoagulopathic ICH and using off-label for

VKA-related ICH as well as traumatic hemorrhage (72–75).

The rFVIIa promotes hemostasis at sites of vascular rupture,

limiting hematoma enlargement after ICH. Preliminary results

have shown a reduction in hematoma volume increase,

mortality, and better functional status after a three-month

administration of rFVIIa, despite a 5% increase in arterial

thromboembolic phenomena (76). The phase III FAST trial

showed no significant difference in mortality or severe dis-

ability at 90 days between different dosages of rFVIIa and

placebo, but confirmed the hemostatic effect and thromboem-

bolic complications (77). In conclusion, the use of rFVIIa

reduces the growth of the hematoma but does not improve

patient survival or functional outcome after ICH; in addition,

rFVIIa increases the incidence of arterial thromboembolic

complications (78). On the basis of these results, routine

utilization of rFVIIa as ultra-early hemostatic therapy for all

patients with ICH cannot be recommended. However, the use

of rFVIIa in conjunction with FFP is associated with shortened

times to correction of INR and reduced the total dose of FFP

required for the correction of coagulopathy in OAT-ICH

patients (79).

As with PCC, rFVIIa has the advantage of limited volume

infusions; even low doses of rFVIIa correct prothrombin time.

INR values cannot be used as a reliable indicator of cessation of

bleeding in patients who have received rFVIIa. A single IV dose

can normalize the INR within minutes; however, it is very

important to keep in mind that INR might increase in

subsequent hours due to the short-half-life of rFVIIa, and

therefore, the drug infusion requires strict follow-up and

monitoring (80). It is not known whether other emerging

coagulation tests such as thromboelastography might be

useful. The dose of rFVIIa for OAT-ICH is not standardized

and optimal dosing is not known. The rFVIIa is administered

as a single, one-time bolus over two- to five-minutes ranging

from 15 to 120mg/kg (mean dose 80–90 mg/kg) (25, 27). Large

doses are associated with a longer duration of effect (81).

Until now, rFVIIa has not been a recognized for the

treatment of OAT-associated bleeding and therefore its use in

these situations is considered off-label (81, 82), even though

suggested by the 2008 American College of Chest Physicians

Guidelines on Antithrombotic Therapy as an alternative to

PCC or FFP with a grade of recommendation IC (6). Among all

the current warfarin-reversal options, rFVIIa, however, is the

most expensive.

Whatever measures are chosen, the INR should be checked

at the end of the infusion, and then every three-hours when the

INR is corrected to confirm its stability. If INR monitoring

reveals a value Z1�5, an additional dose of reversal therapy

should be administered (6, 8, 50, 55). Table 4 summarizes the

advantages and limitations of each measure of OAT reversal.

The role and timing of surgery in OAT-ICHWhen reaching the goal of OATreversal, neurosurgical evacua-

tion of the hematoma should be warranted when indicated

(51, 52, 83). Figure 4 (c,d) shows an example of neurosurgical

hematoma evacuation after OATreversal. Given the absence of

strong scientific evidence to indicate a prominent role of

Table 4 Options for urgent warfarin reversal

Agent Pros Cons

Usefulness for

urgent reversal

Vitamin K1 Widely available; inexpensive; directly reverses

warfarin effect; small volume infused; low infec-

tive and thrombotic risk

Slow onset of action; possible allergy Poor

Fresh-frozen plasma Widely available; contains all coagulation factors;

low thrombotic risk

Large volumes usually needed; requires cross-

matching and thawing; slow onset of action; not

negligible infective risk, possible TRALI

Fair

Prothrombin complex

concentrate

Rapid onset; small volume infused; low infective

risk

Expensive; variable factor concentrations in differ-

ent preparations; not negligible thrombotic risk

Good

Recombinant activated

factor VII

Rapid onset; small volume infused; thrombin

burst; low infective risk

Very expensive; acts directly on only a single factor;

INR correction may be ‘lab artifact’; off label use

Good

TRALI, transfusion acute lung injury.



surgery in determining the outcome, this measure should be

performed in a tailored manner. With the exceptions of the

placement of a ventricular drain in patients with hydrocepha-

lus and evacuation of a large posterior fossa hematoma, the

timing and nature of other neurosurgical interventions is also

controversial. In practice, surgery is performed as a life-saving

measure in patients with large hematomas or cortical hemor-

rhages and secondary neurologic deterioration. American and

European guidelines recommend surgery for patients with

lobar supratentorial hemorrhages within 1 cm of the cortical

surface, particularly for those with good neurological status

who are deteriorating clinically. For patients with profound

sited hemorrhages (basal ganglia, thalamic) and mass effect,

guidelines suggest evacuation with minimally invasive meth-

ods within 12 h (51, 52). Urgent surgical removal of infra-

tentorial hematomas larger than 3 cm is frequently associated

with remarkable recoveries. There is substantial evidence that

the management of patients with ICH in a neurointensive care

unit, where treatment is directed toward monitoring and

managing cardiorespiratory variables and intracranial pres-

sure, is associated with improved outcomes. Attention must be

paid to fluid and glycemic management, minimizing the risk of

ventilator-acquired pneumonia, fever control, provision of

enteral nutrition, and thromboembolic prophylaxis.

There is a robust theoretical basis supporting early surgery.

An aggressive management in the acute phase can be translated

into improved outcomes after ICH (84). Specific treatment

approaches include early diagnosis and hemostasis, aggressive

management of blood pressure, open surgical and minimally

invasive surgical techniques to remove clot, techniques to

remove intraventricular blood, and management of intracra-

nial pressure (84). The OAT-ICH may produce a great volume

hematoma with mass effect, edema, obstructive hydrocepha-

lus, midline shift, intracranial hypertension, herniations, and

death; thus, surgery is a therapeutic possibility. Surgical

evacuation may prevent hematoma expansion, decrease in-

tracranial pressure, mass effect, and prevent the release of

neurotoxic products. Despite these hypothetical benefits,

surgery remains controversial, without a clear demonstra-

tion of efficacy when compared with standard medical therapy

(83, 85).

Most surgeons follow guidelines for clot removal similar to

those applied for spontaneous hematomas of nonanticoagu-

lated patients (51), although the analysis of available clinical

data suggests that patient subgroups that mostly benefit from

surgery are different from anticoagulated patients. The litera-

ture lacks evidence on the effect of early surgery in antic-

oagulated and rapidly worsening patients because most studies

on the surgical evacuation of ICH have considered patients

already treated for correction of INR (83, 86). A study

performed at the Mayo Clinic suggests that emergency evacua-

tion for deteriorating patients with large OAT-ICH is compa-

tible with a favorable outcome independent of anticoagulation

reversal (87). Time shortening of OAT reversal is crucial both

for spontaneous and for posttraumatic ICH to be submitted to

neurosurgery evacuation (88). Ultra-rapid reversal of antic-

oagulation could reduce the time to biological and surgical

hemostasis, and might improve outcome (89). In this case,

neurosurgery could be performed immediately with results

comparable to those of nonanticoagulated patients. However,

guidelines note than there is evidence that ultra-early surgery

(within four-hours) is associated with an increased risk of

rebleeding and higher mortality (475%) (90). Future rando-

mized studies should aim to individuate with higher accuracy

patients who certainly may benefit from surgical treatment.

Furthermore, the role of surgery in OAT-ICH should be

reevaluated in the light of recent technological advances.

Minimally invasive techniques may allow a more efficient

and less traumatic evacuation of the hematoma (91, 92).

Current evidence: benefits, concerns,and challenges

Currently, there are no prospective, randomized, controlled

clinical trials comparing the various VKA-reversal strategies.

There are no controlled trials assessing whether or not PCC or

rFVIIa are superior to a strategy of FFP and vitamin K1, or

comparing PCC and rFVIIa regarding clinical outcome. How-

ever, several small retrospective and prospective studies eval-

uated the effectiveness of INR reversal obtained with the

various agents (44, 74, 93, 94). In summary, they show that a

reversal of INR within two-hours from hospital admission is

associated with low rates of hematoma enlargement and is

achieved in the majority of patients (84%) treated with PCC,

while FFP infusions show only a partial effect in reducing

hematoma enlargement (39%) and vitamin K1 has no effects

(93). In patients with ICH-related coagulopathies of different

etiologies who need neurosurgical interventions, the reversal

of INR before surgery attempted with FFP and rFVIIa is

quicker (mean seven-hours), without thrombotic complica-

tions, with a better functional outcome (95). The beneficial

effect after the reversal of anticoagulation using different

agents is also evident in patients with acute clinical worsening

and a marked mass effect who have emergency surgical

evacuation of hematomas (87). These studies show that there

is limited evidence to support a specific treatment regimen for

VKA-related ICH. Randomized trials using patient mortality

and neurological function as outcomes have been proposed.

However, they do not appear to be easy to carry out due to the

large sample size required, the frequent poor outcome of OAT-

ICH patients, and variability in available products in different

areas of the world. Thus, current approaches derive more from

consensus-based guidelines driven from concern for rapid and

safe coagulopathy correction.

The risk of thrombotic events after OATreversal is a problem

that has affected this type of treatment strategy in patients with

acute OAT-associated bleeding for a long time, although the

percentages of thrombosis are variable on the basis of the

different OATreversal treatments used, ranging from 0% to 7%

(25). In many cases, physicians do not have alternative choices



to reverse OAT adverse effects, particularly if hemorrhage is

severe enough to endanger the life of the patient. Goldstein

and colleagues have shown that the 30-day incidence of

arterial and venous thromboembolic events is about 5% for

patients with OAT-ICH in which OAT is discontinued,

lower than that reported in patients with non-OAT-

ICH (7�2%) (96), whereas Imberti et al. (36) did not

observe thrombotic complications during hospitalization of

OAT-ICH treated with PCC. However, thrombotic events in

the acute phase of OAT-ICH seem not to influence 30-day

mortality (96). Mechanical prophylaxis should be pre-

scribed to patients with OAT-ICH to prevent venous throm-

boembolism (97).

The time for OAT should be restarted after an ICH is an

important question. For each patient, the balance between the

thrombotic risk due to the coexistent thromboembolic disease

for which OAT was prescribed and the risk of bleeding

recurrence should be carefully evaluated.

A case–control study enrolling approximately 50 patients

compared a group of patients in which OAT was restarted

after ICH with one in which OAT was not restarted, and

showed that the risk of ICH recurrences could be low in

those who restarted therapy, whereas the incidence of throm-

botic events could not be negligible in those who did not

restart OAT (98). A very recent review of clinical studies and

case series by Romualdi et al. (99) has demonstrated an

incidence of 2�9% of ICH recurrence after restarting OAT in

patients with prosthetic heart valves suffering from a first

episode of ICH. It is suggested by experts to restart OAT

therapy in patients with prosthetic mechanical heart valves, in

most cases one-week from the hemorrhagic event, while

some concerns exist in restarting OAT in nonvalvular atrial

fibrillation (25).

In patients after OAT-associated major bleeding,

ACCP guidelines suggest the possibility of reducing OAT

intensity, for example prescribing a range of INR between

2�0 and 2�5 in prosthetic mechanical heart valves and

between 1�5 and 2�0 in patients with atrial fibrillation together

with a close monitoring of INR to avoid the risk of overdose

(6) or to replace mechanical with bioprosthetic valves in

selected patients (6). For OAT-ICH in patients with venous

thromboembolism, caval filters’ placement is indicated

to prevent a first episode or a recurrence of pulmonary

embolism (100).

Treatment algorithms and guidelines

Despite the lack of evidence from RCT, there are several

international consensus-based guidelines that address the

treatment regimen in OAT-ICH patients (6, 11, 50–52, 55).

All guidelines emphasize the high morbidity of OAT-ICH,

the urgency of rapid reversal of coagulopathy, the use of

vitamin K1 (usually IV), and the use of PCC, given the rapid

onset of action with these agents and the shortcomings of

FFP alone. However, none provides a specific target INR

for an adequate reversal and the lack of clear evidence

limits the ability to make strong recommendations about the

agent and the dose to be used. Any intracranial bleeding

in a patient on VKA, independent of INR levels when

Z1�5, should be considered as a life-threatening condition

regardless of the hematoma size or the patient’s clinical status

at the first evaluation, because of the high risk of ongoing

hemorrhage, the high fatality rate, and the residual severe

disability from OAT-ICH (Fig. 5). The main recommendations

are summarized in Table 5.

Fig. 5 Proposed algorithm for Hyperacute VKA reversal. CT, computed tomography; FFP, fresh-frozen plasma; INR, international normalized ratio; PCC,

prothrombin complex concentrate; OAT-ICH, oral anticoagulant-associated intracerebral hemorrhage; rFVIIa, recombinant activated factor VII; VKA, vitamin

K antagonist.



Conclusion

The incidence of OAT-ICH has increased recently because it is

associated with a high risk of ongoing bleeding, death, or

disability. Urgent reversal of coagulopathy is the highest

priority. Several agents such as vitamin K1, PCC, rFVIIa,

and/or FFP are available, and there are pros and cons in the

use of each of them. They should be included in the qualifica-

tion of every physician who might have to treat a patient

receiving such therapy. The incorrect or the late management

of therapeutic measures for OAT reversal in the case of ICH

may expose the physician to the risk of legal prosecution,

because effective and safe antidotes are available (101). There-

fore, it is not acceptable that the reversal of OAT is delayed or

incomplete or even omitted. A call for action is needed to

develop a uniform approach for physicians in the management

of patients on OAT, and it is particularly desirable that each

hospital is equipped with internal protocols derived from

recognized guidelines (Fig. 5).

All protocols for OAT-ICH emphasize the immediate cessa-

tion of the anticoagulant medication and the immediate

administration of vitamin K1 (IV). The use of PCC or rFVIIa

may reverse coagulopathy more rapidly than FFP alone;

however, randomized trials testing this are yet to be initiated.

Furthermore, the cost and availability of these agents may limit

their widespread use. In the near future, new oral antithrom-

botic drugs will be used (and will possibly replace VKAs) for

the prophylaxis and treatment of arterial and venous throm-

boembolic disease. Among these, dabigatran, rivaroxaban, and

apixaban are the most studied and have already been shown to

be effective and safe (102–105). After the recent Phase III trial

RE-LY (randomized evaluation of long-term anticoagulation

therapy), the use of dabigatran in atrial fibrillation is more

clearly defined. The results show that the 110-mg dose of

dabigatran was associated with similar rates of stroke and

systemic embolism (primary end points) and lower rates of

major hemorrhage when compared with warfarin; the 150 mg

dose of dabigatran was associated with lower rates of stroke

and systemic embolism but with a similar rate of major

hemorrhage (106).

However, among the main limitations of these new drugs,

the absence of a specific antidote in bleeding complications

could influence their use in clinical practice. Whatever the

antidotes tested for the treatment of the new antithrombotic,

drug-related bleedings consist of PCC, FFP, and rFVIIa;

hence, their knowledge could also be useful for this new

scenario (107, 108).

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the practical management of intracerebral hemorrhage associated with oral anticoagulant therapy

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